Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma.

BACKGROUND: This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. METHODS: Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). RESULTS: Forty-seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%-58%), which was superior to the null hypothesis rate of 30%, but the 2-sided P value (exact test) was .09 (1-sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3-35.0 months), and the median progression-free survival was 7.9 months (95% CI, 3.7-12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. CONCLUSIONS: This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.

Multi-institutional analysis of stereotactic body radiotherapy for sarcoma pulmonary metastases: High rates of local control with favorable toxicity.

BACKGROUND/OBJECTIVES: Oligometastatic sarcoma pulmonary metastases (PM's) are traditionally treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) is an effective, safe alternative to surgery that can achieve excellent local control (LC) with a favorable toxicity profile. METHODS: Patients treated with SBRT for sarcoma PM's from 2011 to 2016 at Massachusetts General Hospital and the University of Pennsylvania were included. Median dose was 50 Gy. Patients underwent computed tomography (CT) or positron emission tomography/CT Q3 months post-SBRT. RESULTS: 44 patients with 56 separate PM's were treated with SBRT. Median age was 59 (range 19-82). 82% received prior chemotherapy, 66% had prior pulmonary resections (range, 1-5 resections), and 32% received prior thoracic radiotherapy. Median lesion size was 2.0 cm (range, 0.5-8.1 cm). Median follow-up was 16 months and 25 months for patients alive at last follow-up. Overall survival at 12 and 24 months was 74% (95% confidence interval [CI], 67%-81%) and 46% (95% CI, 38%-55%). LC at 12 and 24 months was 96% (95% CI, 93%-98%) and 90% (95% CI, 84%-96%). LC and overall survival did not differ based on age, gender, histology, fractionation, lesion location, or size (P > .05). Three developed Common Terminology Criteria for Adverse Events version 4 grade-2 chest-wall toxicities; one had grade-2 pneumonitis. CONCLUSIONS: In the first multi-institutional series on SBRT for sarcoma PM's, SBRT has excellent LC and is well-tolerated. SBRT should be considered as an alternative/complement to resection.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor.

BACKGROUND: Expression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R). METHODS: Using x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor. RESULTS: A total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment. CONCLUSIONS: Treatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.).

Results of a prospective phase 2 study of pazopanib in patients with advanced intermediate-grade or high-grade liposarcoma.

BACKGROUND: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma. METHODS: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12). RESULTS: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy. CONCLUSIONS: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society.

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor.

BACKGROUND: Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS: The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS: One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS: Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2017;90-97. © 2016 American Cancer Society.

Efficacy and safety of trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline-based chemotherapy: Subgroup analysis of a phase 3, randomized clinical trial.

OBJECTIVE: Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). METHODS: Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m2 by 24-hour IV infusion or dacarbazine 1g/m2 by 20-120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. RESULTS: PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41-0.81; P=0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65-1.24; P=0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine (P=0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine (P=0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine (P=0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. CONCLUSIONS: In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.

SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma.

BACKGROUND: Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma. METHODS: Patients received dasatinib twice daily. The primary objective was to estimate the clinical benefit rate (CBR) (complete response or partial response within 6 months or stable disease duration of ≥6 months) with a target of ≥25%. Patients were enrolled into 1 of 7 different cohorts and assessed by imaging every 8 weeks using Choi criteria tumor response and a Bayesian hierarchical design. For each subtype, enrollment was stopped after a minimum of 9 patients were treated if there was a <1% chance the CBR was ≥25%. RESULTS: A total of 200 patients were enrolled. Accrual was stopped early in 5 cohorts because of low CBR. The leiomyosarcoma (LMS) and undifferentiated pleomorphic sarcoma (UPS) cohorts fully accrued and 6 of 47 and 8 of 42 evaluable patients, respectively, exhibited clinical benefit. The probability that the CBR was ≥25% in the LMS and UPS cohorts was 0.008 and 0.10, respectively. The median progression-free survival ranged from 0.9 months in patients with rhabdomyosarcoma to 2.2 months in patients with LMS. The median overall survival was 8.6 months. The most frequent adverse events were constitutional, gastrointestinal, and respiratory, and 36% of patients required dose reduction for toxicity. Serious adverse events attributed to therapy occurred in 11% of patients. CONCLUSIONS: Dasatinib may have activity in patients with UPS but is inactive as a single agent in the other sarcoma subtypes included herein. The Bayesian design allowed for the early termination of accrual in 5 subtypes because of lack of drug activity.

