Phase I/IIa trial of ridaforolimus for sarcoma

Ridaforolimus is an inhibitor of mTOR with evidence of antitumor activity in an I.V. formulation. This multicenter, open-label, 3 + 3 design nonrandomized, dose-escalation, phase I/IIa trial was conducted to determine the safety, pharmacokinetic (PK) and pharmacodynamic parameters, maximum tolerated dose, and antitumor activity of oral ridaforolimus. Patients with metastatic or unresectable solid tumors refractory to therapy were eligible. Seven different continuous and intermittent dosing regimens were examined. Results were as follows: One hundred and forty-seven patients were enrolled in this study among which 85 were patients with sarcoma. Stomatitis was the most common DLT observed. The dosing regimen, 40 mg QD × 5 days/week, provided the best combination of cumulative dose, dose density, and cumulative exposure, and was the recommended dosing regimen for subsequent clinical development. PK was nonlinear, with less than proportional increases in day-1 blood AUC0–∞ and Cmax, particularly with doses >40 mg. The terminal half-life estimate of ridaforolimus (QD × 5 40 mg) was 42.0 h, and the mean half-life ∼30–60 h. The clinical benefit rate, (complete response, partial response, or stable disease for ≥4 months was 24.5% for all patients and 27.1% for patients with sarcoma. Conclusion: Oral ridaforolimus had an acceptable safety profile and exhibited antitumor activity in patients with sarcoma and other malignancies.

Phase II study with sorafenib in advanced STS

This trial investigated the activity and safety of sorafenib, a multitargeted tyrosine-kinase inhibitor, in patients with advanced soft tissue sarcomas (STS). An open-label nonrandomised multicentre phase II study was conducted in advanced STS patients pre-treated with anthracycline-based chemotherapy. Patients received sorafenib 400 mg twice daily for 28 days. The primary end point was the progression-free survival (PFS) rate at 6 months. Toxicity was assessed. Clinical outcomes were evaluated in all histologies and in leiomyosarcoma (L) and angiovascular sarcomas (A). Results were as follows: Between November 2006 and January 2010, 101 patients (36 L, 19 A, and 46 others) were enrolled; 76 patients per-protocol (PP) and 100 per intention-to-treat (ITT) were assessable for the primary end point. In the PP analysis, 11 (14.5%) achieved partial response and 25 (32.9%) stable disease; 6-month PFS rates were all histologies, 34.5%; L, 38.4%; and A, 56.3%. In the ITT analysis, 6-month PFS results were 27.1, 35, and 35.5% in all histologies, L, and A, respectively. When stratified by histology, we observed a better PFS favoring leiomyosarcoma versus other histologies (P = 0.033). Treatment was well tolerated. Conclusions: Sorafenib appears to be a promising option in leiomyosarcoma patients. This finding warrants further evaluation in histology-driven trials.

Pemetrexed in patients with refractory STS

This study evaluated efficacy and safety of pemetrexed in patients with refractory soft tissue sarcoma. Patients received pemetrexed intravenously at a dose of 500 mg/m² every 21 days until progression or unacceptable toxicity. The primary endpoint was objective tumor response. Results were as follows: Fourty-eight of 53 screened patients were included and received a total of 200 cycles (median 2; range 1–30). Median age was 53 years (range, 20–81). The observed toxicity profile was favorable. NCI-CTC hematologic grade 3/4 toxicity consisted of neutropenia in 13 %, anemia in 15 %, and febrile neutropenia in 4 % of patients of patients, respectively. Non-hematologic CTC grade 3/4 toxicity consisted of elevated ASAT/ALAT in 10 %, hyperglycemia in 6 %, infection with or without neutropenia in 6 %, nausea in 2 % and stomatitis in 2 % of patients. No other grade 3 toxicities and no treatment-related toxic deaths were observed. Overall response as defined by RECIST was 5 %, 16 patients experienced stable disease (40 %). The estimated 3- and 6-months progression-free rates were 33.3 % and 14.6 %, respectively. Conclusions: In patients with refractory STS, pemetrexed is well tolerated and moderately effective. The confirmed objective response rate in STS is low, however, disease stabilizations are seen in a high proportion of patients.

Inhaled lipid cisplatin (ILC) in osteosarcoma lung metastases

Osteosarcoma treatment failure is most often from the inability to control metastatic disease in the lungs. Encapsulating cisplatin within lipid complexes and delivering the agent via inhalation targets lung metastases with minimal systemic exposure. An open-label, phase Ib/IIa study was performed to characterize the safety and efficacy of inhaled lipid cisplatin (ILC) in recurrent osteosarcoma patients who only had pulmonary metastases. ILC was administered via nebulizer every 2 weeks (=1 cycle). Response was evaluated radiographically every 2 cycles. Cisplatin levels were measured in patients. When possible, metastasectomy was undertaken in patients after 2 cycles. Results were as follows: Nineteen patients were treated. No patients experienced hematologic toxicity, nephrotoxicity or ototoxicity. Nausea/vomiting (≥grade 3) was attributed to study drug in one patient. Respiratory symptoms were observed in 13/19 patients with only one patient experiencing a ≥grade 3 respiratory symptom (not related to study drug). Systemic cisplatin exposure was minimal. Eleven patients had bulky disease, and all progressed prior to cycle 7. Eight patients had all lesions ≤2 cm. One patient had a sustained partial response. An additional two patients had stable disease after 2 cycles, underwent metastasectomy, and remained free from pulmonary recurrence 1 year after initiation of therapy. Conclusions: ILC is well tolerated in heavily treated osteosarcoma patients and did not appear to have the typical toxicities associated with intravenous cisplatin. Three of eight patients with less bulky disease had sustained benefit. Further study of ILC is warranted.

Chemotherapy for advanced uterine leiomyosarcoma

The goal of this systematic review was to investigate and compare the treatment effects of systemic chemotherapy (i.e. doxorubicin, gemcitabine, gemcitabine plus docetaxel, or trabectedin) in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma. A 2005 systematic review (searching the literature from 1980 to June 2004) on systemic therapy in advanced uterine sarcoma was used as the basis for this updated review. MEDLINE and EMBASE (from January 2004 to June 2011), the Cochrane Library, some main guideline websites and the American Society of Clinical Oncology and the Connective Tissue Oncology Society annual meeting abstracts were searched. One arm from a randomized controlled trial (RCT), four single-arm phase II trials and one abstract were included in this systematic review. The studies of gemcitabine plus docetaxel have reported numerically longer median overall survival (14.7–17.9 months versus 12.1 months) and numerically higher objective response rates (27–53% versus 25%) than those reported in the study of doxorubicin alone. The combination of gemcitabine plus docetaxel resulted in more toxicity than doxorubicin alone. The available study for single-agent gemcitabine reported a tumor response rate of 21%, which is not superior to the 25% response rate with doxorubicin alone. One abstract (pooling data from two RCTs) failed to show the superiority of gemcitabine plus docetaxel over gemcitabine alone for tumor response rate (23% versus 18%) and progression-free survival (6 versus 4.9 months). To date, there is insufficient evidence to support or refute the use of trabectedin in the target patients. Doxorubicin, gemcitabine, and gemcitabine plus docetaxel are treatment options in women with inoperable, locally advanced, recurrent, or metastatic uterine leiomyosarcoma as first- or second-line therapy. Well-designed and good-quality RCTs are required to investigate the efficacy of chemotherapy and quality of life in target patients with uterine leiomyosarcoma.

