11520 Background: Sarcoma cells are most immunogenic earlier in the disease. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first-line therapy. Methods: Eligible patients include previously untreated male or female patients, ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma (STS), with measurable disease by RECIST v1.1. Immune checkpoint inhibitors I (1 mg/kg i.v. q 12 weeks) and N (3 mg/kg i.v. q 2 weeks) were given with T (1.2 mg/m2 i.v. q 3 weeks), a tumoricidal agent that depletes growth-promoting macrophages in the tumor microenvironment. Primary endpoint: Objective response rate by RECIST v1.1; Secondary endpoints: (1) Progression-free survival (PFS) at 6 months, (2) Overall survival (OS) at 6, 9, 12, 24, and 48 months, and (3) Incidence of adverse events. Results: Efficacy analysis: There were forty-one evaluable subjects. Best overall response rate was 19.5%; disease control rate 87.8%. The median OS was >12.5 months; median PFS was >6.0 months (6-month OS rate: 75%; 6-month PFS rate: 50%). Safety analysis: Grade 3 TRAEs include fatigue (n = 5), increased TSH (n = 3), decreased TSH (n = 1), adrenal insufficiency (n = 1), hyperglycemia (n = 1), dehydration (n = 1), hyponatremia (n = 2), bipedal edema (n = 2), increased AST (n = 8), increased ALT (n = 19), increased ALP (n = 2), increased CPK (n = 3), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 6), thrombocytopenia (n = 2), and neutropenia (n = 2). Grade 4 TRAES include neutropenia (n = 1), thrombocytopenia (n = 2), and increased CPK (n = 2). Conclusions: These data suggest that combinatorial therapy with Ipilimumab, Nivolumab and Trabectedin (1) may have synergistic activity in achieving disease control, and (2) is safe with manageable toxicity for patients with previously untreated STS. Clinical trial information: NCT03138161 . [Table: see text]
11016 Background: Sarcoma cells are most immunogenic earlier in the disease course and prior to treatment when the immune system can recognize and destroy them. Hypothesis: Immune checkpoint inhibitors would be most effective when given as first line therapy. Methods: This is an IRB-approved dose-seeking Phase 1/2 protocol using defined doses of I (1 mg/kg i.v. q 12 weeks), N (3 mg/kg i.v. q 2 weeks) and escalating doses of T (1.0, 1.2, 1.5 mg/m2 i.v. q 3 weeks), employing the “Cohort of Three” design, followed by a Phase 2 using the MTD of trabectedin. Results: Nine subjects were treated in Phase 1 of the study, and 31 subjects in Phase 2. Safety analysis: at Dose 1: Grade 3 treatment-related adverse events (TRAEs) included fatigue (n = 1), increased TSH (n = 1). At Dose 2, Grade 4 TRAEs included thrombocytopenia with bleeding, DLT (n = 1), increased CK (n = 1); Grade 3 TRAEs included anemia (n = 1), myalgia (n = 1), increased TSH (n = 1), decreased TSH (n = 1), increased AST (n = 1). Efficacy analysis (evaluable patients): At Dose 1: Disease Control Rate (DCR = CR, PR, SD) was 67%, median PFS, 18 weeks; median OS, 50 weeks; At Dose 2: PR (n-1), DCR 60%, median PFS, 24 weeks; median OS, > 46 weeks. At Phase 2, MTD Dose 2 (PUPs): Safety analysis (n = 31): Grade 3 TRAEs included fatigue (n = 2), increased ALT (n = 6), increased AST (n = 4), hypernatremia (n = 1), hyponatremia (n = 1), dehydration (n = 1), rash (n = 1), port cellulitis (n = 1), psoriasis exacerbation (n = 1), increased TSH (n = 1), decreased hemoglobin (n = 2), neutropenia (n = 1). Efficacy analysis (N = 23 evaluable): PR (n-5; 2 UPS, 1 synovial sarcoma, 1 liposarcoma, 1 leiomyosarcoma,), BORR 22%, DCR 96%. Median PFS and OS not yet reached. After 4 treatment cycles, one resected tumor showed 80% necrosis and a greater number (30%) of CD8+ killer T cells, in the TME compared to archived pre-treatment tumor. Conclusions: These data suggest that the SAINT protocol (1) is safe with manageable adverse events, with no additive toxicity, and (2) may control tumor growth. Phase 2 of the study is on-going. Clinical trial information: NCT03138161.
