Doxorubicin Vs. Intensified Doxorubicin + Ifos

Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide—which have been used to treat soft-tissue sarcoma for more than 30 years—still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. The investigators assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. They did this phase 3 randomized controlled trial (EORTC 62012) at 38 hospitals in ten countries. They included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18—60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimization method to either doxorubicin (75 mg/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2; 25 mg/m2 per day, days 1—3) plus ifosfamide (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomization was stratified by center, performance status (0 vs. 1), age (<50 vs. ≥50 years), presence of liver metastases, and histopathological grade (2 vs. 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. Findings were as follows: Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31—77) in the doxorubicin only group and 59 months (36—72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12·8 months [95·5% CI 10·5—14·3] in the doxorubicin group vs. 14·3 months [12·5—16·5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0·83 [95·5% CI 0·67—1·03]; stratified log-rank test p=0·076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7·4 months [95% CI 6·6—8·3]) than for the doxorubicin group (4·6 months [2·9—5·6]; HR 0·74 [95% CI 0·60—0·90], stratified log-rank test p=0·003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs. 31 [14%] of 228; p<0·0006). The most common grade 3 and 4 toxic effects—which were all more common with doxorubicin and ifosfamide than with doxorubicin alone—were leucopenia (97 [43%] of 224 patients vs. 40 [18%] of 223 patients), neutropenia (93 [42%] vs. 83 [37%]), febrile neutropenia (103 (46%) vs. 30 [13%]), anaemia (78 [35%] vs. 10 [5%]), and thrombocytopenia (75 [33%]) vs. one [<1%]). Interpretation: The results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumor shrinkage. These findings should help individualize the care of patients with this disease.

Trial of Pulmonary Metastasectomy & Isolated Lung Perfusion w/Melphalan

The 5-year overall survival rate of patients undergoing complete surgical resection of pulmonary metastases (PM) from colorectal cancer (CRC) and sarcoma remains low (20-50%). Local recurrence rate is high (48-66%). Isolated lung perfusion (ILuP) allows the delivery of high-dose locoregional chemotherapy with minimal systemic leakage to improve local control. From 2006 to 2011, 50 patients, 28 male, median age 57 years (15-76), with PM from CRC (n = 30) or sarcoma (n = 20) were included in a phase II clinical trial conducted in four cardiothoracic surgical centers. In total, 62 ILuP procedures were performed, 12 bilaterally, with 45mg of melphalan at 37°C, followed by resection of all palpable PM. Survival was calculated according to the Kaplan-Meier method. Results were as follows: Operative mortality was 0%, and 90-day morbidity was mainly respiratory (grade 3: 42%, grade 4: 2%). After a median follow-up of 24 months (3-63 mo), 18 patients died, two without recurrence. Thirty patients had recurrent disease. Median time to local pulmonary progression was not reached. The 3-year overall survival and disease-free survival were 57% ± 9% and 36% ± 8%, respectively. Lung function data showed a decrease in forced expiratory volume in 1 second and diffusing capacity of the alveolocapillary membrane of 21.6% and 25.8% after 1 month, and 10.4% and 11.3% after 12 months, compared with preoperative values. Conclusion: Compared with historical series of PM resection without ILuP, favorable results are obtained in terms of local control without long-term adverse effects. These data support the further investigation of ILuP as additional treatment in patients with resectable PM from CRC or sarcoma.

Patient Preferences for Clinical Follow-Up after STS Treatment

Patients treated for soft tissue sarcoma (STS) require long-term follow-up to detect recurrent or metastatic disease, yet marked differences exist in clinical approaches to the length of follow-up, frequency of consultations and investigations undertaken at follow-up visits. There has been no published work assessing patient expectations or the acceptability of post-treatment follow-up strategies. This study aimed to assess the patient acceptability of different follow-up strategies following curative surgery for soft tissue sarcoma and to investigate the hypothetical levels of recurrence risk at which different follow-up regimes were acceptable. Patients were recruited from the Royal Orthopaedic Hospital in Birmingham. The study used a cross-sectional survey incorporating a best-worst scaling discrete choice experiment to assess patient preferences regarding different aspects of follow-up. Results were as follows: 132 patients participated (47% response). The nature of investigations undertaken during follow-up was the most important aspect of post-surgical care. Patients typically preferred appointments routinely consisting of clinical examination and chest X-ray, and for follow-up to remain in secondary care rather than general practice. Conclusion: Clear protocols for STS patient follow-up can improve consistency and equity of care. In determining the optimum follow-up plan for STS patients from the patient perspective, this study provides valuable information that should be considered alongside the clinical effectiveness of follow-up strategies to maximize patient outcomes and use NHS resources appropriately.

Assessment of Psychosocial Problems in Cancer Genetic Counseling Practice

This study evaluated the efficacy of a cancer genetics–specific questionnaire in facilitating communication about, awareness of, and management of psychosocial problems, as well as in lowering distress levels. Individuals referred to genetic counseling for cancer at two family cancer clinics in the Netherlands were randomly assigned to an intervention or a control group. All participants completed the psychosocial questionnaire before counseling. In the intervention group, the counselors received the results of this questionnaire before the counseling session. All sessions were audiotaped for content analysis. Primary outcomes were the frequency with which psychosocial problems were discussed, the genetic counselors' awareness of these problems, and their management. Secondary outcomes included cancer worries and psychological distress, duration and dynamics of the counseling, and satisfaction. Results were as follows: The frequency with which psychosocial problems were discussed with 246 participating counselees was significantly higher in the intervention group (n = 127) than in the control group (n = 119; P = .004), as was the counselors' awareness of psychosocial problems regarding hereditary predisposition (P < .001), living with cancer (P = .01), and general emotions (P < .001). Counselors initiated more discussion of psychosocial problems in the intervention group (P < .001), without affecting the length of the counseling session. No significant differences were found on management (P = .19). The intervention group reported significantly lower levels of cancer worries (P = .005) and distress (P = .02) after counseling. Conclusion: The routine assessment of psychosocial problems by questionnaire facilitates genetic counselors' recognition and discussion of their clients' psychosocial problems and reduces clients' distress levels.