Hypertension with pazopanib in patients with cancer

The purpose of this study was to gain a better understanding of the overall incidence and risk of hypertension in cancer patients who receive pazopanib and to compare the differences in incidence among sorafenib, sunitinib, and pazopanib. Several databases were searched, including PubMed, Embase, and Cochrane databases. Eligible studies were phase II and III prospective clinical trials of patients with cancer assigned single drug pazopanib 800 mg/day with data on hypertension available. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated employing fixed or random effects models depending on the heterogeneity of the included trials. Results were as follows: A total of 1,651 patients with a variety of solid tumors from 13 clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hypertension in cancer patients were 35.9 % (95 % CI 31.5–40.6 %) and 6.5 % (95 % CI 5.2–8.0 %), respectively. The use of pazopanib was associated with an increased risk of developing all-grade (RR 4.97, 95 % CI 3.38–7.30, p < 0.001) and high-grade hypertension (RR 2.87, 95 % CI 1.16–7.12, p = 0.023). Additionally, there was no significant difference in the incidence of all-grade (RR 1.21, 95 % CI 0.96–1.53, p = 0.11) and high-grade hypertension (RR 1.29, 95 % CI 0.80–2.07, p = 0.30) between RCC and non-RCC patients. Interestingly, the risk of all-grade hypertension with pazopanib was substantially higher than sorafenib (RR 1.99; 95 % CI 1.73–2.29, p = 0.00) and sunitinib (RR 2.20; 95 % CI 1.92–2.52, p = 0.00), while the risk of pazopanib-induced high-grade hypertension was similar to sorafenib (RR 0.98; 95 % CI 0.75–1.30, p = 0.90) and sunitinib (RR 0.81; 95 % CI 0.62–1.06, p = 0.12). Conclusions: The use of pazopanib is associated with a significantly increased risk of developing hypertension. Close monitoring and appropriate managements are recommended during the therapy. Future studies are still needed to investigate the risk reduction and possible use of pazopanib in selected patients.

Topotecan & cyclophosphamide in adults with relapsed sarcoma

The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing’s sarcoma (EWS). The investigators of this study sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75mg/m2/day (days 1–5) and C = cyclophosphamide at 250mg/m2/day (days 1–5) every 21 days. Results were as follows: Fifteen patients, median age 31 years (range 17.5–56) had nonpleomorphic rhabdomyosarcoma (RMS), EWS, synovial sarcoma (SS) leiomyosarcoma (LMS), and desmoplastic small round cell tumor (DSRCT,). Median time to progression was 2.5 months (range 1.6–13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. Conclusion: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients.

Durable cancer regression with an anti-PD-1 antibody

Results from the first-in-human phase I trial of the anti–programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. In this study, the investigators provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective. Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy. Results were as follows: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy. Conclusion: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.

Stage 1 testing of temozolomide

The DNA methylating agent temozolomide was developed primarily for treatment of glioblastoma. However, preclinical data have suggested a broader application for treatment of childhood cancer. In this study, Temozolomide was tested against the PPTP solid tumor and ALL models. Temozolomide was tested against the PPTP in vitro panel at concentrations ranging from 0.1 to 1,000µM and was tested against the PPTP in vivo panels at doses from 22 to 100mg/kg administered orally daily for 5 days, repeated at day 21. Results were as follows: In vitro temozolomide showed cytotoxicity with a median relative IC50 (rIC50) value of 380µM against the PPTP cell lines (range 1 to >1,000µM). The three lines with rIC50 values lesser than 10µM had low MGMT expression compared to the remaining cell lines. In vivo temozolomide demonstrated significant toxicity at 100mg/kg, but induced tumor regressions in 15 of 23 evaluable solid tumor models (13 maintained CR [MCR], 2 CR) and 5 of 8 ALL models (3 MCR, 2 CR). There was a steep dose response curve, with lower activity at 66mg/kg temozolomide and with tumor regressions at 22 and 44mg/kg restricted to models with low MGMT expression. Conclusions: Temozolomide demonstrated high level antitumor activity against both solid tumor and leukemia models, but also elicited significant toxicity at the highest dose level. Lowering the dose of TMZ to more closely match clinical exposures markedly reduced the antitumor activity for many xenograft lines with responsiveness at lower doses closely related to low MGMT expression.

 

Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE): A Phase III Trial

Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. This clinical trial investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 trial was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomization system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. Findings: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4•6 months (95% CI 3•7—4•8) for pazopanib compared with 1•6 months (0•9—1•8) for placebo (hazard ratio [HR] 0•31, 95% CI 0•24—0•40; p<0•0001). Overall survival was 12•5 months (10•6—14•8) with pazopanib versus 10•7 months (8•7—12•8) with placebo (HR 0•86, 0•67—1•11; p=0•25). The most common adverse events were fatigue (60 in the placebo group [49%] vs. 155 in the pazopanib group [65%]), diarrhea (20 [16%] vs. 138 [58%]), nausea (34 [28%] vs. 129 [54%]), weight loss (25 [20%] vs. 115 [48%]), and hypertension (8 [7%] vs. 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Interpretation: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.

Carbon Ion Radiotherapy for Sarcoma of the Extremities

The purpose of this prospective phase I/II trial was to determine the effectiveness of carbon ion radiotherapy (CIRT) for localized primary sarcomas of the extremities. From April 2000 to May 2010, 17 (male/female: 12/5) patients with localized primary sarcoma of the extremities received CIRT. The median age was 53 years (range: 14–87years). Nine patients had primary diseases and eight had recurrent diseases. Of the 17 patients, eight refused amputation, and the remaining nine refused surgical resection. Tumors were located in the upper limbs in four patients and lower limbs in 13. Histological diagnosis was osteosarcoma in three patients, liposarcoma in two, synovial sarcoma in two, rhabdomyosarcoma in two, pleomorphic sarcoma in two, and miscellaneous in six. The CIRT dose to the limb was 52.8GyE for one patient, 64GyE for three, 70.4GyE for 13 in 16 fixed fractions over 4weeks. Records were reviewed and outcomes including radiologic response, local control (progression-free), and survival were analyzed. Results were as follows: The median follow-up was 37months (range: 11–97months). Radiological response rate was 65% (PR in 11, SD in 5, and PD in 1). The local control rate at 5 years was 76%. The overall survival rate at 5years was 56%. Of the 17 patients, 10 survived without disease progression. Four patients had local recurrences, one was salvaged by repeated CIRT and the other three died due to systemic diseases. Distant failure was observed in six patients. One patient suffered from femoral fracture (grade 3) and received surgical fixation 27months after CIRT. No other severe reactions (grade 3) were observed. Conclusions: CIRT is suggested to be an effective and safe treatment for patients who refuse surgery for localized primary sarcomas of the extremities.