TPS11572 Background: Talimogene laherparepvec (TVEC), an oncolytic HSV expressing huGMCSF, may be synergistic with trabectedin (T) and nivolumab (N) in treating advanced sarcoma. Objectives: (1) To evaluate the best overall response by RECIST v1.1, progression-free survival rate (PFS), and overall survival rate, (2) To determine the incidence of conversion of an unresectable tumor to a resectable one, and (3) To evaluate the incidence of adverse events related to the drug combination. Methods: This is an open label phase 2 study. A total of 40 patients will receive T (1.2 mg/m2 CIV over 24 hours q3 weeks), N (240 mg IV over 30 min q 2 weeks) and TVEC (intratumorally q 2 weeks according to tumor size). Eligible patients are those with histopathologically confirmed diagnosis of locally advanced, unresectable or metastatic sarcoma including desmoid tumor and chordoma, previously untreated or treated, with measurable disease by RECIST v1.1, and at least, one accessible tumor for intratumoral injection of TVEC. Currently, 31 of the 40 patients have been enrolled. Statistical Considerations: Continuous variables will be summarized by the sample size (n), mean, standard deviation, first and third quartiles, minimum and maximum. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. Safety (incidence and severity of adverse events and significant laboratory abnormalities) will be performed on all patients (ITT population). Patient incidence of all treatment emergent AEs will be tabulated by system organ class and preferred term. Clinical trial information: 03886311 .
11057 Background: Immune checkpoint inhibitors that promote sustained T cell activation may have synergistic activity with an mTOR inhibitor. This phase 1/2 study is aimed to investigate if ABI-009 a novel albumin-bound mTOR inhibitor is feasible and improve clinical outcomes in combination with nivolumab. Methods: Eligible patients with advanced UPS, LPS, CS, OS, or Ewing sarcoma are treated with the standard dose of nivolumab (240 mg given IV every 3 weeks, Day 1 of every 21-day Cycle). ABI-009 will be given IV on Days 8 and 15 of each cycle starting on Cycle 2 following the 2nd nivolumab dose. Phase 1 portion is a dose-finding study using the 3+3 design. The starting dose of ABI-009 is 56 mg/m2, and sequentially escalating doses are 75 and 100 mg/m2. The primary endpoint is to identify the maximum-tolerated dose (MTD) of ABI-009 + nivolumab, secondary endpoints include disease control rate, progression-free survival (PFS), and overall survival (OS). Exploratory endpoints include correlation of PFS and OS with PD-L1 and other biomarkers. The Phase 2 part of study will enroll 31 additional patients to further assess efficacy and safety at the MTD. Results: 9 patients were treated in Phase 1 (n = 3 each dose level); 5/9 patients had OS, 3/9 CS, and 1 had Ewing sarcoma. No dose-limiting toxicities (DLTs) were observed, the MTD was not reached, and 100 mg/m2 ABI-009 was designated as the recommended phase 2 dose. Safety analysis: At Dose 1: Grade 3 treatment-related adverse events (TRAEs) included hyper dyslipidemia (n = 1), and hyperglycemia (n = 1). At Dose 2: Grade 3 TRAEs included increased ALT (n = 1). At Dose 3: Grade 3 TRAEs included hypophosphatemia (n = 1). Seven of 9 patients have discontinued treatment: 5 patients due to PD, 2 with SD opted to stop treatment due to drug-related Grade 2 AEs (pruritus, acneiform rash, and 2 with SD are still on therapy at Dose 3. The median PFS at dose level 3 has not yet been reached. Conclusions: The MTD was not reached and Dose 3 (100 mg/m2) has been designated as the phase 2 dose of ABI- 009, combinable with nivolumab. Enrollment to phase 2 is ongoing. Clinical trial information: NCT03190174.
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 nabsirolimus 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/m 2 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, progressionfree survival, overall survival, and correlation between response using Immune-related Response Evaluation Criteria for Solid Tumors (irRECIST) versus RECIST v1.1. Results: The maximumtolerated dose was 100 mg/m 2 . 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 nabsirolimus 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 nabsirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).
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