Sunitinib in Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, marked by NR4A3 rearrangement. Herein the investigators report on the activity of sunitinib in a series of 10 patients, strengthening what was initially observed in two cases. From July 2011, 10 patients with progressive metastatic translocated EMC have been consecutively treated with sunitinib 37.5 mg/day, on a named-use basis. In an attempt to interpret the activity of sunitinib in EMC, genotype/phenotype correlations were carried out by fluorescence in situ hybridization (FISH) analyses. Moreover, transcriptome, immunohistochemical and biochemical analyses of a limited set of samples were performed focusing on some putative targets of sunitinib. Results were as follows: Eight of 10 patients are still on therapy. Six patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (PR), two were stable, two progressed. Positron emission tomography (PET) was consistent in 6/6 evaluable cases. One patient underwent surgery after sunitinib, with evidence of a pathologic response. At a median follow-up of 8.5 months (range 2–28), no secondary resistance was detected. Median progression free survival (PFS) has not been reached. Interestingly, all responsive cases turned out to express the typical EWSR1–NR4A3 fusion, while refractory cases carried the alternative TAF15–NR4A3 fusion. Among putative sunitinib targets, only RET was expressed and activated in analyzed samples. Conclusions: This report confirms the therapeutic activity of sunitinib in EMC. Genotype/phenotype analyses support a correlation between response and EWSR1–NR4A3 fusion. Involvement of RET deserves further investigation.

Phase II Study of Cediranib in Advanced GIST or STS

Cediranib is a potent VEGF signaling inhibitor with activity against all three VEGF receptors and KIT. This phase II study evaluated the antitumor activity of cediranib in patients with metastatic gastrointestinal stromal tumor (GIST) resistant/intolerant to imatinib, or metastatic soft-tissue sarcomas (STS; ClinicalTrials.gov, NCT00385203). Patients received cediranib 45 mg/day. Primary objective was to determine the antitumor activity of cediranib according to changes in 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG-PET) tumor uptake in patients with GIST using maximum standardized uptake values (SUVmax). Secondary objectives included objective tumor response and tolerability in patients with GIST/STS. Results were as follows: Thirty-four of 36 enrolled patients were treated (GIST n = 24; STS n = 10). At day 29, five patients had confirmed decreases in SUVmax (≥10% from day 8) and two had confirmed partial metabolic responses (≥25% decrease), but arithmetic mean percentage changes in SUVmax, averaged across the cohort, were not significant at day 8 [6.8%; 95% confidence interval (CI), 19.95-33.54) or day 29 (4.6%; 95% CI, 8.05-17.34). Eleven patients with GIST achieved a best objective tumor response of stable disease; eight achieved stable disease ≥16 weeks. In patients with STS, four of six with alveolar soft-part sarcoma (ASPS) achieved confirmed and durable partial responses. The commonest adverse events were diarrhea (85%), fatigue (74%), and hypertension (68%). Conclusions: In patients progressing on imatinib/sunitinib, cediranib 45 mg/day demonstrated evidence of activity by (18)FDG-PET, but did not reduce average SUVmax. Evidence of antitumor activity was seen in ASPS.

Fractionated Stereotactic Intensity Modulated Radiotherapy with(out) Surgery

The authors used a Fleming single–stage design to study the phase II efficacy of using a focally directed treatment strategy for symptomatic brain metastases by the use of fractionated stereotactic radiotherapy (fSRT) with or without surgery and omitting the routine use of adjuvant whole–brain radiation therapy. They reveal that a focally directed treatment strategy using fSRT with or without surgery appears to be an effective initial strategy. Based on the results of this phase II clinical trial, further study is warranted. The authors used a Fleming single-stage design of 40 patients. Patients were eligible if they presented with 1 to 3 newly diagnosed symptomatic brain metastases, Karnofsky performance scale (KPS) greater than 60, and histological confirmation of primary disease. Patients underwent fSRT with the use of a dose of 30 Gy in 5 intensity-modulated fractions as primary or adjuvant treatment after surgical resection. The primary end point was the proportion of patients who experienced neurological death. Secondary end points were overall survival, time to KPS <70, and progression-free survival. Results were as follows: Of 40 patients accrued, 39 were eligible for analysis. The proportion of patients dying of neurological causes was 13% (5 patients), which includes 3 patients with an unknown cause of death. Median overall survival, time to KPS <70, and progression-free survival were 16 (95% confidence interval, 9-23), 14 (95% confidence interval, 7-20), and 11 (95% confidence interval, 4-21) months, respectively.

Phase I Study of LCL161 in Advanced Solid Tumors

LCL161 antagonizes the function of inhibitor of apoptosis proteins (IAPs), thereby promoting cancer cell death. This first-in-human dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of LCL161 in patients with advanced solid tumors. A second part of the study assessed the relative bioavailability of a tablet versus solution formulation. LCL161 was administered orally, once weekly, on a 21-day cycle to adult patients with advanced solid tumors by using an adaptive Bayesian logistic regression model with overdose control–guided dose escalation. Results were as follows: Fifty-three patients received at least one dose of LCL161 (dose range, 10 to 3,000 mg). LCL161 was well tolerated at doses up to 1,800 mg. Cytokine release syndrome (CRS) was the only dose-limiting toxicity (in three [6%] of 53 patients) and was the most common grades 3 to 4 event (in five [9%] of 53 patients). Vomiting, nausea, asthenia/fatigue, and anorexia were common but not severe. Although the MTD was not formally determined, an 1,800-mg dose was selected in compliance with the protocol for additional study, given the dose-limiting CRS at higher doses and pharmacodynamic activity at lower doses. LCL161 was rapidly absorbed, and exposure was generally increased with dose. The tablet formulation of LCL161 was better tolerated than the solution; tablet and solution formulations had similar exposures, and the solution was discontinued. No patient had an objective response. LCL161 induced degradation of cellular IAP1 protein in the blood, skin, and tumor and increased circulating cytokine levels. Conclusion: The 1,800-mg dose of LCL161, administered as a single agent once weekly, in tablet formulation is the recommended dose for additional study. This combined dose and formulation was well tolerated and had significant pharmacodynamic activity, which warrants additional investigation.

Phase II Trial of Panobinostat in Advanced STS

Soft tissue sarcomas (STS) are rare tumors for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. The investigators conducted a single-arm, open-label, multicenter phase II study to assess the efficacy and tolerability of panobinostat given orally, 40mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. Results were as follows: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. Conclusion: Panobinostat was poorly tolerated at 40mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Outcome of Patients with Sarcoma in Phase I Trials

Although sarcomas account for only 1% of all solid tumors, patients with sarcomas comprise a larger proportion of patients entering phase I trials, due to the limited number of registered or active drugs for these diseases. To help in patient selection, the investigators evaluated the utility of the predictive Royal Marsden Score which had been derived in carcinoma patients. In addition, they analyzed efficacy and toxicity regarding the sarcoma population enrolled in phase I trials. Data was used from a European Database comprising 2182 patients treated in phase I trials in 14 European institutions between 2005 and 2007. Results were as follows: One hundred and seventy-eight patients diagnosed with advanced sarcoma or other mesenchymal tumours were identified and accounted for 217 phase I trial participations during the study period. Histological type, class of drug, number of metastatic sites, high serum lactate dehydrogenase activity (LDH), low albumin and high white blood cell count were independent prognostic factors. Poor performance status (PS), liver metastases and high leucocyte count were associated with increased risk of early death. The class of drug used was the strongest predictor of progression-free survival (PFS) duration, inhibitors of angiogenesis and histone deacetylase giving the best results. Poor PS, high serum LDH and low lymphocyte count correlated with shorter PFS. In this heterogeneous population, PFS with investigational agents appeared comparable with that previously published for patients receiving standard treatments beyond first line. Conclusion: Prognostic factors in sarcoma patients do not differ from a broader phase I population. Efficacy measures suggest that some patients with sarcoma derive benefit from therapy in this setting which could therefore be considered for patients with no remaining standard therapeutic option.