Quality of Surgery & Neoadjuvant Therapy in the ISG-GEIS Trial

The purpose of this trial was to explore the correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m² and ifosfamide 9 g/m² and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. Results were as follows: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45–74 months), the 5-year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT–RT and with positive surgical margins, the CI of LR was 0. Conclusions: In this setting of high-risk STS treated by preoperative CT or CT–RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT–RT may be a reasonable option to maximize the chance of cure.

Phase I Study of Humanized Monoclonal Antibody AVE1642

Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments. Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m2 (B) docetaxel, 1250 mg/m2 gemcitabine/100 mg erlotinib (C1), or 60 mg/m2 doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3. Results were as follows: Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m2 gemcitabine/75 mg erlotinib) and D2 (50 mg/m2 doxorubicin). Grade 3–4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations ≥12 weeks, giving a control rate of 25/57 (44%). On treatment IGF-II rose by 68 ± 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 ± 21 ng/ml with disease control (P < 0.001). Conclusion: AVE1642 was tolerable with 75–100 mg/m2 docetaxel and 1000 mg/m2 gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response.

Clinical Trial End Points for Assessing Efficacy of Novel Therapies

Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. In this paper, the authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS.

Use of Cardiac Markers for Monitoring Doxorubixin-induced Cardiotoxicity

The aim of this study was to evaluate N-terminal probrain natriuretic peptides (NT-pro-BNP), cardiac troponin T, and creatinine kinase, MB isoenzyme (CK-MB) in the determination of subclinical left ventricular (LV) dysfunction by echocardiography in patients treated with doxorubicin. The investigators performed a cross-sectional case study of systolic, diastolic function and tissue Doppler imaging by echocardiography in children with cancer who received a certain cumulative dose of doxorubicin. Blood levels for NT-pro-BNP, cardiac troponin T, and CK-MB were analyzed within 6 hours of the cardiac study. Of 30 patients, 5 (16.7%) had LV dysfunction with an abnormally high NT-pro-BNP level of 363±78 pg/mL, whereas patients with normal LV function had an NT-pro-BNP level of 148±173 pg/mL (P=0.012). The NT-pro-BNP level not only inversely correlated with fractional shortening (r=-0.43, P=0.017) and ejection fraction (r=-0.45, P=0.013) but also correlated with mitral deceleration time (r=0.41, P=0.021) and a cumulative dose of doxorubicin (r=0.44, P=0.014). For tissue Doppler imaging, NT-pro-BNP correlated with a peak systolic velocity at the myocardial segment (Sm) (r=-0.40, P=0.027). NT-pro-BNP is a sensitive test and has a moderate relationship with the LV systolic and diastolic function, thus making it a useful cardiac marker for the monitoring of early anthracycline cardiotoxicity.

Phase I Study of Bevacizumab, Sorafenib, & Low-dose Cyclophosphamide

The purpose of this phase I trial was to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib, bevacizumab, and low-dose oral cyclophosphamide in children and young adults with recurrent/refractory solid tumors. Sorafenib dose was escalated from 90 mg/m2 to 110 mg/m2 twice daily with fixed doses of bevacizumab at 5 mg/kg every 3 weeks and cyclophosphamide at 50 mg/m2 daily. Once sorafenib's MTD was established, bevacizumab dose was escalated. Each course was 21 days. PK and PD studies were performed during the first course. Results were as follows: Nineteen patients (11 males; median age, 9.2 years) received a median of 4 courses (range, 1 to 23). DLTs during course 1 included grade 3 rash (2), increased lipase (1), anorexia (1), and thrombus (1). With an additional 71 courses of therapy, the most common toxicities ≥ grade 3 included neutropenia (9), lymphopenia (9), and rashes (4). Five of 17 evaluable patients had partial tumor responses, and 5 had disease stabilization (>2 courses). Median day 1 cyclophosphamide apparent oral clearance was 3.13 L/h/m2. Median day 1 sorafenib apparent oral clearance was 44 and 39 ml/min/m2 at the 2 dose levels evaluated, and steady-state concentrations ranged from 1.64 to 4.8 mg/L. Inhibition of serum VEGFR2 was inversely correlated with sorafenib steady-state concentrations (p=0.019). Conclusion: The recommended phase II doses are sorafenib, 90 mg/m2 twice daily; bevacizumab, 15 mg/kg q3 weeks; and cyclophosphamide, 50 mg/m2 once daily. This regimen is feasible with promising evidence of antitumor activity that warrants further investigation.

Phase I Trial of Lexatumumab for Pediatric Solid Tumors

Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results were as follows: Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion: Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.

Phase I Study of Single-Agent Anti–Programmed Death-1 (MDX-1106)

Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti–PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non–small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti–PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. Results were as follows: Anti–PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti–PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. Conclusion: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.

Communicating the Purpose of Pediatric Phase I Trials

Quality informed consent should provide a clear understanding of the purpose of the research. Given the ethical challenges of pediatric phase I cancer trials, it is important to investigate physician-parent communication during informed consent conferences (ICCs) and parental understanding of the purpose of these studies. In this multisite Informed Consent in Pediatric Phase I Cancer Trials study, 85 ICCs for phase I research between June 2008 and May 2011 were directly observed, and 60 parents were subsequently interviewed. The scientific purpose was defined as composite understanding of drug safety, dose finding, and dose escalation. The investigators determined the frequency with which physicians explained these and other phase I–related concepts during the ICC. Parent interviews were analyzed to determine understanding. Results were as follows: The child was present at 83 of 85 ICCs. Only 32% of parents demonstrated substantial understanding of the scientific purpose of phase I cancer trials; 35% demonstrated little or no understanding. Parents of higher socioeconomic status and racial majority status were more likely to understand the scientific purpose. Factors associated with understanding included physician explanation of the goal of the applicable phase I protocol offered (explained in 85% of ICCs) and explanation of the dose cohorts (explained in 43% of ICCs). Physicians explained drug safety in 23% of ICCs, dose finding in 52% of ICCs, and dose escalation in 53% of ICCs. Conclusion: Many parents of children participating in phase I trials do not understand the purpose of these trials. Physician-parent communication about the purpose of phase I research is lacking during ICCs.

Phase 2 Clinical Trial exploring crizotinib in patients with advanced tumors induced by causal alterations of ALK and/or MET ("CREATE")

EORTC 90101 CREATE assesses the antitumor activity and safety of crizotinib across predefined tumor types (including 4 types of soft tissue sarcoma) in patients whose tumors are possibly harboring specific alterations in ALK and/or MET. The primary endpoint is the response rate to crizotinib as assessed according to RECIST 1.1. The trial involves the following sarcoma subtypes:

• Inflammatory myofibroblastic tumor (IMFT; can be associated with ALK alterations)
• Alveolar soft part sarcoma (ASPS; can be associated with MET alterations)
• Clear cell sarcoma (CCSA; can be associated with MET alterations)
• Alveolar rhabdomyosarcoma (ARMS; can be associated with MET and ALK alterations)

Recruitment of patients to the trial follows a two-step procedure.

