Overview

This is an open label, dose-seeking phase 1/2 study using escalating doses of LURBINECTEDIN administered intravenously with fixed doses of IPILIMUMAB and NIVOLUMAB administered intravenously.

Eligibility

Inclusion Criteria:

        Individuals must meet all of the inclusion criteria in order to be eligible to participate
        in the study, as follows:
          1. Male or Female ≥ 18 years of age
          2. Pathologically confirmed diagnosis of locally advanced unresectable or metastatic soft
             tissue sarcoma
          3. For the Phase 1 Part of Study, only previously treated participants will be enrolled.
             For the Phase 2 Part of Study, previously untreated participants will be enrolled.
          4. Ability to understand the purposes and risks of the study and has signed and dated a
             written informed consent form approved by the principal investigator's IRB/Ethics
             Committee
          5. Willingness to comply with all study procedures and availability for the duration of
             the study.
          6. Measurable disease by RECIST v1.1
          7. ECOG performance status ≤ 1
          8. Life expectancy of at least 3 months
               1. 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);
               2. AST (SGOT), ALT (SGPT) and alkaline phosphatase < 3 x ULN (< 5 x ULN if liver
                  metastases)
               3. Acceptable renal function: Creatinine < 1.5 times ULN or > 60 mL/min (using the
                  Cockcroft Gault formula)
          9. Acceptable hematologic status (without hematologic support e.g. growth factors or
             transfusion within 21 days of first dose of study agents): ANC >= 1500 cells/μL;
             Platelet count >= 100,000/μL; Hemoglobin >= 9.0 g/dL; Normal PT, PTT, INR
         10. 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:
          1. 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.
          2. Subjects with carcinomatous meningitis
          3. Anticancer treatment with radiation therapy, targeted therapy or other antitumor
             treatment within 2 weeks prior to study entry. Anticancer treatment with chemotherapy
             within 21 days prior to study entry.
          4. Subjects who participated in an investigational drug or device study within 14 days
             prior to study entry
          5. Females who are pregnant or breast-feeding
          6. Unwillingness or inability to comply with the study protocol for any reason
          7. Concurrent or prior immunotherapy with anti-CTLA4 or anti-PD-1 inhibitors
          8. Non-oncology vaccine therapy used for prevention of infectious disease within 4 weeks
             of trial enrollment
          9. 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)
         10. Systemic immunosuppression, including HIV positive status with or without AIDS
         11. Skin rash (psoriasis, eczema) affecting > 25% body surface area
         12. Inflammatory bowel disease (Crohn's or ulcerative colitis)
         13. Ongoing or uncontrolled diarrhea within 4 weeks of trial enrollment
         14. Recent history of acute diverticulitis, intraabdominal abscess or gastrointestinal
             obstruction within 6 months of trial enrollment, which are known risk factors for
             bowel perforation
         15. Participants with congestive heart failure or recent cardiac event
         16. Evidence of severe or uncontrolled systemic disease or any other concurrent condition,
             including psychiatric, which in the principal investigator or sub-investigator's
             opinion makes it undesirable for the participant to participate in the trial or which
             would jeopardize compliance with the trial
         17. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
             chronic infection
         18. Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS).
         19. Current, active, or previous history of heavy alcohol abuse
         20. Pituitary endocrinopathy
         21. Adrenal insufficiency or excess