Efficacy of trabectedin in malignant solitary fibrous tumors: a retrospective analysis from the French Sarcoma Group.

BACKGROUND: Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs. METHODS: Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m(2), q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan-Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1). RESULTS: Eleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11-4.12). CONCLUSION: Trabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.

A phase IIb multicentre study comparing the efficacy of trabectedin to doxorubicin in patients with advanced or metastatic untreated soft tissue sarcoma: the TRUSTS trial.

PURPOSE: To evaluate whether trabectedin as first-line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression-free survival (PFS), compared to doxorubicin and, in the phase IIb part here, to select the most appropriate trabectedin treatment schedule (3-hour or 24-hour infusion) in terms of safety, convenience and efficacy. PATIENTS AND METHODS: In this randomised multicentre prospective dose-selection phase IIb superiority trial, 133 patients were randomised between doxorubicin (n=43), trabectedin (3-hour infusion, T3h) (n=47) and trabectedin (24-hour infusion, T24h) (n=43). PFS was defined as time from random assignment until objective progression by response evaluation criteria in solid tumours (RECIST 1.1), a global deterioration of the health status requiring discontinuation of the treatment, or death from any cause. RESULTS: The study was terminated due to lack of superiority in both trabectedin treatment arms as compared to the doxorubicin control arm. Median PFS was 2.8months in the T3h arm, 3.1months in the T24h arm and 5.5months in the doxorubicin arm. No significant improvements in PFS were observed in the trabectedin arms as compared to the doxorubicin arm (T24h versus doxorubicin: hazard ratio (HR) 1.13, 95% confidence interval (CI) 0.67-1.90, P=.675; T3h versus doxorubicin: HR 1.50, 95% CI 0.91-2.48, P=.944). Only one toxic death occurred in the T3h arm, but treatment had to be stopped due to toxicity in 7 (15.2%) (T3h), 8 (19.5%) (T24h) and 1 (2.5%) doxorubicin patients. CONCLUSION: Doxorubicin continues to be the standard treatment in eligible patients with advanced/metastatic soft-tissue sarcoma (STS). Trabectedin 1.5mg/m(2)/24-hour infusion is the overall proven approach to delivering this agent in the second-line setting for patients with advanced or metastatic STS.

Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: a randomized controlled open-label trial.

BACKGROUND: Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance. PATIENTS AND METHODS: Prospective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI. RESULTS: Forty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833). CONCLUSIONS: Primary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.

A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours.

BACKGROUND: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. METHODS: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. RESULTS: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). CONCLUSION: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

Correlation between overall survival and growth modulation index in pre-treated sarcoma patients: a study from the French Sarcoma Group.

BACKGROUND: Growth modulation index (GMI), the ratio of two times to progression measured in patients receiving two successive treatments (GMI = TTP2/TTP1), has been proposed as a criterion of phase II clinical trials. Nevertheless, its use has been limited until now. PATIENTS AND METHODS: We carried out a retrospective multicentre study in soft tissue sarcoma patients receiving a second-line treatment after doxorubicin-based regimens to evaluate the link between overall survival and GMI. Second-line treatments were classified as 'active' according to the EORTC-STBSG criteria (3-month progression-free rate >40% or 6-month PFR >14%). Comparisons used chi-squared and log-rank tests. RESULTS: The population consisted in 106 men and 121 women, 110 patients (48%) received 'active drugs'. Median OS from the second-line start was 317 days. Sixty-nine patients experienced GMI >1.33 (30.4%). Treatments with 'active drug' were not associated with OS improvement: 490 versus 407 days (P = 0.524). Median OS was highly correlated with GMI: 324, 302 and 710 days with GMI <1, GMI = [1.00-1.33], and GMI >1.33, respectively (P < 0.0001). In logistic regression analysis, the sole predictive factor was the number of doxorubicin-based chemotherapy cycles. CONCLUSION: GMI seems to be an interesting end point that provides additional information compared with classical criteria. GMI >1.33 is associated with significant OS improvement.

Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib.

BACKGROUND: This phase III open-label trial investigated the efficacy of nilotinib in patients with advanced gastrointestinal stromal tumors following prior imatinib and sunitinib failure. PATIENTS AND METHODS: Patients were randomized 2:1 to nilotinib 400 mg b.i.d. or best supportive care (BSC; BSC without tyrosine kinase inhibitor, BSC+imatinib, or BSC+sunitinib). Primary efficacy end point was progression-free survival (PFS) based on blinded central radiology review (CRR). Patients progressing on BSC could cross over to nilotinib. RESULTS: Two hundred and forty-eight patients enrolled. Median PFS was similar between arms (nilotinib 109 days, BSC 111 days; P=0.56). Local investigator-based intent-to-treat (ITT) analysis showed a significantly longer median PFS with nilotinib (119 versus 70 days; P=0.0007). A trend in longer median overall survival (OS) was noted with nilotinib (332 versus 280 days; P=0.29). Post hoc subset analyses in patients with progression and only one prior regimen each of imatinib and sunitinib revealed a significant difference in median OS of >4 months in favor of nilotinib (405 versus 280 days; P=0.02). Nilotinib was well tolerated. CONCLUSION: In the ITT analysis, no significant difference in PFS was observed between treatment arms based on CRR. In the post hoc subset analyses, nilotinib provided significantly longer median OS.