• Registration step 1: Patients must have the local diagnosis of advanced and/or metastatic anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, papillary renal cell carcinoma type 1, alveolar soft part sarcoma, clear cell sarcoma or alveolar rhabdomyosarcoma deemed incurable by conventional surgery, radiotherapy or systemic therapy. Proven presence of specific ALK and/or MET pathway alteration in tumor tissue is not mandatory at this point. A prerequisite for trial participation is the availability of a formalin-fixed, paraffin-embedded, tumor-containing tissue block from primary tumor and/or a metastatic site and shipment to a central biorepository. Slides are not accepted, and blocks are not returned. Fresh-frozen biopsies are accepted as alternative. Patients must sign informed consent for the shipment and central collection of the tissue block. After quality control of the available biological material by the central biorepository unstained slides from the tissue block will be sent to the central laboratory facilities of this trial at the University Hospitals of Leuven (central contact: Prof. Dr. P. Schöffski). Reference pathologists in Leuven will confirm the actual diagnosis in real time, which then triggers step 2 of the registration procedure.
• Registration step 2: Patients will be screened for actual participation in the treatment phase of the trial in the study site. Major selection criteria: Measurable disease according to RECIST 1.1. Any previous systemic anticancer therapy or major surgery completed at least 4 weeks prior to initiation of study medication. No prior therapy directly targeting ALK and/or MET, no previous treatment with crizotinib. Minimum age 15 years. ECOG performance status 0, 1 or 2. ANC ≥ 1 x 109/L, platelets ≥ 30 x 109/L, hemoglobin ≥ 8 g/dL, serum creatinine ≤ 2 x ULN, bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 2.5 x ULN in the absence of liver metastases and ≤ 5 x UNL if liver function abnormalities are due to the underlying malignancy. QTc interval <470 msec. Further disease-specific selection criteria apply to the six individual tumor cohorts. Patients with anaplastic large cell lymphoma and alveolar rhabdomyosarcoma must have had previous systemic therapy. The protocol defines no limitations regarding previous treatments in any of the cohorts of the trial.

After completion of screening and registration procedures crizotinib will be administered orally at a dose of one capsule of 250 mg twice daily at approximately the same time each day on a continuous daily dosing schedule, i.e. no break in dosing, in the absence of drug related toxicity. Treatment will be continued until disease progression or intolerance.

In parallel with the screening procedures the central laboratory of this trial at the University Hospitals Leuven will perform a molecular analysis of tumor tissue (“integrated translational research”), with the intention to group patients into two separate subcohorts per disease entity: ALK/MET positive or ALK/MET negative patients. Patients with either positive or negative tumors will be allowed to be treated with crizotinib in this trial. In a consecutive step, tissue of patients will also be subject to in-depth molecular profiling of the underlying genetic changes associated with the six tumor types. Stopping rules for each of the 12 subcohorts of this trial are defined in the protocol.  The trial is open for recruitment within the Network of Core Institutes (NOCI) of EORTC, which includes around 20 large academic institutions in multiple countries in Europe.

Contact for trial-related questions:

Prof. Dr. Patrick Schöffski, MPH
Head, Department of General Medical Oncology
Leuven Cancer Institute
University Hospitals Leuven
Herestraat 49
B-3000 Leuven, Belgium
Phone +32 16 346900
Fax +32 16 346901

Gemcitabine vs. gemcitabine and docetaxel in LMS

This Phase II study aimed to evaluate the efficacy and toxicity of single-agent gemcitabine versus gemcitabine plus docetaxel as second-line therapy in patients with uterine and nonuterine leiomyosarcoma (LMS). Patients had metastatic or unresectable LMS and had received one prior anthracycline-based regimen. A total of 90 patients received either single-agent gemcitabine (arm A; gemcitabine, 1,000 mg/m2 i.v. for 100 minutes on days 1, 8, and 15 of a 28-day cycle) or a combination of gemcitabine and docetaxel (arm B; gemcitabine, 900 mg/m2 i.v. for 90 minutes on days 1 and 8, plus docetaxel, 100 mg/m2 i.v. for 1 hour on day 8 of a 21-day cycle with lenograstim). The primary endpoint was the objective response rate. Results were as follows: The objective response rates were 19% and 24% in arm A (gemcitabine) and arm B (gemcitabine plus docetaxel), respectively, for patients with uterine LMS. For patients with nonuterine LMS, the objective response rates were 14% and 5% for arms A and B, respectively. The median progression-free survival times for arms A and B were 5.5 months and 4.7 months, respectively, for patients with uterine LMS. For patients with nonuterine LMS, the median progression-free survival times were 6.3 months and 3.8 months for arms A and B, respectively. One toxic death occurred in arm B. Conclusions: Both single-agent gemcitabine and gemcitabine plus docetaxel were found to be effective second-line therapies for leiomyosarcomas, with a 3-month progression-free survival rate of 40% for LMS with both uterine and nonuterine sites of origin. Single-agent gemcitabine yielded results similar to those of gemcitabine plus docetaxel in this trial, but patients using single-agent gemcitabine experienced less toxicity.

Topotecan and cyclophosphamide in adults with relapsed sarcoma

The combination of topotecan and cyclophosphamide (TC) has activity in pediatric patients with recurrent sarcoma, especially Ewing’s sarcoma (EWS). The investigators in this study sought to determine the toxicity of and response to TC in adults with recurrent sarcoma. Adults treated with TC from 2005 to 2010 were reviewed who received T = topotecan at 0.75mg/m2/day (days 1–5) and C = cyclophosphamide at 250mg/m2/day (days 1–5) every 21 days. Results were as follows: Fifteen patients, median age 31 years (range 17.5–56) had nonpleomorphic rhabdomyosarcoma (RMS, n = 6), EWS, n = 5, synovial sarcoma (SS, n = 2) leiomyosarcoma (LMS, n= 1), and desmoplastic small round cell tumor (DSRCT, n = 1). Median time to progression was 2.5 months (range 1.6–13.0). Partial responses were seen in 2/6 RMS and 1/2 SS. Stable disease was seen in 2/5 EWS, 1/2 SS and 1 DSRCT. The most common reason for stopping treatment was progressive disease 12/15, (80%). Hematologic toxicity was common; 7 (47%) patients required blood product transfusion, 5 (33%) patients had fever/neutropenia. At median follow-up time of 7.7 months, all but 1 patient had died of disease. Conclusion: TC combination is tolerable but has only modest activity in adults with recurrent sarcoma. Other regimens deserve exploration for this high-risk group of patients.

Phase I trial of trabectedin in children and adolescents

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24-hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors. Patients between the ages of 4 and 16 years old with refractory solid tumors received trabectedin as a 24-hour infusion every 21 days. Dexamethasone and prophylactic growth factor support were administered with each cycle. Pharmacokinetic studies were conducted during cycle 1. Results were as follows: Patients (n=12) median (range) age 14.5 (8–16) years received trabectedin at 1.1 (n=3), 1.5 (n=6), or 1.7 (n=3) mg/m2. At the 1.5mg/m2 dose level, one patient had dose limiting anorexia and fatigue. At 1.7mg/m2, two patients experienced dose limiting toxicity, dehydration, and gamma-glutamyl transpeptidase elevation. Non-dose limiting toxicities included elevated serum transaminases, myelosuppression, nausea, emesis, and fatigue. Plasma pharmacokinetic parameters were similar to historical data in adults. One partial response was observed in a patient with neuroendocrine carcinoma. Stable disease (≥6 cycles) was achieved in three patients (osteosarcoma n=2, desmoplastic small round cell tumor n=1). Conclusions: The MTD of trabectedin in pediatric patients with refractory solid tumors is 1.5mg/m2 IV over 24hours every 21 days. Dexamethasone to ameliorate hepatic toxicity and prophylactic growth factor support are required.