Efficacy and safety of stereotactic body radiation therapy for the treatment of pulmonary metastases from sarcoma: A potential alternative to resection.

BACKGROUND/OBJECTIVES: Oligometastatic sarcoma pulmonary metastases (PM) are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic body radiotherapy (SBRT) can be an alternative to surgery that can achieve high rates of local control (LC) with limited toxicity. METHODS: Thirty consecutive sarcoma patients received SBRT to 39 PM's from 2011 to 2015 at two university hospitals to a median dose of 50 Gy in 4-5 fractions with CyberKnife or linear accelerator. Patients underwent CT or PET/CT scans q3 months after SBRT. RESULTS: 77% received prior chemotherapy, 70% had 1-3 prior pulmonary resections, and 26% received prior thoracic radiotherapy. Median lesion size was 2.4 cm (range 0.5-8.1 cm). Median follow-up was 16 and 23 months for patients alive at last follow-up. At 12 and 24 months, LC was 94% and 86%, and OS was 76% and 43%. LC and OS did not differ by SBRT technique, fractionation regimen, lesion location, histology, or size (all P > 0.05). Three developed grade 2 chest-wall toxicity with no other grade ≥2 toxicities. CONCLUSIONS: This is the largest series on SBRT for sarcoma PM's and demonstrates that SBRT is well-tolerated with excellent LC across tumor locations and sizes. SBRT should be considered in these patients, and prospective studies are warranted. J. Surg. Oncol. 2016;114:65-69. © 2016 Wiley Periodicals, Inc.

Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas. METHODS: We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517. FINDINGS: Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group. INTERPRETATION: The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas. FUNDING: Sanofi.

A phase 2 trial of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF-1R), in patients with recurrent or refractory rhabdomyosarcoma, osteosarcoma, synovial sarcoma, and other soft tissue sarcomas: results of a Sarcoma Alliance for Research Through Collaboration study.

BACKGROUND: Insulin-like growth factor-1 receptor (IGF-1R) is implicated in the pathogenesis of rhabdomyosarcoma (RMS), osteosarcoma (OS), and synovial sarcoma (SS). The authors conducted a multi-institutional phase 2 trial of the monoclonal antibody R1507 in patients with various subtypes of recurrent or refractory sarcomas. METHODS: Eligibility criteria included age ≥ 2 years and a diagnosis of recurrent or refractory RMS, OS, SS, and other soft tissue sarcomas. Patients received a weekly dose of 9 mg/kg R1507 intravenously. The primary endpoint was the best objective response rate using World Health Organization criteria. Tumor imaging was performed every 6 weeks × 4 and every 12 weeks thereafter. RESULTS: From December 2007 through August 2009, 163 eligible patients from 33 institutions were enrolled. The median patient age was 31 years (range, 7-85 years). Histologic diagnoses included OS (n = 38), RMS (n = 36), SS (n = 23), and other sarcomas (n = 66). The overall objective response rate was 2.5% (95% confidence interval, 0.7%-6.2%). Partial responses were observed in 4 patients, including 2 patients with OS, 1 patient with RMS, and 1 patient with alveolar soft part sarcoma. Four additional patients (3 with RMS and 1 with myxoid liposarcoma) had a ≥ 50% decrease in tumor size that lasted for <4 weeks. The median progression-free survival was 5.7 weeks, and the median overall survival was 11 months. The most common grade 3/4 toxicities were metabolic (12%), hematologic (6%), gastrointestinal (4%), and general constitutional symptoms (8%). CONCLUSIONS: R1507 is safe and well tolerated but has limited activity in patients with recurrent or refractory bone and soft tissue sarcomas. Additional studies to help identify the predictive factors associated with clinical benefit in selected histologies such as RMS appear to be warranted.