SAINT:Trabectedin, Ipilimumab and Nivolumab as First Line Treatment for Advanced Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This is an open label, dose-seeking phase 1/2 study using escalating doses of TRABECTEDIN given intravenously with defined doses of IPILIMUMAB and NIVOLUMAB based on preliminary results of the Checkmate 012 trial for NSCLC (Hellman et al., 2016). For the Phase 1 Part of Study, only previously treated patients will be enrolled. For the Phase 2 Part of Study, previously untreated patients will be enrolled.

Detailed Description
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I. Dose Escalation Phase 1 of Study: The study will employ the standard Cohort of Three design (Storer, 1989). Three patients are treated at each dose level with expansion to six patients per cohort if DLT is observed in one of the three initially-enrolled patients at each dose level. If no DLT occurs after 2 doses, escalation to the next dose level will be permitted. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. Patients in the dose escalation study may continue treatment at their designated dose levels until disease progression or unacceptable toxicity occurs or up to 9 six-week cycles (one year) of therapy (up 18 TRABECTEDIN doses). No intra-patient dose escalation will take place. Dose of IPILIMUMAB: 1 mg/kg IV over 30 min. q 12 weeks, beginning 2 weeks after first dose of TRABECTEDIN, until disease progression or unacceptable toxicity, up to 5 doses Dose of NIVOLUMAB: 3 mg/kg over 30 min. q 2 weeks, beginning 2 weeks after first dose of TRABECTEDIN, until disease progression or unacceptable toxicity, up to 26 doses Dose of TRABECTEDIN: Escalating doses of TRABECTEDIN IV as continuous intravenous infusion (CIV) over 24 hrs) q 3 weeks: Dose Level I: 1 mg/m2 (n = 3-6); Dose Level II: 1.2 mg/m2 (n=3-6); Dose Level III: 1.5 mg.m2 (n=3-6) II. Expansion Phase 2 of Study: Following dose escalation, an additional 22-28 previously untreated patients will receive TRABECTEDIN at the MTD and defined doses of IPILIMUMAB and NIVOLUMAB to assess overall safety and potential efficacy in a greater number of patients. Patients in the expansion phase of the study may continue treatment until significant disease progression (see criteria for discontinuation of therapy) or unacceptable toxicity occurs up to 9 six-week cycles (one year) of therapy. Surgical Resection: After one or more treatment cycles, the principal investigator may recommend surgical debulking, complete surgical removal or a biopsy. If residual disease is present either by histopathological examination or by CT scan/MRI, repeat treatment cycles may be given 4 weeks after surgery, if the surgical incision has healed, and if the patient has < grade I toxicity. Resected or biopsied tumors will be analyzed for the effects of this triple therapy on response, and immune cell trafficking in the tumor microenvironment. Fresh and paraffin embedded tissue blocks will be analyzed by FACS for PD-L1 and other biomarkers, including Tregs, CD8+, CD4+ cells etc. Immunohistochemistry for cyclin G1, cyclin D1 and Ki67 will be conducted to determine the tumor's proliferative state. Histopathologic examination for tumor necrosis and mitotic index will also be determined.

Official Title
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SAINT: A Phase 1/2 Study of Safe Amounts of IPLIMUMAB, NIVOLUMAB and TRABECTEDIN as First Line Treatment of Advanced Soft Tissue Sarcoma (STS)