Phase I study of nelfinavir in liposarcoma

HIV protease inhibitors are associated with HIV protease inhibitor–related lipodystrophy syndrome. The investigators hypothesized that liposarcomas would be similarly susceptible to the apoptotic effects of an HIV protease inhibitor, nelfinavir. They conducted a phase I trial of nelfinavir for liposarcomas. There was no limit to prior chemotherapy. The starting dose was 1,250 mg twice daily (Level 1). Doses were escalated in cohorts of three to a maximally evaluated dose of 4,250 mg (Level 5). One cycle was 28 days. Steady-state pharmacokinetics (PKs) for nelfinavir and its primary active metabolite, M8, were determined at Levels 4 (3,000 mg) and 5. Results were as follows: Twenty subjects (13 males) were enrolled. Median (range) age was 64 years (37–81). One subject at Level 1 experienced reversible, grade 3 pancreatitis after 1 week and was replaced. No other dose-limiting toxicities were observed. Median (range) number of cycles was 3 (0.6–13.5). Overall best responses observed were 1 partial response, 1 minor response, 4 stable disease, and 13 progressive disease. Mean peak plasma levels and AUCs for nelfinavir were higher at Level 4 (7.3 mg/L; 60.9 mg/L × h) than 5 (6.3 mg/L; 37.7 mg/L × h). The mean ratio of M8:nelfinavir AUCs for both levels was ~1:3. Conclusions: PKs demonstrate auto-induction of nelfinavir clearance at the doses studied, although the mechanism remains unclear. Peak plasma concentrations were within range where anticancer activity was demonstrated in vitro. M8 metabolite is present at ~1/3 the level of nelfinavir and may also contribute to the anticancer activity observed.

Phase I study of bevacizumab and temsirolimus with liposomal doxorubicin

Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the anti-angiogenesis antibody bevacizumab may augment antitumor activity, as well as re-sensitize cells to anthracyclines. The investigators here initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (n=136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types. Results were as follows: The most common cancers were breast (n=29), epithelial ovarian (n=23) and colorectal cancer (n=17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension and fistula. This regimen led to a 21% (n=28) stable disease (SD) ≥ 6 months and 21% (n=29) rate of partial or complete remission (PR/CR) (total SD ≥ 6 months/PR/CR = 42% [n=57]). PR/CR was most common in parotid gland adenocarcinoma (4 of 6, 67%), metaplastic breast cancer (5 of 12, 42%), endometrial endometrioid carcinoma (6 of 15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11 of 28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m2 and bevacizumab 15 mg/kg every three weeks, with temsirolimus 25 mg weekly. Conclusions: Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

Phase I study of sorafenib in children

The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias. Sorafenib was administered orally q12h for consecutive 28 day cycles. Pharmacokinetics (day 1 and steady state) and pharmacodynamics were performed during cycle 1. Results were as follows: Of sixty-five patients enrolled, 60 were eligible. In the solid tumor cohort (n=49), 4/6 patients experienced a DLT (hypertension, pain, rash/urticaria, thrombocytopenia, ALT/AST) at the starting dose (150 mg/m2/dose which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients, but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for ≥ 4 cycles was observed in 14 solid tumor patients, and two patients with acute myeloid leukemia and FLT3 internal tandem duplication experienced a decrease in bone marrow blasts to <5%.

Phase I study of Mixed Bacterial Vaccine (Coley's Toxins) in NY-ESO-1 Expressing Cancers

Mixed bacterial vaccine (MBV, Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. The mechanism of action is suspected to have an immunologic basis, yet it is poorly defined up to now. The investigators developed a new, biochemically well defined and current good manufacturing practice–compliant MBV preparation, which has been investigated in patients with NY-ESO-1 expressing cancers. Patients received MBV subcutaneously at a starting dose of 250 EU (endotoxin units) twice a week. The MBV dose was escalated in each patient until a body temperature of 38°C to 39.5°C was induced or up to the maximum dose of 547.000 EU. Changes in serum cytokine levels were determined and immune responses to NY-ESO-1 were evaluated. Tumor response was assessed according to RECIST. Results were as follows: Twelve patients were enrolled and 11 of them developed fever after the administration of MBV. Ten of 12 patients showed a consistent increase in serum IL-6 levels with the highest levels coinciding with the highest body temperature. A subgroup of patients showed increasing levels of TNF-α, IFN-γ, and IL1-β. A patient with metastatic bladder cancer showed a partial tumor response strongly correlated with MBV-induced fever and highly elevated levels of several cytokines. Conclusions: MBV at fever-inducing dose levels can lead to a massive induction of immunoregulatory cytokines that may be involved in inducing tumor regressions. The investigators propose to further explore the role of MBV as a potent immune modulator at higher dose levels and in conjunction with antigen-specific cancer vaccines.

Phase I trial of trastuzumab and alvespimycin hydrochloride

The investigators of this study conducted a phase I dose-escalation study to define the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics of alvespimycin (17-DMAG), a heat shock protein 90 (Hsp90) inhibitor, given in combination with trastuzumab. Patients were treated with trastuzumab followed by intravenous alvespimycin on a weekly schedule. Hsp90 client proteins were measured at baseline and serially in peripheral blood lymphocytes (PBL) during cycle 1. Patients with advanced solid tumors progressing on standard therapy were eligible. Results were as follows: Twenty-eight patients (25, breast; 3, ovarian) were enrolled onto three dose cohorts: 60 (n = 9), 80 (n = 13), and 100 mg/m2 (n = 6). Dose-limiting toxicities (DLT) were: grade III left ventricular systolic dysfunction presenting as congestive heart failure in 1 patient (100 mg/m2), and reversible grade III keratitis in two patients (80 mg/m2). Drug-related grade III toxicity included one episode each of fatigue, diarrhea, myalgia, and back pain. Common mild to moderate toxicities included diarrhea, fatigue, myalgia, arthralgia, nausea, blurry vision, headache, back pain, and dry eyes. There was one partial response and seven cases of stable disease (range, 4–10 months), all in HER2+ MBC. In addition, an ovarian cancer patient had complete resolution of ascites and pleural effusion that lasted 24.8 months. There was no change in PK upon weekly dosing. Hsp70 effect continued to increase across four weeks and was most pronounced at 80 and 100 mg/m2. Conclusion: The combination of alvespimycin and trastuzumab is safe and tolerable at MTD. Antitumor activity was seen in patients with refractory HER2+ MBC and ovarian cancer. The recommended dose of alvespimycin for further study in this combination is 80 mg/m2 weekly.

Phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors

A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors. Oral vorinostat was administered on days 1–5 and 8–12 of a 21-day cycle (starting dose 180mg/m2/day with dose escalations to 230 and 300mg/m2/day). Bortezomib (1.3mg/m2 i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1. Results were as follows: Twenty-three eligible patients [17 male, median age 12 years (range: 1–20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300mg/m2/day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n=1) and Grade 3 nausea and anorexia (n=1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. The investigators did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients. Conclusion: The recommended Phase 2 dose and schedule is vorinostat (230mg/m2/day PO on days 1–5 and 8–12) in combination with bortezomib (1.3mg/m2/day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.

Phase I study of RO5126766, a dual MEK/RAF inhibitor, in solid tumors

This phase I study assessed the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics, pharmacodynamics, and clinical activity of the first-in-class dual MEK/RAF inhibitor, RO5126766. Initial dose-escalation was conducted using once daily dosing over 28 consecutive days in 4-week cycles. Further escalation was completed using 2 intermittent dosing schedules [7 days on treatment followed by 7 days off (7on/7off); 4 days on treatment followed by 3 days off (4on/3off)]. Results were as follows: Fifty-two patients received RO5126766 at doses of 0.1 to 2.7 mg once daily, 2.7 to 4.0 mg (4 on/3 off), or 2.7 to 5.0 mg (7 on/7 off). The most common DLTs were elevated creatine phosphokinase (CPK) and blurred vision. The MTD for each dosing schedule was 2.25 mg once daily, 4.0 mg (4 on/3 off), and 2.7 mg (7 on/7 off). The dose/schedule recommended for phase II (RP2D) investigation was 2.7 mg (4 on/3 off). Frequent adverse events included rash-related disorders (94.2%), elevated CPK (55.8%), and diarrhea (51.9%). Cmax occurred 1 to 2 hours after dosing and mean terminal half-life was approximately 60 hours. Pharmacodynamic changes included reduced ERK phosphorylation, an increase in apoptosis in tumor tissue, and a reduction in fluorodeoxyglucose (FDG) uptake after 15 days of dosing. Three partial responses were seen: two in BRAF-mutant melanoma tumors and one in an NRAS-mutant melanoma. Conclusion: This first-in-human study shows that oral RO5126766 has manageable toxicity, a favorable pharmacokinetic/pharmacodynamic profile, and encouraging preliminary antitumor activity in this population of heavily pretreated patients, achieving tumor shrinkage in around 40% of patients across all dose levels and all tumor types.

Phase II study of trebananib in patients with angiosarcoma

We received a note in mid-June from Corrie Painter of Angiosarcoma Awareness, Inc. that, "the first ever clinical trial specifically designed for angiosarcoma (sponsored by the NCI) is about to start enrolling patients." The announcement on the Angiosarcoma Awareness, Inc. website stated, in part, "Because angiosarcoma is so rare, clinical trials designed specifically for this disease are typically not thought to be able to recruit enough patients. Angiosarcoma Awareness has been instrumental in allowing doctors to see that there is a population of angiosarcoma patients large enough to design trials. They have initiated the first NCI clinical trial for angiosarcoma."

Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity

The investigators of this study compared two chemotherapy regimens that included methotrexate (MTX), cisplatin (CDP), and doxorubicin (ADM) with or without ifosfamide (IFO) in patients with nonmetastatic osteosarcoma of the extremity. Patients age ≤ 40 years randomly received regimens with the same cumulative doses of drugs (ADM 420 mg/m2, MTX 120 g/m2, CDP 600 mg/m2, and IFO 30 g/m2) but with different durations (arm A, 44 weeks; arm B, 34 weeks). IFO was given postoperatively when pathologic response to MTX-CDP-ADM was poor (arm A) or given in the primary phase of chemotherapy with MTX-CDP-ADM (arm B). End points of the study included pathologic response to preoperative chemotherapy, toxicity, and survival. Given the feasibility of accrual, the statistical plan only permitted detection of a 15% difference in 5-year overall survival (OS). Results were as follows: From April 2001 to December 2006, 246 patients were enrolled. Two hundred thirty patients (94%) underwent limb salvage surgery (arm A, 92%; arm B, 96%; P = .5). Chemotherapy-induced necrosis was good in 45% of patients (48% in arm A, 42% in arm B; P = .3). Four patients died of treatment-related toxicity (arm A, n = 1; arm B, n = 3). A significantly higher incidence of hematologic toxicity was reported in arm B. With a median follow-up of 66 months (range, 1 to 104 months), 5-year OS and event-free survival (EFS) rates were not significantly different between arm A and arm B, with OS being 73% (95% CI, 65% to 81%) in arm A and 74% (95% CI, 66% to 82%) in arm B and EFS being 64% (95% CI, 56% to 73%) in arm A and 55% (95% CI, 46% to 64%) in arm B. Conclusion: IFO added to MTX, CDP, and ADM from the preoperative phase does not improve the good responder rate and increases hematologic toxicity. IFO should only be considered in patients who have a poor histologic response to MTX, CDP, and ADM.

Primary metastatic Ewing's family tumors: results of the Italian Sarcoma Group and Scandinavian Sarcoma Group ISG/SSG IV Study including myeloablative chemotherapy and total-lung irradiation

The Italian Sarcoma Group and the Scandinavian Sarcoma Group designed a joint study to improve the prognosis for patients with Ewing's family tumors and synchronous metastatic disease limited to the lungs, or the pleura, or a single bone. The study was opened in 1999 and closed to the enrollment in 2008. The program consisted of intensive five-drug combination chemotherapy, surgery and/or radiotherapy as local treatment, and consolidation treatment with high-dose busulfan/melphalan plus autologous stem cell rescue and total-lung irradiation. Results were as follows: During the study period, 102 consecutive patients were enrolled. The median follow-up was 62 months (range 24–124). The 5-year event-free survival probability was 0.43 [standard deviation (SD) = 0.05] and the 5-year overall survival probability was 0.52 (SD = 0.052). Unfavorable prognostic factors emerging on multivariate analysis were a poor histological/radiological response at the site of the primary tumor [relative risk (RR) = 3.4], and incomplete radiological remission of lung metastases after primary chemotherapy (RR = 2.6). One toxic death and one secondary leukemia were recorded. Conclusions: This intensive approach is feasible and long-term survival is achievable in ∼50% of patients. New treatment approaches are warranted for patients responding poorly to primary chemotherapy.

Randomized Comparison of Intensified Six-Drug Versus Standard Three-Drug Chemotherapy for High-Risk Nonmetastatic Rhabdomyosarcoma and Other Chemotherapy-Sensitive Childhood Soft Tissue Sarcomas

The MMT95 study was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial. From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m2 (both arms), epirubicin 450 mg/m2, etoposide 1,350 mg/m2 (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery. Results were as follows: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens. Conclusion: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.

