Activity of TNT: a phase 2 study using talimogene laherparepvec, nivolumab and trabectedin for previously treated patients with advanced sarcomas (NCT# 03886311).

Background: Intratumoral injection of talimogene laherparepvec evokes a cytotoxic immune response. Therefore, the combination of talimogene laherparepvec with trabectedin and nivolumab may have synergistic effects in advanced sarcomas. Patients and methods: This phase 2 trial was conducted from May 30, 2019 to January 31, 2022. Endpoints: Primary: Progression free survival rate at month 12. Secondary: Best overall response, progression free survival rate at 6 and 9 months, overall survival rate at 6, 9, and 12 months, incidence of conversion of an unresectable tumor to a resectable tumor, and incidence of adverse events. Eligible patients had to be ≥ 18 years of age, have advanced histologically proven sarcoma, at least 1 previous chemotherapy regimen, and at least one accessible tumor for intratumoral injection. Treatment: Trabectedin intravenously (1.2 mg/m2 q3 weeks), nivolumab intravenously (3 mg/kg q2 weeks), and intratumoral talimogene laherparepvec (1x108 plaque forming units/ml q2 weeks). Results: Median time of follow-up: 15.2 months. Efficacy analysis: Thirty-nine patients who had completed at least one treatment cycle and had a follow-up computerized tomography were evaluable for efficacy analysis. Median number of prior therapies: 4 (range 1-11). Progression free survival rate at month 12, 36.7%. Confirmed Best Overall Response by Response Evaluation Criteria in Solid Tumors v1.1 = 3 partial responses, 30 stable disease, 6 progressive disease. Best Overall Response Rate, 7.7%, Disease Control Rate, 84.6%; median progression free survival, 7.8 (95% Confidence Intervals: 4.1-13.1) months; 6-, 9-, 12-month progression free survival rates, 54.5%/45.9%/36.7%; median overall survival 19.3 (95% Confidence Intervals: 12.8 -.) months; 6-, 9- and 12-month overall survival rate, 86.9%/73.3%/73.3%. One patient had a complete surgical resection. Fifty percent of patients had a ≥ grade 3 treatment related adverse events which included anemia (6%), thrombocytopenia (6%), neutropenia (4%), increased alanine transaminase (4%), decreased left ventricular ejection fraction (4%), dehydration (4%), hyponatremia (4%). Conclusions: Taken together these data suggest that the TNT regimen is effective and safe for advanced previously treated sarcomas, and is worth being further studied in a randomized phase 3 trial as first- or second- line treatment for patients with advanced sarcomas.

A Phase I/II Investigation of Safety and Efficacy of Nivolumab and nab-Sirolimus in Patients With a Variety of Tumors With Genetic Mutations in the mTOR Pathway.

BACKGROUND/AIM: Advanced sarcoma has a poor prognosis. Dysregulation of the mammalian target of rapamycin (mTOR) occurs in various types of cancer. We aimed to determine the safety and efficacy of mTOR inhibitor nab-sirolimus when combined with the immune checkpoint inhibitor nivolumab. PATIENTS AND METHODS: Previously treated patients ≥18 years with confirmed diagnosis of advanced sarcoma or tumor with mutations in the mTOR pathway were treated with 3 mg/kg nivolumab intravenously every 3 weeks; escalating doses of nab-sirolimus at 56, 75 or 100 mg/m2 were administered intravenously on days 8 and 15 beginning in cycle 2. The primary aim was to determine the maximum-tolerated dose; we also determined disease control, objective response, progression-free survival, overall survival, and correlation between response using Immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) versus RECIST v1.1. RESULTS: The maximum-tolerated dose was 100 mg/m2 There were two patients with partial response, 12 with stable disease and 11 with progressive disease. Median progression-free and overall survival were 12 and 47 weeks, respectively. The best responders (partial responses) were patients with undifferentiated pleomorphic sarcoma with loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), tuberous sclerosis complex 2 (TSC2) mutation and estrogen receptor-positive leiomyosarcoma. Treatment-related adverse events of grade 3 or more included thrombocytopenia, oral mucositis, rash, hyperlipidemia and increased serum alanine aminotransferase. CONCLUSION: The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).

SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma.

BACKGROUND: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. METHODS: Phase I endpoints-maximum tolerated dose in previously treated patients; Phase II endpoints-best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments-escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments-maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. RESULTS: Phase I (n = 9)-the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)-6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4-7.9), median overall survival, 24.6 months (CI 95%: 17.0-.); Grade 3/4 therapy-related adverse events (n = 92)-increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). CONCLUSION: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Results of NC-6300 (Nanoparticle Epirubicin) in an Expansion Cohort of Patients with Angiosarcoma.

BACKGROUND: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken. METHODS: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival. RESULTS: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment. CONCLUSION: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061).