Conditions
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Advanced Soft Tissue Sarcoma, Metastatic Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Trabectedin
* Drug: Ipilimumab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals must meet all of the inclusion criteria in order to be eligible to participate in the study, as follows: Male or Female ≥ 18 years of age Pathologically confirmed diagnosis of locally advanced unresectable or metastatic soft tissue sarcoma For the Phase 1 Part of Study, only previously treated patients will be enrolled. For the Phase 2 Part of Study, previously untreated patients will be enrolled. Ability to understand the purposes and risks of the study and has signed and dated a written informed consent form approved by the investigator's IRB/Ethics Committee Willingness to comply with all study procedures and availability for the duration of the study. Measurable disease by RECIST v1.1 ECOG performance status ≤1 Life expectancy of at least 3 months Acceptable liver function: Bilirubin ≤ 1.5 times upper limit of normal (ULN; except subjects with Gilbert Syndrome who must have a total bilirubin level ≤ 3.0 ULN);AST (SGOT), ALT (SGPT) and alkaline phosphatase ≤ 3 x ULN (≤ 5 x ULN if liver metastases) Acceptable renal function: Creatinine ≤1.5 times ULN or ≥ 60 mL/min (using the Cockcroft Gault formula) Acceptable hematologic status (without hematologic support): WBC ≥2000/µL; ANC ≥ 1500 cells/μL; Platelet count ≥ 100,000/μL; Hemoglobin ≥ 9.0 g/dL; Normal PT, PTT, INR All women of childbearing potential must have a negative pregnancy test and all subjects must agree to use highly effective means of contraception (surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 5 months for women and 7 months for men after the last dose. Exclusion Criteria: All individuals meeting any of the exclusion criteria at baseline will be excluded from study participation, as follows: Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways Subjects with untreated CNS metastases. Subjects are eligible if CNS metastases have been adequately treated and have neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to treatment initiation. In addition, subjects must be either off corticosteroids, or on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to treatment initiation. Subjects with carcinomatous meningitis Anticancer treatment with radiation therapy, chemotherapy, targeted therapy or other antitumor treatment within 2 weeks prior to study entry Subjects who participated in an investigational drug or device study within 14 days prior to study entry Females who are pregnant or breast-feeding Unwillingness or inability to comply with the study protocol for any reason Concurrent or prior immunotherapy with anti-CTLA4 or anti-PD-1 inhibitors Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks of trial enrollment Autoimmune disease including rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis and motor neuropathy considered to be of autoimmune origin (e.g. Guillain-Barre Syndrome) Systemic immunosuppression, including HIV positive status with or without AIDS Skin rash (psoriasis, eczema) affecting ≥ 25% body surface area Inflammatory bowel disease (Crohn's or ulcerative colitis) Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal obstruction within 6 months of trial enrollment, which are known risk factors for bowel perforation Patients with congestive heart failure or recent cardiac event Evidence of severe or uncontrolled systemic disease or any other concurrent condition, including psychiatric, which in the principal investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the trial Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Inadequate hematologic, renal or hepatic function defined by any of the following screening laboratory values: WBC ≤2000/µL; Neutrophils ≤1500/µL; Platelets ≤ 100,000/µL; hemoglobin ≤9.0 g/dL; Serum creatinine ≥1.5 x ULN or creatinine clearance ≤ 60 mL/min (using the Cockcroft Gault formula); AST/ALT ≥3 x ULN (≥ 5 x ULN if liver metastases); Total Bilirubin ≥1.5 x ULN (except subjects with Gilbert Syndrome who must have a total bilirubin level ≥ 3.0 ULN) Current, active or previous history of heavy alcohol abuse Pituitary endocrinopathy Adrenal insufficiency or excess

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>Phase 1: 3-6 will be treated with escalating doses of Trabectedin every 3 weeks up to 18 doses. Dose Level 1 is 1.0 mg/m2; Dose Level 2,1.2 mg/m2; Dose Level 3,1.5 mg/m2. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses. Phase 2: All patients will be treated with the maximum tolerated dose of Trabectedin every 3 weeks. Beginning 2 weeks after the first dose of Trabectedin, all patients will be treated with Ipilimumab at 1 mg/kg every 12 weeks up to 5 doses, and Nivolumab at 3 mg/kg every 2 weeks up to 26 doses. | Drug: Trabectedin<br>* Trabectedinis an alkylating drug indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.<br>* Other names: Yondelis;Drug: Ipilimumab<br>* Ipilimumab is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for (1) treatment of unresectable or metastatic melanoma, and (2) adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.<br>* Other names: Yervoy;Drug: Nivolumab<br>* A fully human immunoglobulin (Ig) G4 monoclonal antibody directed against the negative immunoregulatory human cell surface receptor programmed cell death-1 (PD-1, PCD-1) with immune checkpoint inhibitory and antineoplastic activities. Nivolumab binds to and blocks the activation of PD-1, an Ig superfamily transmembrane protein, by its ligands programmed cell death ligand (PD-L1), overexpressed on certain cancer cells, and programmed cell death ligand (PD-L2), which is primarily expressed on APCs (antigen presenting cells). This results in the activation of T-cells and cell-medicated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and plays a key role in tumor evasion from host immunity.<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | Dose escalation study, determination of maximum tolerated dose (MTD) in previoiusly treated patients with soft tissue sarcoma followed by expansion to previously untreated patients with advanced STS | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR), disease control rate (DCR) | Effect of triple therapy with trabectedin, ipilimumab and nivolumab on ORR and DCR in advanced soft tissue sarcoma | 24 months | 
| Progression free survival (PFS), 6 month PFS rate | Effect of triple therapy with trabectedin, ipilimumab and nivolumab on progression free survival (PFS), 6 month PFS rate | 24 months | 
| Overall survival (OS), 6 month OS rate | Effect of triple therapy with trabectedin, ipilimumab and nivolumab on overall survival in advanced soft tissue sarcoma | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer immunotherapy, combination chemo-/immunotherapy