Pemetrexed in patients with refractory soft tissue sarcoma: A non-comparative multicenter phase II study of the German Sarcoma Group AIO-STS 005

This study evaluated efficacy and safety of pemetrexed in patients with refractory soft tissue sarcoma. Patients received pemetrexed intravenously at a dose of 500 mg/m² every 21 days until progression or unacceptable toxicity. The primary endpoint was objective tumor response. Results were as follows: Fourty-eight of 53 screened patients were included and received a total of 200 cycles (median 2; range 1–30). Median age was 53 years (range, 20–81). The observed toxicity profile was favorable. NCI-CTC hematologic grade 3/4 toxicity consisted of neutropenia in 13 %, anemia in 15 %, and febrile neutropenia in 4 % of patients of patients, respectively. Non-hematologic CTC grade 3/4 toxicity consisted of elevated ASAT/ALAT in 10 %, hyperglycemia in 6 %, infection with or without neutropenia in 6 %, nausea in 2 % and stomatitis in 2 % of patients. No other grade 3 toxicities and no treatment-related toxic deaths were observed. Overall response as defined by RECIST was 5 %, 16 patients experienced stable disease (40 %). The estimated 3- and 6-months progression-free rates were 33.3 % and 14.6 %, respectively. Conclusions: In patients with refractory STS, pemetrexed is well tolerated and moderately effective. The confirmed objective response rate in STS is low, however, disease stabilizations are seen in a high proportion of patients (ClinicalTrials.gov NCT00427466).

Phase II trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. This was a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. Pemetrexed, at a dose of 1910mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10+10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. Results were as follows: Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in five patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n=1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). Conclusions: Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.

Phase II study of paclitaxel in combination with carboplatin for patients with recurrent or persistent uterine sarcoma

In this Phase II trial, paclitaxel was administrated at 175 mg/m2 intravenously over 3 h plus carboplatin at AUC 5 intravenously over 30 min every 3–week cycle in patients with recurrent or progressive uterine sarcoma, who were unsuitable candidates for curative treatment with either surgery or radiotherapy. The Simon’s two–stage optimal design was chosen for defining the total number of patients required for the phase II study. A total of 13 patients were entered in the study at the first stage of trial. A median of four cycles were administrated per patient, with a range of one to nine cycles. Prior to the study, 4 (30.8%) of the 13 patients had received radiotherapy or chemotherapy. The response was measured by evaluation of the size of the mass by CT scan. Results were as follows: The overall response rate was 15.4% (2/13), with two patients exhibiting partial responses. There was 1 (7.7%) case of stable disease and 9 (69.2%) cases of progression disease. The median progression free survival was 2.23 months (95% confidence interval 1.94–3.67). Peripheral neuropathy and hematologic toxicity, including anemia and neutropenia, were the most frequent adverse events. One patient died from treatment–related toxicities. Conclusion: Paclitaxel in combination with carboplatin demonstrated acceptable levels of toxicity, but it was not active in the treatment of recurrent or progressive uterine sarcoma. This regimen might have limited role for advanced uterine sarcomas.

A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report

Aflibercept is a novel decoy receptor that efficiently neutralizes circulating vascular endothelial growth factor (VEGF). Here a pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of aflibercept. Cohorts of 3-6 children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5 or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were performed with the initial dose. Results were as follows: 21 eligible patients were enrolled; 18 were fully evaluable for toxicity. One of 6 patients receiving 2.0 mg/kg/dose developed dose-limiting intra-tumoral hemorrhage and 2 of 6 receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the 6 patients receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD. The most common non-dose limiting toxicities were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free to bound aflibercept serum concentration was 2.10 on day 8, but only 0.44 by day 15. A rapid decrease in VEGF (p<0.05) and increase in PlGF (p<0.05) from baseline was observed in response to aflibercept by day 2. Conclusion: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower that the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of anti-tumor activity, but were dose-limiting.

Phase 1 Study of Aurora A Kinase Inhibitor MLN8237 in Advanced Solid Tumors

This phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors. Sequential cohorts of patients received MLN8237 5-150 mg orally once-daily (QD) or twice-daily (BID) for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics were characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed. Results were as follows: Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose-proportionally (5-150 mg/day), and were similar for PIC and ECT. The terminal half-life was 23 h. At the MTD of 50 mg BID on the 7-day schedule, the MI of the skin basal epithelium was increased within 24 h after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting >1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months. Conclusion: This first-in-human trial of MLN8237 demonstrated tolerability and favorable pharmacokinetics in this patient population. The recommended phase 2 dose of MLN8237 is 50 mg BID orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies.

Analysis of published phase I/II clinical trials in osteosarcoma and Ewing sarcoma confirms limited outcomes...

High grade primary bone sarcomas are rare cancers that affect mostly children and young adults. Osteosarcoma and Ewing sarcoma are the most common histological subtypes in this age group, with current multimodality treatment strategies achieving 55-70% overall survival. As there remains an urgent need to develop new therapeutic interventions, the authors of this paper reviewed published phase I/II trials that have been reported for osteosarcoma and Ewing sarcoma in the last twenty years. Results were as follows: The authors conducted a literature search for clinical trials between 1990 and 2010, either for trials enrolling bone sarcoma patients as part of a general sarcoma indication or trials specifically in osteosarcoma and Ewing sarcoma. They identified 42 clinical trials that fulfilled the search criteria for general sarcoma that enrolled these patient groups, and eight and twenty specific trials for Ewing and osteosarcoma patients, respectively. For the phase I trials which enrolled different tumor types results were incomplete, because the sarcoma patients were not mentioned in the PubMed abstract. A total of 3,736 sarcoma patients were included in these trials over this period, 1,114 for osteosarcoma and 1,263 for Ewing sarcoma. As a proportion of the worldwide disease burden over this period, these numbers reflect a very small percentage of the potential patient recruitment, approximately 0.6% for Ewing sarcoma and 0.2% for osteosarcoma. However, these data show an increase in recent activity overall and suggest there is still much room for improvement in the current trial development structures. Conclusion: Lack of resources and commercial investment will inevitably limit opportunity to develop sufficiently rapid improvements in clinical outcomes. International collaboration exists in many well founded co-operative groups for phase III trials, but progress may be more effective if there were also more investment of molecular and translational research into disease focused phase I/II clinical trials. Examples of new models for early translational and early phase trial collaboration include the European based EuroBoNeT network, the Sarcoma Alliance for Research through Collaboration network (SARC) and the new European collaborative translational trial network, EuroSarc.

Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomized, double-blind, placebo-controlled phase 3 trial

Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. The investigators of this trial studied the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomization system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. Results were as follows: 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4•6 months (95% CI 3•7—4•8) for pazopanib compared with 1•6 months (0•9—1•8) for placebo (hazard ratio [HR] 0•31, 95% CI 0•24—0•40; p<0•0001). Overall survival was 12•5 months (10•6—14•8) with pazopanib versus 10•7 months (8•7—12•8) with placebo (HR 0•86, 0•67—1•11; p=0•25). The most common adverse events were fatigue (60 in the placebo group [49%] vs. 155 in the pazopanib group [65%]), diarrhea (20 [16%] vs. 138 [58%]), nausea (34 [28%] vs. 129 [54%]), weight loss (25 [20%] vs. 115 [48%]), and hypertension (8 [7%] vs. 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Conclusion: Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy.