Phase I Study of SAR245409 (XL765), a PI3K/mTOR inhibitor

This phase I, first-in-human study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409, an inhibitor of pan-Class I PI3K and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Eighty-three patients received SAR245409. Doses ranged from 15-120 mg twice daily, and 70-100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events (AEs) and response. Assessments included PK, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results were as follows: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related AEs were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%) and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 AEs were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin and tumor samples. Best response was stable disease (SD) in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with SD were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusions: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant SD.

Phase 3 study of doxorubicin alone vs. intensified doxorubicin + ifosfamide in advanced STS

Effective targeted treatment is unavailable for most sarcomas and doxorubicin and ifosfamide—which have been used to treat soft-tissue sarcoma for more than 30 years—still have an important role. Whether doxorubicin alone or the combination of doxorubicin and ifosfamide should be used routinely is still controversial. We assessed whether dose intensification of doxorubicin with ifosfamide improves survival of patients with advanced soft-tissue sarcoma compared with doxorubicin alone. We did this phase 3 randomised controlled trial (EORTC 62012) at 38 hospitals in ten countries. We included patients with locally advanced, unresectable, or metastatic high-grade soft-tissue sarcoma, age 18—60 years with a WHO performance status of 0 or 1. They were randomly assigned (1:1) by the minimisation method to either doxorubicin (75 mg/m2 by intravenous bolus on day 1 or 72 h continuous intravenous infusion) or intensified doxorubicin (75 mg/m2; 25 mg/m2 per day, days 1—3) plus ifosfamide (10 g/m2 over 4 days with mesna and pegfilgrastim) as first-line treatment. Randomisation was stratified by centre, performance status (0 vs 1), age (<50 vs ≥50 years), presence of liver metastases, and histopathological grade (2 vs 3). Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to six cycles. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00061984. Between April 30, 2003, and May 25, 2010, 228 patients were randomly assigned to receive doxorubicin and 227 to receive doxorubicin and ifosfamide. Median follow-up was 56 months (IQR 31—77) in the doxorubicin only group and 59 months (36—72) in the combination group. There was no significant difference in overall survival between groups (median overall survival 12-8 months [95•5% CI 10•5—14•3] in the doxorubicin group vs 14•3 months [12•5—16•5] in the doxorubicin and ifosfamide group; hazard ratio [HR] 0•83 [95•5% CI 0•67—1•03]; stratified log-rank test p=0•076). Median progression-free survival was significantly higher for the doxorubicin and ifosfamide group (7•4 months [95% CI 6•6—8•3]) than for the doxorubicin group (4•6 months [2•9—5•6]; HR 0•74 [95% CI 0•60—0•90], stratified log-rank test p=0•003). More patients in the doxorubicin and ifosfamide group than in the doxorubicin group had an overall response (60 [26%] of 227 patients vs 31 [14%] of 228; p<0•0006). The most common grade 3 and 4 toxic effects—which were all more common with doxorubicin and ifosfamide than with doxorubicin alone—were leucopenia (97 [43%] of 224 patients vs 40 [18%] of 223 patients), neutropenia (93 [42%] vs 83 [37%]), febrile neutropenia (103 (46%) vs 30 [13%]), anaemia (78 [35%] vs 10 [5%]), and thrombocytopenia (75 [33%]) vs one [<1%]). Interpretation: Our results do not support the use of intensified doxorubicin and ifosfamide for palliation of advanced soft-tissue sarcoma unless the specific goal is tumour shrinkage. These findings should help individualise the care of patients with this disease.

Long-term responders and survivors on pazopanib for advanced STS

Pazopanib recently received approval for the treatment of certain soft tissue sarcoma (STS) subtypes. The authors conducted a retrospective analysis on pooled data from two EORTC trials on pazopanib in STS in order to characterize long-term responders and survivors. Selected patients were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226). Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Thirty-six percent of patients had a PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, defined as long-term survivors. Patient characteristics were studied for their association with long-term outcomes. Results were as follows: The median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. Seventy-six patients (22.1%) were both long-term responders and long-term survivors. The analysis confirmed the importance of known prognostic factors in metastatic STS patients treated with systemic treatment, such as performance status and tumor grading, and additionally hemoglobin at baseline as new prognostic factor. They identified 12 patients (3.5%) remaining on pazopanib for more than 2 years: nine aged younger than 50 years, nine females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Conclusions: Thirty-six percent and 34% of all STS patients who received pazopanib in these studies had a long PFS and/or OS, respectively. For more than 2 years, 3.5% of patients remained progression free under pazopanib. Good performance status, low/intermediate grade of the primary tumor and a normal hemoglobin level at baseline were advantageous for long-term outcome

Phase Ib of Sorafenib in Combination With Everolimus

Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways—everolimus and sorafenib—were investigated. Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. Results were as follows: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. Conclusion: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.

Phase I Study of Oral Rigosertib (ON 01910.Na) in Advanced Solid Tumors

The purpose of this study was to determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing. Results were as follows: Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. Conclusions: The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.