A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma.

BACKGROUND: Osteosarcoma is the most common primary malignant tumour in young adults. An effective treatment strategy for relapsed patients is still not defined. Pemetrexed is a multitargeted antifolate with a mode of action similar to, and a range of action broader than that of methotrexate. The primary objective of this phase II study was to determine tumour response rate in patients with high-grade, advanced/metastatic osteosarcoma. Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety. METHODS: Pemetrexed 500mg/m(2) was administered on day 1 of 21-day cycles with folic acid and vitamin B(12) supplementation. At least 5 tumour responses in a targeted population of 32 were required to consider further investigation. RESULTS: Thirty-two patients (median age, 43.3 years; range, 18.6-76.0) with 1 prior chemotherapy regimen for high-grade advanced/metastatic osteosarcoma were enrolled. Thirty (93.8%) patients had an ECOG performance status ≤ 1 and 29 (90.6%) had metastases in the lung. One patient had partial response (3.1%) and 5 (15.6%) had stable disease. Median PFS and OS were 1.4 months (95% CI: 1.4-1.7) and 5.5 months (95% CI: 2.3-10.5), respectively. The most common drug-related grade 3/4 toxicities were leukopaenia, asthaenia and elevated alanine aminotransferase in 3 (9.4%) patients each. One patient died due to multi-organ failure considered possibly related to the study drug. CONCLUSIONS: Pemetrexed 500mg/m(2) administered on day 1 of 21-day cycles as second-line treatment to patients with advanced/metastatic high-grade osteosarcoma was generally well tolerated but did not meet minimal response expectations for further investigation in this patient population.

High-dose chemotherapy consolidation for chemosensitive advanced soft tissue sarcoma patients: an open-label, randomized controlled trial.

BACKGROUND: Metastatic soft tissue sarcoma (STS) prognosis remains poor and few cytotoxic agents offer proven efficacy. This randomized open phase III study examines whether high-dose (HD) chemotherapy with peripheral blood stem cells (PBSCs) could improve overall survival (OS) of chemosensitive patients. PATIENTS AND METHODS: Advanced STS patients aged 18-65 years received four courses of standard mesna, adryamycin, ifosfamide and dacarbazine (MAID) treatment. Chemotherapy-responding patients and patients with at least stable disease amenable to complete surgical resection were randomized to receive standard dose (SD) with two successive MAID cycles or HD treatments of one MAID then MICE intensification: mesna (3.6 g/m(2), day 1-5), ifosfamide (2.5 g/m(2), day 1-4), carboplatin [area under the curve (AUC) 5/day 2-4] and etoposide (300 mg/m(2), day 1-4) with PBSC reinjection at day 7. RESULTS: From 2000 to 2008, 207 patients received four cycles of MAID and 87 assessable patients were randomly assigned to receive the following: 46 SD, 41 HD, with 45 and 38 maintained for analyses after secondary centralized histological review. Futility analyses led to study closure in November 2008. Three-year OS was 49.4% for the SD group versus 32.7% for HD arm, hazard ratio= 1.26, 95% confidence interval 0.70-2.29; progression-free survival was 32.4% and 14.0%, respectively. HD treatment led to higher grades 3-4 toxicity. CONCLUSION: This study failed to show an OS advantage for advanced STS patients treated with dose-intensified chemotherapy with PBSC.

[Adjuvant chemotherapy of adults soft tissue sarcomas]. / Chimiothérapie adjuvante des sarcomes des tissus mous de l'adulte.

The main progress in the management of soft tissue sarcomas have been obtained in the field of local control. Although the main evolutive, vital, risk of these diseases is metastatic dissemination, efficacy of adjuvant chemotherapy remains a controversial issue. Thus, adjuvant chemotherapy cannot be considered as a standard for any situation. The last results of clinical trials, meta-analysis and population studies are presented and discussed in this article. New therapeutic strategies are to be developed to prevent metastases in soft tissue sarcomas. This needs a better understanding of the biology of those tumors, of metastases risk factors and of the determinants of systemic therapies efficacy in these tumors.

[Chemotherapy options for patients with advanced soft-tissue sarcoma beyond anthracyclines]. / Prise en charge des sarcomes des tissus mous avancés : quelle chimiothérapie après échappement aux anthracyclines?

Doxorubicin monotherapy is the standard first-line treatment in patients with advanced soft-tissue sarcomas. Ifosfamide still remains the standard 2nd line treatment after doxorubicin-failure. However, recent data have demonstrated that histological subtypes differ in their sensitivity to cytotoxic drugs. Therefore, gemcitabine should be considered as the best option after doxorubicin failure in leiomyosarcoma patients. Trabectedine should be used preferentially in myxoid liposarcomas and leiomyosarcomas patients whereas paclitaxel should be considered as a first or second-line treatment of choice in angiosarcoma patients. Further studies are needed in order to identify predictive factors of clinical benefit in advanced soft-tissue sarcoma patients treated with cytotoxic agents in combination or not with targeted therapies.