18F-FDG-PET/CT Imaging as an Early Survival Predictor in Patients with Primary High-Grade Soft Tissue Sarcomas Undergoing Neoadjuvant Therapy

Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). The investigators of this study prospectively evaluated whether 2[18F]fluoro-2-deoxy-d-glucose (18F-FDG)-PET/computed tomographic (CT) imaging after the initial cycle of neoadjuvant therapy could predict overall survival in these patients. Thirty-nine patients underwent 18F-FDG-PET/CT before and after one cycle of neoadjuvant therapy. Fifty-six patients underwent end-of-treatment PET. Overall survival was, among others, correlated with changes of SUVpeak and histopathology. Results were as follows: One-, two-, and five-year survival rates were 95% ± 3.0%, 86% ± 4.6%, and 68% ± 6.6%, respectively. Median time to death was 30.9 months (mean, 27.7; range, 6.9–50.1). Optimal cutoff values for early and late decreases in SUVpeak (26% and 57%, respectively) were significant predictors of survival in univariate survival analysis [P = 0.041; HR, 0.27; 95% confidence interval (CI), 0.08–0.95 and P = 0.045; HR, 0.31; 95% CI, 0.10–0.98]. Seven of 15 early PET nonresponders but only four of 24 early PET responders died during follow-up (P = 0.068). The only other significant survival predictor was surgical margin positivity (P = 0.041; HR, 3.31; 95% CI, 1.05–10.42). By multivariable analysis, early metabolic response (P = 0.016) and positivity of surgical margins (P = 0.036) remained significant survival predictors. Conclusion: 18F-FDG-PET predicted survival after the initial cycle of neoadjuvant chemotherapy in patients with STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care.

Phase II Study of Ganitumab, a Fully Human Anti–Type-1 Insulin-Like Growth Factor Receptor Antibody, in Patients With Metastatic Ewing Family Tumors or Desmoplastic Small Round Cell Tumors

Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. Results were as follows: Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. Conclusion: Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

A phase II study of tasisulam sodium (LY573636 sodium) as second-line or third-line treatment for patients with unresectable or metastatic soft tissue sarcoma

Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight–based dosing algorithm targeting a peak plasma concentration (Cmax) of 420 μg/mL; a 360-μg/mL dose level was also explored. Results were as follows: The median age of patients treated at 420 μg/mL was 58.3 years (range, 18.6–80.4; n=63). Median PFS was 2.64 months (90 % CI, 1.41–3.38), with a 6-month PFS rate of 11 % (90 % CI, 4–17). Median OS was 8.71 months (90 % CI, 7.39–16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n=27; partial response/confirmed, n=2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n=1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 μg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 μg/mL and 15.8 % in those treated at 360 μg/mL (n=38). Conclusions: Tasisulam at a target Cmax of 420 μg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined.

Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma

Activation of the mammalian target of rapamycin (mTOR) pathway has been demonstrated in sarcoma. Trials using mTOR inhibitor in sarcoma have shown low objective response rates but progression-free survival (PFS) rates suggest cytostatic effects. The combination of sirolimus and cyclophosphamide demonstrated synergistic anti-sarcoma activity in preclinical models; therefore, the investigators here conducted a phase II trial of sirolimus and cyclophosphamide in patients with advanced sarcoma. Patients received 4mg sirolimus daily and 200mg cyclophosphamide d1-7 and 15-21 every 28days. The primary objective was to estimate the 24-week PFS rate with a target of 25%. Patients were followed for World Health Organisation (WHO) criteria tumor response by imaging every 8weeks. Serum levels of sirolimus, lipids and vascular endothelial growth factor were measured. Tumor tissue was analyzed for mTOR, S6 ribosomal protein and cytochrome P450 3A4/5 by quantitative immunofluorescence. Results were as follows: Forty-nine eligible patients were enrolled from September 2008 to December 2009. Patients received a median of four cycles of therapy. Starting doses of drugs were tolerated in 79%. One patient achieved partial tumor response, 10 were progression-free for 24weeks and two completed 12 cycles of treatment. Median PFS and overall survival (OS) were 3.4 and 9.9months, respectively. Serious adverse events attributed to therapy occurred in 11% and included infection, pneumonitis and thrombosis. Hypertriglyceridaemia from treatment and lower tumor phosphorylated-mTOR are associated with longer survival. Conclusions: Sirolimus and cyclophosphamide were tolerated by the majority of patients. About 20% of patients had stable sarcoma for at least 6months but objective tumor response was infrequent.

Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors

In this study, temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R). Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months. Results were as follows: Twenty patients [17 with Ewing's sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I–II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose. Conclusion: Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors.

A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours

The objectives of this phase I study were to assess the safety and tolerability of E7080 in patients with advanced, refractory solid tumors; to determine the maximum tolerated dose (MTD) and pharmacokinetics profile of E7080; and to explore preliminary evidence of its anti-tumor efficacy. E7080 was administered orally in escalating doses on a once-daily continuous schedule in 28-day cycles to eligible patients. Samples for pharmacokinetic analyses were collected on days 1, 8, 15 and 22 of cycle 1 and day 1 of cycle 2. Anti-tumor efficacy was assessed every two cycles. Results were as follows: Eighty-two patients received E7080 in dose cohorts from 0.2 to 32 mg. Dose-limiting toxicities were grade 3 proteinuria (two patients) at 32 mg, and the MTD was defined as 25 mg. The most frequently observed cumulative toxicities (all grades) were hypertension (40% of patients), diarrhea (45%), nausea (37%), stomatitis (32%) and vomiting (23%). Seven patients (9%) had a partial response and 38 patients (46%) had stable disease as best response. E7080 has dose-linear kinetics with no drug accumulation after 4 weeks’ administration. Conclusion: E7080 is well tolerated at doses up to 25 mg per day. Encouraging anti-tumor efficacy was observed in patients with melanoma and renal cell carcinoma.

Phase I Study of RO4929097, a Gamma Secretase Inhibitor of Notch Signaling, in Patients With Refractory Metastatic or Locally Advanced Solid Tumors

The purpose of this study was to determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [18F] fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. Results were as follows: Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. Conclusion: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

Safety, Pharmacokinetic, and Pharmacodynamic Phase I Dose-Escalation Trial of PF-00562271, an Inhibitor of Focal Adhesion Kinase, in Advanced Solid Tumors

PF-00562271 is a novel inhibitor of focal adhesion kinase (FAK). The objectives of this study were to identify the recommended phase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF-00562271. Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF-00562271 on single-dose midazolam PK in a subgroup of patients. Results were as follows: Ninety-nine patients (median age, 60 years; 98% with Eastern Cooperative Oncology Group performance status of 0 or 1) were treated in 12 fasting and three fed cohorts. The 125-mg twice-per-day fed dose was deemed the maximum-tolerated dose (MTD) and RP2D. Grade 3 dose-limiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). PF-00562271 exposure increased with increasing dose; serum concentration–time profiles showed characteristic nonlinear disposition. Steady-state exposures were reached within 1 week. On coadministration, geometric mean values of midazolam maximal observed serum concentration and area under the serum concentration–time curve increased by 60% and more than two-fold, respectively. Of 14 patients evaluable by [18F] fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles. Conclusion: The MTD and RP2D of PF-00562271 is 125 mg twice per day with food. PF-00562271 displayed time- and dose-dependent nonlinear PK and is likely a potent CYP 3A inhibitor. This first-in-class study supports further investigation of FAK as a promising therapeutic target.