Phase I study of SAR245409 (XL765) in advanced solid tumors

This phase I, first-in-human study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics and preliminary efficacy of SAR245409, an inhibitor of pan-Class I PI3K and mTOR, administered orally once or twice daily in patients with advanced solid tumors. Eighty-three patients received SAR245409. Doses ranged from 15-120 mg twice daily, and 70-100 mg once daily. A 3+3 dose-escalation design was used to determine the MTD. Patients were evaluated for adverse events (AEs) and response. Assessments included PK, pharmacodynamic impact of SAR245409 on PI3K pathway signaling in hair sheath cells, skin and tumor, and characterization of tumor molecular alterations. Results were as follows: The MTDs were 50 mg twice daily and 90 mg once daily. The most frequent treatment-related AEs were nausea (36.1%), diarrhea (21.7%), vomiting (19.3%) and decreased appetite (16.9%). The most frequent treatment-related grade 3/4 AEs were increases in alanine aminotransferase (6.0%) and aspartate aminotransferase (4.8%). SAR245409 had a relatively short plasma half-life (2.96-7.52 hours). At MTDs, once- and twice-daily regimens yielded similar mean steady-state plasma exposure. A reduction in PI3K and mTORC1/mTORC2 pathway signaling was observed in serial hair sheath cells, skin and tumor samples. Best response was stable disease (SD) in 48% of evaluable patients; seven patients had minor tumor regression. Twelve patients with SD were treated for ≥16 weeks. No trend was observed correlating tumor molecular alteration with antitumor activity. Conclusions: SAR245409 had a manageable safety profile, demonstrated reduced PI3K and mTORC1/mTORC2 pathway signaling and was associated with clinically relevant SD.

Phase I Study of Temsirolimus and Bryostatin-1 in RCC & Metastatic STS

Temsirolimus, an inhibitor of mammalian target of rapamycin (mTOR) complex 1, is approved for the treatment of metastatic renal cell carcinoma (RCC). Bryostatin-1 inhibits protein kinase C, a downstream effector of mTOR complex 2. Previously, the investigators observed antitumor effects with the combination of temsirolimus and bryostatin-1 in RCC cell lines. In this Phase I study, four cohorts of patients received weekly bryostatin-1 (20 μg/m2) with temsirolimus (10, 15, 25, or 37.5 mg) in 28-day cycles. Results were as follows: Thirty patients received a total of 138 cycles across four dose levels. Twenty-five patients had RCC (17 clear cell, 7 papillary, and 1 unclassified). Two sarcoma patients with prior cytotoxic therapy experienced dose-limiting toxicity at 15 mg of temsirolimus (grade 3 neutropenia and grade 3 hypophosphatemia). Subsequently, patients with prior cytotoxic therapy were excluded. Two additional dose-limiting toxicities were noted with 37.5 mg of temsirolimus (grade 3 neutropenia and grade 3 creatinine elevation). Consequently, the maximum tolerated dose was defined as temsirolimus at 25 mg and bryostatin-1 at 20 μg/m2 every 28 days. Of the 25 RCC patients, 3 patients had partial responses that lasted for 14 months, 28 months, and ≥80 months, respectively. Partial responses were seen in both clear cell and papillary histology. Conclusion: This combination of 37.5 mg of temsirolimus with 20 μg/m2 of bryostatin-1 was reasonably safe and well tolerated. Durable responses were observed in 3 of 25 patients with RCC.

Phase I Study of Lurbinectedin (PM01183) in Advanced Solid Tumors

Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. Results were as follows: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m2. Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m2, with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. Conclusion: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.

Ionising radiation-free whole-body MRI versus 18F-fluorodeoxyglucose PET/CT scans for children and young adults

Imaging tests are essential for staging of children with cancer. However, CT and radiotracer-based imaging procedures are associated with substantial exposure to ionising radiation and risk of secondary cancer development later in life. The investigators’ aim was to create a highly effective, clinically feasible, ionising radiation-free staging method based on whole-body diffusion-weighted MRI and the iron supplement ferumoxytol, used off-label as a contrast agent. They compared whole-body diffusion-weighted MRI with standard clinical 18F-fluorodeoxyglucose (18F-FDG) PET/CT scans in children and young adults with malignant lymphomas and sarcomas. Whole-body diffusion-weighted magnetic resonance images were generated by coregistration of colour-encoded ferumoxytol-enhanced whole-body diffusion-weighted MRI scans for tumor detection with ferumoxytol-enhanced T1-weighted MRI scans for anatomical orientation, similar to the concept of integrated 18F-FDG PET/CT scans. Tumor staging results were compared using Cohen's κ statistics. Histopathology and follow-up imaging served as the standard of reference. Data was assessed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01542879. Findings: 22 of 23 recruited patients were analyzed because one patient discontinued before completion of the whole-body scan. Mean exposure to ionising radiation was 12•5 mSv (SD 4•1) for 18F-FDG PET/CT compared with zero for whole-body diffusion-weighted MRI. 18F-FDG PET/CT detected 163 of 174 malignant lesions at 1325 anatomical regions and whole-body diffusion-weighted MRI detected 158. Comparing 18F-FDG PET/CT to whole-body diffusion-weighted MRI, sensitivities were 93•7% (95% CI 89•0—96•8) versus 90•8% (85•5—94•7); specificities 97•7% (95% CI 96•7—98•5) versus 99•5% (98•9—99•8); and diagnostic accuracies 97•2% (93•6—99•4) versus 98•3% (97•4—99•2). Tumor staging results showed very good agreement between both imaging modalities with a κ of 0•93 (0•81—1•00). No adverse events after administration of ferumoxytol were recorded. Interpretation: Ferumoxytol-enhanced whole-body diffusion-weighted MRI could be an alternative to 18F-FDG PET/CT for staging of children and young adults with cancer that is free of ionising radiation. This new imaging test might help to prevent long-term side-effects from radiographic staging procedures.

Improving the Care of Children with an Electronic Feedback Intervention

This study aimed to determine whether feeding back patient-reported outcomes (PROs) to providers and families of children with advanced cancer improves symptom distress and health-related quality of life (HRQoL). This study was a parallel, multicentered pilot randomized controlled trial. At most once per week, children age ≥ 2 years old with advanced cancer or their parent completed the computer-based Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) survey consisting of age- and respondent-adapted versions of the Memorial Symptom Assessment Scale (MSAS), Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL4.0), and an overall Sickness question. In the intervention group (n = 51), oncologists and families received printed reports summarizing PROs; e-mails were sent to oncologists and subspecialists when predetermined scores were exceeded. No feedback was provided in the control group (n = 53). Primary outcomes included linear trends of MSAS, PedsQL4.0 total and subscale scores, and Sickness scores during 20 weeks of follow-up, along with child, parent, and provider satisfaction with PediQUEST feedback. Results were as follows: Feedback did not significantly affect average MSAS, PedsQL4.0, or Sickness score trends. Post hoc subgroup analyses among children age ≥ 8 years who survived 20 weeks showed that feedback improved PedsQL4.0 emotional (+8.1; 95% CI, 1.8 to 14.4) and Sickness (−8.2; 95% CI, −14.2 to −2.2) scores. PediQUEST reports were valued by children, parents, and providers and contributed at least sometimes to physician initiation of a psychosocial consult (56%). Conclusion: Although routine feedback of PROs did not significantly affect the child’s symptoms or HRQoL, changes were in expected directions and improvements observed in emotional HRQoL through exploratory analyses were encouraging. Importantly, children, parents, and providers value PRO feedback.

