Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03138161
Recruitment Status : Recruiting
First Posted : May 3, 2017
Last Update Posted : September 2, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Sarcoma Oncology Research Center, LLC

Tracking Information
First Submitted Date  ICMJE April 14, 2017
First Posted Date  ICMJE May 3, 2017
Last Update Posted Date September 2, 2020
Actual Study Start Date  ICMJE April 13, 2017
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2017)
Maximum tolerated dose [ Time Frame: 6 months ]
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
Original Primary Outcome Measures  ICMJE
 (submitted: April 28, 2017)
Safety [ Time Frame: 40 months ]
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2017)
  • Objective response rate (ORR), disease control rate (DCR) [ Time Frame: 24 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on ORR and DCR in advanced soft tissue sarcoma
  • Progression free survival (PFS), 6 month PFS rate [ Time Frame: 24 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on progression free survival (PFS), 6 month PFS rate
  • Overall survival (OS), 6 month OS rate [ Time Frame: 24 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on overall survival in advanced soft tissue sarcoma
Original Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2017)
  • Objective response rate (ORR), disease control rate (DCR) [ Time Frame: 24 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on ORR and DCR in advanced soft tissue sarcoma
  • Progression free survival (PFS), 6 month PFS rate [ Time Frame: 40 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on progression free survival (PFS), 6 month PFS rate
  • Overall survival (OS), 6 month OS rate [ Time Frame: 48 months ]
    Effect of triple therapy with trabectedin, ipilimumab and nivolumab on overall survival in advanced soft tissue sarcoma
Current Other Pre-specified Outcome Measures
 (submitted: May 4, 2017)
  • Tumor response and PD-1, PD-L1 expression in tumors [ Time Frame: 30 months ]
    Correlation of response with PD-L1 expression and other biomarkers in patients' tumors
  • Dexamethasone and immune related events [ Time Frame: 30 months ]
    • Correlation of the timing and effect of dexamethasone use (necessarily given with TRABECTEDIN) on absolute lymphocyte count and the immune response, including immune related adverse events
Original Other Pre-specified Outcome Measures
 (submitted: April 28, 2017)
  • Tumor response and PD-1, PD-L1 expression in tumors [ Time Frame: 40 months ]
    Correlation of response with PD-L1 expression and other biomarkers in patients' tumors
  • Dexamethasone and immune related events [ Time Frame: 48 months ]
    • Correlation of the timing and effect of dexamethasone use (necessarily given with TRABECTEDIN) on absolute lymphocyte count and the immune response, including immune related adverse events
 
Descriptive Information
Brief Title  ICMJE SAINT:Trabectedin, Ipilimumab and Nivolumab as First Line Treatment for Advanced Soft Tissue Sarcoma
Official Title  ICMJE SAINT: A Phase 1/2 Study of Safe Amounts of IPLIMUMAB, NIVOLUMAB and TRABECTEDIN as First Line Treatment of Advanced Soft Tissue Sarcoma (STS)
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Soft Tissue Sarcoma
  • Metastatic Soft Tissue Sarcoma
Intervention  ICMJE
  • Drug: Trabectedin
    Trabectedinis an alkylating drug indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen.
    Other Name: Yondelis
  • Drug: Ipilimumab
    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.
    Other Name: Yervoy
  • Drug: Nivolumab
    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.
    Other Name: Opdivo
Study Arms  ICMJE Experimental: Phase 1

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.

Interventions:
  • Drug: Trabectedin
  • Drug: Ipilimumab
  • Drug: Nivolumab
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 28, 2017)
45
Original Actual Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 31, 2021
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Erlinda M Gordon, MD 310-552-9999 egordon@sarcomaoncology.com
Contact: Victoria Chua-Alcala, MD 310-552-9999 vchua@sarcomaoncology.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03138161
Other Study ID Numbers  ICMJE SOC-1702
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sarcoma Oncology Research Center, LLC
Study Sponsor  ICMJE Sarcoma Oncology Research Center, LLC
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Erlinda M Gordon, MD Sarcoma Oncology Research Center
PRS Account Sarcoma Oncology Research Center, LLC
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP