Clinical Trials /

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

NCT03138161

Description:

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.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: SOC-1702
  • NCT ID: NCT03138161

Conditions

  • Advanced Soft Tissue Sarcoma
  • Metastatic Soft Tissue Sarcoma

Interventions

DrugSynonymsArms
TrabectedinYondelisPhase 1
IpilimumabYervoyPhase 1
NivolumabOpdivoPhase 1

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1ExperimentalPhase 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.
  • Trabectedin
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose
Time Frame:6 months
Safety Issue:
Description: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

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Sarcoma Oncology Research Center, LLC

Trial Keywords

  • cancer immunotherapy, combination chemo-/immunotherapy

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