Single versus multiple fractions of repeat radiation for painful bone metastases

Although repeat radiation treatment has been shown to palliate pain in patients with bone metastases from multiple primary origin sites, data for the best possible dose fractionation schedules are lacking. The authors aimed to assess two dose fractionation schedules in patients with painful bone metastases needing repeat radiation therapy. They did a multicenter, non-blinded, randomized, controlled trial in nine countries worldwide. They enrolled patients 18 years or older who had radiologically confirmed, painful (i.e., pain measured as ≥2 points using the Brief Pain Inventory) bone metastases, had received previous radiation therapy, and were taking a stable dose and schedule of pain-relieving drugs (if prescribed). Patients were randomly assigned (1:1) to receive either 8 Gy in a single fraction or 20 Gy in multiple fractions by a central computer-generated allocation sequence using dynamic minimization to conceal assignment, stratified by previous radiation fraction schedule, response to initial radiation, and treatment center. Patients, caregivers, and investigators were not masked to treatment allocation. The primary endpoint was overall pain response at 2 months, which was defined as the sum of complete and partial pain responses to treatment, assessed using both Brief Pain Inventory scores and changes in analgesic consumption. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00080912. Findings: Between Jan 7, 2004, and May 24, 2012, the authors randomly assigned 425 patients to each treatment group. 19 (4%) patients in the 8 Gy group and 12 (3%) in the 20 Gy group were found to be ineligible after randomization, and 140 (33%) and 132 (31%) patients, respectively, were not assessable at 2 months and were counted as missing data in the intention-to-treat analysis. In the intention-to-treat population, 118 (28%) patients allocated to 8 Gy treatment and 135 (32%) allocated to 20 Gy treatment had an overall pain response to treatment (p=0•21; response difference of 4•00% [upper limit of the 95% CI 9•2, less than the prespecified non-inferiority margin of 10%]). In the per-protocol population, 116 (45%) of 258 patients and 134 (51%) of 263 patients, respectively, had an overall pain response to treatment (p=0•17; response difference 6•00% [upper limit of the 95% CI 13•2, greater than the prespecified non-inferiority margin of 10%]). The most frequently reported acute radiation-related toxicities at 14 days were lack of appetite (201 [56%] of 358 assessable patients who received 8 Gy vs. 229 [66%] of 349 assessable patients who received 20 Gy; p=0•011) and diarrhea (81 [23%] of 357 vs. 108 [31%] of 349; p=0•018). Pathological fractures occurred in 30 (7%) of 425 patients assigned to 8 Gy and 20 (5%) of 425 assigned to 20 Gy (odds ratio [OR] 1•54, 95% CI 0•85—2•75; p=0•15), and spinal cord or cauda equina compressions were reported in seven (2%) of 425 versus two (<1%) of 425, respectively (OR 3•54, 95% CI 0•73—17•15; p=0•094). Interpretation: In patients with painful bone metastases requiring repeat radiation therapy, treatment with 8 Gy in a single fraction seems to be non-inferior and less toxic than 20 Gy in multiple fractions; however, as findings were not robust in a per-protocol analysis, trade-offs between efficacy and toxicity might exist.

Long-term responders and survivors on pazopanib for advanced soft tissue sarcomas

Pazopanib recently received approval for the treatment of certain soft tissue sarcoma (STS) subtypes. We conducted a retrospective analysis on pooled data from two EORTC trials on pazopanib in STS in order to characterize long-term responders and survivors. Patients and methods: Selected patients were treated with pazopanib in phase II (n = 118) and phase III study (PALETTE) (n = 226). Combined median progression-free survival (PFS) was 4.4 months; the median overall survival (OS) was 11.7 months. Thirty-six percent of patients had a PFS ≥ 6 months and were defined as long-term responders; 34% of patients survived ≥18 months, defined as long-term survivors. Patient characteristics were studied for their association with long-term outcomes. Results: The median follow-up was 2.3 years. Patient characteristics were compared among four subgroups based on short-/long-term PFS and OS, respectively. Seventy-six patients (22.1%) were both long-term responders and long-term survivors. The analysis confirmed the importance of known prognostic factors in metastatic STS patients treated with systemic treatment, such as performance status and tumor grading, and additionally hemoglobin at baseline as new prognostic factor. We identified 12 patients (3.5%) remaining on pazopanib for more than 2 years: nine aged younger than 50 years, nine females, four with smooth muscle tumors and nine with low or intermediate grade tumors at initial diagnosis. The median time on pazopanib in these patients was 2.4 years with the longest duration of 3.7 years. Conclusions: Thirty-six percent and 34% of all STS patients who received pazopanib in these studies had a long PFS and/or OS, respectively. For more than 2 years, 3.5% of patients remained progression free under pazopanib. Good performance status, low/intermediate grade of the primary tumor and a normal hemoglobin level at baseline were advantageous for long-term outcome.

Mid-Therapy FDG PET and Sarcoma Patient Outcome

Our previous research investigated the ability of [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging results to predict outcome in patients with sarcoma. Tumor uptake of FDG before and after neoadjuvant chemotherapy was predictive of patient outcome. With this background, a prospective clinical study was designed to assess whether tumor FDG uptake levels in the middle of neoadjuvant chemotherapy added additional prognostic information to pre-therapy imaging data. Methods: Sixty-five patients with either bone or soft-tissue sarcoma were treated with neoadjuvant-based chemotherapy according to the standard clinical practice for each tumor group. All patients had FDG PET studies before therapy, mid-therapy (after two cycles of chemotherapy), and before resection. Tumor FDG uptake (SUVmax, the maximum standardized uptake value) at each imaging time point, tumor type (bone or soft-tissue sarcoma), tumor size, and histopathologic grade were recorded for each patient. The time from the pre-therapy FDG PET study to events of local tumor recurrence, metastasis, or death were extracted from the clinical records for comparison with the imaging data. Univariate and multivariate analyses of the imaging and clinical data were performed. Results: Univariate and multivariate data analyses showed that the difference (measured as the percentage reduction) between the pre-therapy and mid-therapy maximum tumor uptake values added prognostic value to patient outcome predictions independently of other patient variables. Conclusions: The utility of a tumor pre-therapy FDG PET scan as a biomarker for the outcome of patients with sarcoma was strengthened by a mid-therapy scan to evaluate the interim treatment response.

A Phase II trial of PM00104 in Ewing's Sarcoma

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m2 on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. Results were as follows: No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9–3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. Conclusion: PM00104 showed modest activity in Ewing sarcoma at 2 mg/m2 on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.

Pazopanib and Ifosfamide: Results of a Phase I Study

The vascular endothelial growth factor receptor (VEGFR) pathway plays a pivotal role in solid malignancies and is probably involved in chemotherapy resistance. Pazopanib, inhibitor of, among other receptors, VEGFR1–3, has activity as single agent and is attractive to enhance anti-tumor activity of chemotherapy. The investigators of this trial conducted a dose-finding and pharmacokinetic and pharmacodynamics study of pazopanib combined with two different schedules of ifosfamide. In a 3+3+3 design, patients with advanced solid tumors received escalating doses of oral pazopanib combined with ifosfamide either given 3 days continuously or given 3-h bolus infusion daily for 3 days (9gm−2 per cycle, every 3 weeks). Pharmacokinetic data of ifosfamide and pazopanib were obtained. Plasma levels of placental-derived growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), soluble VEGFR2 (sVEGFR2) and circulating endothelial cells were monitored as biomarkers. Results were as follows: Sixty-one patients were included. Pazopanib with continuous ifosfamide infusion appeared to be safe up to 1000mg per day, while combination with bolus infusion ifosfamide turned out to be too toxic based on a variety of adverse events. Ifosfamide-dependent decline in pazopanib exposure was observed. Increases in PlGF and VEGF-A with concurrent decline in sVEGFR2 levels, consistent with pazopanib-mediated VEGFR2 inhibition, were observed after addition of ifosfamide. Conclusion: Continuous as opposed to bolus infusion ifosfamide can safely be combined with pazopanib. Ifosfamide co-administration results in lower exposure to pazopanib, not hindering biological effects of pazopanib. Recommended dose of pazopanib for further studies combined with 3 days continuous ifosfamide (9gm−2 per cycle, every 3 weeks) is 800mg daily.

Phase 1 Study of the Oral Hedgehog Inhibitor Sonidegib (LDE225)

This phase 1 trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog (Hh) signaling, in patients with advanced solid tumors. Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma (MB) and basal cell carcinoma (BCC), at doses ranging from 100 to 3000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose PK run-in period. Dose-escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, PK, and biomarkers in skin and tumor biopsies were assessed. Results were as follows: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear PK at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with MB and BCC were associated with evidence of Hh pathway activation. Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed MB, which is strongly associated with activated Hh pathway, as determined by gene expression.

Immunologic response to the survivin-derived multi-epitope vaccine EMD640744

Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses. This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide® ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy. Results were as follows: In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event. Conclusions: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

Stereotactic Body Radiation for Spinal Metastases : Phase 1—2 Trial

Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the technique's effectiveness in controlling the symptom burden of spinal metastases has not been well described. The investigators studied the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms. 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1—2 study. Patients received a total dose of 27—30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered with ClinicalTrials.gov, number NCT00508443. Findings: Median follow-up was 15·9 months (IQR 9·5—30·3). The number of patients reporting no pain from bone metastases, as measured by the BPI, increased from 39 of 149 (26%) before SBRT to 55 of 102 (54%) 6 months after SBRT (p<0·0001). BPI-reported pain reduction from baseline to 4 weeks after SBRT was clinically meaningful (mean 3·4 [SD 2·9] on the BPI pain-at-its-worst item at baseline, 2·1 [2·4] at 4 weeks; effect size 0·47, p=0·00076). These improvements were accompanied by significant reduction in opioid use during the first 6 months after SBRT (43 [28·9%] of 149 patients with strong opioid use at baseline vs. 20 [20·0%] of 100 at 6 months; p=0·011). Ordinal regression modelling showed that patients reported significant pain reduction according to the MDASI during the first 6 months after SBRT (p=0·00003), and significant reductions in a composite score of the six MDASI symptom interference with daily life items (p=0·0066). Only a few instances of non-neurological grade 3 toxicities occurred: nausea (one event), vomiting (one), diarrhea (one), fatigue (one), dysphagia (one), neck pain (one), and diaphoresis (one); pain associated with severe tongue oedema and trismus occurred twice; and non-cardiac chest pain was reported three times. No grade 4 toxicities occurred. Progression-free survival after SBRT was 80·5% (95% CI 72·9—86·1) at 1 year and 72·4% (63·1—79·7) at 2 years. Interpretation: SBRT is an effective primary or salvage treatment for mechanically stable spinal metastasis. Significant reductions in patient-reported pain and other symptoms were evident 6 months after SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities.

EGFR T790M mutations and BIM mRNA expression in the phase III EURTAC trial

Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) in patients harboring activating EGFR mutations. In this study the investigators evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations and BIM mRNA expression in 95 patients with EGFR-mutant NSCLC included in the EURTAC trial (trial registration: NCT00446225). Results were as follows: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and PNA-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, while among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P<0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BIM expression levels, while among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P=0.0003). Overall survival was 28.6 months for patients with high BIM expression and 22.1 months for those with low/intermediate BIM expression (P=0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (hazard ratio [HR]=0.35; P=0.0003), while high BIM expression was a marker of longer PFS (HR=0.49; P=0.0122) and overall survival (HR=0.53; P=0.0323). Conclusions: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BIM mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies.

Baseline circulating VEGF-A in patients with vascular sarcomas receiving sorafenib

The investigators of this study carried out a stratified phase II study of sorafenib (So) in patients with advanced angiosarcoma (n=32) and epithelioid hemangioendothelioma (n=13). This report concerns the correlative analysis of the predictive values of circulating pro/anti-angiogenetic biomarkers. Using the ELISA method (R&D Systems), circulating biomarkers (VEGF-A, in picograms per milliliter), thrombospondin-1 (TSP1, in micrograms per milliliter), stem cell factor (SCF, in picograms per milliliter), placental growth factor (PlGF, in picograms per milliliter), VEGF-C (in picograms per milliliter), and E-selectin (in nanograms per milliliter) were measured before So treatment and after 7 days. VEGF-A (mean value 475 vs. 541, p=0.002), TSP1 (16 vs. 24, p=0.0002), and PlGF (20.9 vs. 40.7, p=0.0001) significantly increased during the treatment. Treatment did not affect the levels of SCF, VEGF-C, and E-selectin. Only two biomarkers were associated with better outcome as follows: VEGF-A and PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p=0.04 and 0.03, respectively). There was a correlation between the circulating level of VEGF-A and time to progression (TTP) (r=−0.47, p=0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PIGF, but there was a correlation between the circulating level of PIGF at baseline and TTP. Low level of VEGF-A at baseline (<500) was significantly associated with better outcome.

GDC-0449 in patients with advanced chondrosarcomas

Pre-clinical data have suggested a therapeutic role of Hedgehog (Hh) pathway inhibitors in chondrosarcoma. This phase II trial included patients with progressive advanced chondrosarcoma. They received GDC-0449 150 mg/day (days 1–28, 28-day cycle). The primary end point was the 6-month clinical benefit rate (CBR) defined as the proportion of patients with non-progressive disease at 6 months. A 6-month CBR of 40% was considered as a reasonable objective to claim drug efficacy. Results were as follows: Between February 2011 and February 2012, 45 patients were included. Twenty had received prior chemotherapy. Thirty-nine were assessable for efficacy. The 6-month CBR was 25.6% (95% confidence interval 13.0–42.1). All stable patients had grade 1 or 2 conventional chondrosarcoma with documented progression within the 6 months before inclusion. All but one with available data also had overexpression of the Hh ligand. Median progression-free and overall survivals were 3.5 and 12.4 months, respectively. The most frequent adverse events were grade 1 or 2 myalgia, dysgeusia and alopecia. Conclusions: GDC-0449 did not meet the primary end point of this trial. Results suggest some activity in a subset of patients with progressive grade 1 or 2 conventional chondrosarcoma. Further studies assessing its role in combination with chemotherapy are warranted.

Neo-adjuvant imatinib in advanced or recurrent DFSP

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous tumor. COL1A1-PDGFB gene fusion is frequent in DFSP, rendering tumor cell proliferation and survival dependent on PDGFRB signaling. This trial investigated imatinib as neo-adjuvant treatment of DFSP including long-term follow-up. The primary endpoint of this multicenter phase-II trial was response; secondary endpoints were safety, tumor relapse, and response biomarkers. Patients with advanced primary or locally recurrent DFSP and measurable disease by RECIST were eligible and received imatinib 600 mg/d until definitive surgery with histopathological proof of tumor-free margins. Results were as follows: 16 patients received imatinib; 14 patients were evaluable for all endpoints. Median treatment duration was 3.1 months; median tumor shrinkage was 31.5%. Best overall response was 7.1% CR, 50.0% PR, 35.7% SD, and 7.1% PD. Toxicity was moderate with 25.0% grade 3-4 events. During a median follow-up of 6.4 years, one patient developed secondary resistance to imatinib but responded to second-line sunitinib. This patient also presented local recurrence, distant metastasis and death from DFSP. Exploratory analysis showed that response to imatinib was associated with decreased tumor cellularity and formation of strong hyalinic fibrosis. Weak PDGFRB phosphorylation and pigmented-type DFSP were associated with non-response. Additional to PDGFRB, the kinases EGFR and insulin receptor were found activated in a high percentage of DFSPs. Conclusion: The neo-adjuvant use of imatinib 600 mg/d in DFSP is efficacious and well-tolerated. Long-term follow-up results do not definitely support smaller surgical margins after successful imatinib pre-treatment, and presume that secondary resistance to imatinib might promote accelerated disease progression.

Phase 2 trial of aromatase inhibition with letrozole in ULMS

Advanced uterine leiomyosarcoma (ULMS) is an incurable disease. A significant percentage of cases of ULMS express estrogen and/or progesterone receptors (ER and/or PR). To the authors' knowledge, the role of estrogen suppression in disease management is not known. The authors performed a single-arm phase 2 study of the aromatase inhibitor letrozole at a dose of 2.5 mg daily in patients with unresectable ULMS with ER and/or PR expression confirmed by immunohistochemistry. Tumor assessments were performed at baseline, 6 weeks, 12 weeks, and every 8 weeks thereafter. Toxicity was monitored throughout treatment. The primary endpoint was the progression-free survival at 12 weeks. Results were as follows: A total of 27 patients were accrued, with a median of 2 prior treatment regimens (range, 0-9 treatment regimens). The median duration of protocol treatment was 2.2 months (range, 0.4 months-9.9 months). The 12-week progression-free survival rate was 50% (90% confidence interval, 30%-67%). The best response was stable disease in 14 patients (54%; 90% CI, 36%-71%). Three patients, all of whom had tumors expressing ER and PR in>90% of tumor cells, continued to receive letrozole for>24 weeks. The most common reason for treatment discontinuation was disease progression (85%). Letrozole was found to be well tolerated. Conclusions: Letrozole met protocol-defined criteria as an agent with activity in patients with advanced ULMS. Patients with the longest progression-free survival rate were those whose tumors strongly and diffusely expressed ER and PR.

A phase II trial of an oral antiangiogenic (metronomic) regimen in children

Preclinical models show that an antiangiogenic regimen at low-dose daily (metronomic) dosing may be effective against chemotherapy-resistant tumors. The investigators of this study undertook a prospective, open-label, single-arm, multi-institutional phase II study to evaluate the efficacy of a “5-drug” oral regimen in children with recurrent or progressive cancer. Patients ≤21 years old with recurrent or progressive tumors were eligible. Treatment consisted of continuous oral celecoxib, thalidomide, and fenofibrate, with alternating 21-day cycles of low-dose cyclophosphamide and etoposide. Primary endpoint was to assess, within eight disease strata, activity of the 5-drug regimen over 27 weeks. Blood and urine angiogenesis markers were assessed. Results were as follows: One hundred one patients were enrolled; 97 began treatment. Median age was 10 years (range: 191 days–21 years); 47 (49%) were female. Disease strata included high-grade glioma (HGG, 21 patients), ependymoma (19), low-grade glioma (LGG, 12), bone tumors (12), medulloblastoma/primitive neuroectodermal tumor (PNET, 8), leukemia (4), neuroblastoma (3), and miscellaneous tumors (18). Treatment was generally well tolerated; most common toxicities were hematologic. Twenty-four (25%) patients completed 27 weeks therapy without progression, including HGG: 1 (5%), ependymoma: 7 (37%), LGG: 7 (58%), medulloblastoma/PNET: 1, neuroblastoma: 1, and miscellaneous tumors: 7 (39%). Best response was complete response (one patient with medulloblastoma), partial response (12), stable disease (36), progressive disease (47), and inevaluable (1). Baseline serum thrombospondin levels were significantly higher in patients successfully completing therapy than in those who progressed (P=0.009). Conclusion: The 5-drug regimen was well tolerated. Clinical activity was demonstrated in some but not all tumor strata.

Activity endpoints reported in STS phase II trials

Despite extensive research over the past 3 decades, few investigational drugs are considered as promising and these drugs failed to improve overall survival. Therefore the authors of this study performed a systematic review of the literature to improve our understanding of the reasons that explain these failures. They reviewed 53 phase II trial reports that investigated new treatments in patients with advanced soft tissue sarcoma from 1999 to 2011. They critically reviewed the selected primary endpoint used in these trials. Results were as follows: Forty percent of trials were not interpretable because of major inherent methodological flaws. Only 3 primary endpoints were correlated with median overall survival (mOS): 3- and 6-month progression free rates and median progression-free survival. Nevertheless, the mOS was not significantly higher in the cases of active drugs. Discussion: We need to improve the definition of primary active endpoints and develop better designs for future trials. The current definition of promising drugs must be refined.

Preoperative chemoradiation plus sorafenib for extremity STS

The investigators of this trial conducted a phase I trial of the addition of sorafenib to a chemoradiotherapy regimen in patients with high-risk (intermediate/high grade, >5 cm) extremity soft tissue sarcoma undergoing limb salvage surgery. They conducted a correlative study of quantitative dynamic contrast-enhanced MRI (DCE-MRI) to assess response to treatment. Patients were treated at increasing dose levels of sorafenib (200 mg daily, 400 mg daily, 400 mg twice daily) initiated 14 days before three preoperative and three postoperative cycles of epirubicin/ifosfamide. Radiation (28 Gy) was administered during cycle 2 with epirubicin omitted. The primary objective was to determine the maximum tolerated dose (MTD) of sorafenib. DCE-MRI was conducted at baseline, after 2 weeks of sorafenib, and before surgery. The imaging data were subjected to quantitative pharmacokinetic analyses. Results were as follows: Eighteen subjects were enrolled, of which 16 were evaluable. The MTD of sorafenib was 400 mg daily. Common grade 3–4 adverse events included neutropenia (94%), hypophosphatemia (75%), anemia (69%), thrombocytopenia (50%), and neutropenic fever/infection (50%). Of note, 38% developed wound complications requiring surgical intervention. The rate of ≥95% histopathologic tumor necrosis was 44%. Changes in DCE-MRI biomarker ΔKtrans after 2 weeks of sorafenib correlated with histologic response (R2 = 0.67, P = 0.012) at surgery. Conclusion: The addition of sorafenib to preoperative chemoradiotherapy is feasible and warrants further investigation in a larger trial. DCE-MRI detected changes in tumor perfusion after 2 weeks of sorafenib and may be a minimally invasive tool for rapid assessment of drug effect in soft tissue sarcoma.

Tumor growth rate an early indicator of antitumor activity in phase I trials

Response Evaluation Criteria in Solid Tumors (RECIST) evaluation does not take into account the pretreatment tumor kinetics and may provide incomplete information about experimental drug activity. Tumor growth rate (TGR) allows for a dynamic and quantitative assessment of the tumor kinetics. How TGR varies along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. In this study, medical records from all patients (N 1⁄4 253) prospectively treated in 20 phase I trials were analyzed. TGR was computed during the pretreatment period (reference) and the experimental period. Associations between TGR, standard prognostic scores [Royal Marsden Hospital (RMH) score], and outcome [progression-free survival (PFS) and overall survival (OS)] were computed (multivariate analysis). Results were as follows: The investigators observed a reduction of TGR between the reference versus experimental periods (38% vs. 4.4%; P < 0.00001). Although most patients were classified as stable disease (65%) or progressive disease (25%) by RECIST at the first evaluation, 82% and 65% of them exhibited a decrease in TGR, respectively. In a multivariate analysis, only the decrease of TGR was associated with PFS (P 1⁄4 0.004), whereas the RMH score was the only variable associated with OS (P 1⁄4 0.0008). Only the investigated regimens delivered were associated with a decrease of TGR (P < 0.00001, multivariate analysis). Computing TGR profiles across different clinical trials reveals specific patterns of antitumor activity. Conclusions: Exploring TGR in phase I patients is simple and provides clinically relevant information: (i) an early and subtle assessment of signs of antitumor activity; (ii) independent association with PFS; and (iii) it reveals drug-specific profiles, suggesting potential utility for guiding the further development of the investigational drugs.

A phase 1 trial of imetelstat in children with solid tumors

Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC ) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase 2 dose of imetelstat in children with recurrent or refractory solid tumors. Imetelstat was administered intravenously over two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m2 were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle. Results were as follows: Twenty subjects were enrolled (median age 14 years, range 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in two of six patients at 360 mg/m2. Pharmacokinetics were dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m2. Two confirmed partial responses osteosarcoma (n=1) and Ewing sarcoma (n=1) were observed. Conclusions: The recommended phase 2 dose of imetelstat given on days 1 and 8 of 21-day cycle is 285 mg/m2.

Phase I trial of sorafenib with ifosfamide in advanced sarcoma

This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m2 respectively). A 3+3 dose escalation design with cohorts of 3–6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. Results were as follows: Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m2 and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m2. Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. Conclusions: RD was sorafenib 400 mg bid plus ifosfamide 6 g/m2, allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.

Phase I study of pazopanib in patients with hepatic dysfunction

Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 3+3 design was used. Results were as follows: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0–24)] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose–proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)–approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day.

The US postmarketing surveillance study of adult osteosarcoma and teriparatide

The Osteosarcoma Surveillance Study, an ongoing 15-year surveillance study initiated in 2003, is a postmarketing commitment to the United States (US) Food and Drug Administration to evaluate a potential association between teriparatide, rhPTH(1–34), a recombinant human parathyroid hormone analog (self-injectable medication to treat osteoporosis), and development of osteosarcoma in response to a finding from preclinical (animal) studies. Incident cases of primary osteosarcoma diagnosed in adults (aged ≥40 years) on or after January 1, 2003, are identified through population-based state, regional, and comprehensive cancer center registries in the US. Information on possible prior treatment with teriparatide, on demographics, and on risk factors is ascertained by patient or proxy telephone interview after patient consent. Between June 2004 and September 30, 2011, 1448 cases (diagnosed 2003 to 2009) were identified by participating cancer registries (estimated to be 62% of all adult cases in the US for that time period); 549 patients or proxies were interviewed. Interviewed patients were similar to noninterviewed patients with regard to mean age, sex, race, and geographical distribution and tumor type and site of tumor. Mean age of those interviewed was 61 years, 46% were female, 86% were white, and 77% were alive when the case was reported to the study investigators. Data collected in the study provide descriptive information on a large number of adults with osteosarcoma, an uncommon malignant bone tumor. After 7 years of the study, there were no osteosarcoma patients who had a prior history of teriparatide treatment. Thus, approximately halfway through this 15-year study, the study has not detected a pattern indicative of a causal association between teriparatide treatment and osteosarcoma in humans.