Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer
Condition: Epithelial Ovarian Cancer; Peritoneal Neoplasms; Fallopian Tube Neoplasms
MeSH terms: Neoplasms; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Peritoneal Neoplasms; Fallopian Tube Neoplasms
Intervention: Birinapant (TL32711)
Intervention description: 47mg/m^2 intravenous (IV) on days 1, 8 and 15 of each 28 day cycle
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NF-Kappa B Pathway; Response Biomarkers; Progression-Free Survival; Pharmacokinetics; Pharmacodynamics

Summary:

      Background:

      - Birinapant is an experimental cancer treatment drug. It removes certain proteins in cells,
      which helps to kill the cells. The drug is more likely to cause the death of cancer cells
      than normal cells because cancer cells have more of these proteins. Studies suggest that it
      can help treat ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.
      Researchers want to see how well Birinapant works against the three types of cancer.

      Objectives:

      - To test the effectiveness of Birinapant for ovarian, primary peritoneal, or fallopian tube
      cancer.

      Eligibility:

      - Women at least 18 years of age who have ovarian, primary peritoneal, or fallopian tube
      cancer that has not responded to standard treatment.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will also be collected. Tumor tissue samples may be collected before treatment.
           Imaging studies will also be performed.

        -  Participants will have an infusion of Birinapant once per week for 3 weeks in a row,
           followed by a break for a week on the fourth week. This 4-week schedule is one cycle of
           treatment.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Another optional tumor biopsy will be collected 6 weeks after the start of treatment.

        -  Treatment will continue as long as the cancer does not grow and the side effects are not
           severe.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Study participants will be eligible for study participation if they are/have:

          -  Females greater than or equal to 18 years of age. Because no dosing or adverse event
             data are currently available on the use of birinapant in patients < 18 years of age,
             children are excluded from this study, but will be eligible for future pediatric
             trials.

          -  Able to understand and voluntarily sign a written informed consent, and are willing
             and able to comply with the protocol requirements including the requirement for
             biopsies for research purposes.

          -  Advanced metastatic or unresectable epithelial ovarian cancer, primary peritoneal
             cancer or fallopian tube cancer that is relapsed and resistant or refractory to prior
             platinum-based standard care systemic regimen. Patients who are unable to receive
             further platinum, due to either allergic reaction or other medical reason, are
             eligible for the protocol. There is no limitation on the amount of prior therapies
             allowed.

          -  Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal
             therapy, and radiation therapy, immunotherapy and monoclonal antibodies, alternative
             therapy or investigational therapeutic agents). Patients who have had cranial
             radiation therapy need to have completed it greater than or equal to 8 weeks prior to
             commencing on study. Patients are permitted to receive investigational imaging agents
             while on study.

          -  Patients who have had major surgery must be fully recovered and require a recovery
             period of greater than or equal to 4 weeks prior to enrolling on study.

          -  Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP),
             National Cancer Institute (NCI).

        A block of the primary tumor, or access to recut slides is preferred. If this is
        unavailable, a recent resection specimen of a metastatic site is required for entry. In
        addition, access to archival formalin fixed paraffin embedded (FFPE) tumor blocks will be
        requested to perform correlative studies. Study participants with the following histologic
        epithelial ovarian cancer cell types are eligible: Serous adenocarcinoma, endometrioid
        adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell
        adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant
        Brenner's Tumor, or adenocarcinoma not otherwise specified (N.O.S).

          -  Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
             defined as at least one lesion that can be accurately measured in at least one
             dimension (longest diameter to be recorded for non-nodal lesions and short axis for
             nodal lesions) as greater than or equal to 20 mm with conventional techniques or as
             greater than or equal to 10 mm with spiral computed tomography (CT) scan, magnetic
             resonance imaging (MRI), or calipers by clinical exam and a sentinel lesion adequate
             for core biopsy through percutaneous biopsy. See Section 13 for the evaluation of
             measurable disease.

          -  Life expectancy greater than 3 months.

          -  Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
             less than or equal to 2.

          -  Adequate renal function, defined as serum creatinine less than or equal to 1.5 X upper
             limit of normal (ULN), or measured creatinine clearance greater than or equal to 60
             ml/min/1.73m^2.

          -  Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) levels less than or equal to 3 X ULN and total bilirubin < 1.5
             X ULN, unless known diagnosis of Gilberts syndrome.

          -  Adequate bone marrow function, defined as absolute neutrophil (ANC) greater than or
             equal to 1,500/mm^3 (greater than or equal to1.5 X10^6/L), platelet count greater than
             or equal to 75,000/mm^3 (greater than or equal to 75 X10^6/L), and hemoglobin greater
             than or equal to 10 mg/dL (transfusion to obtain hemoglobin greater than or equal to
             10 mg/dL within 24 hours prior to dosing is allowed).

          -  Contraception is not a consideration as these patients have all had surgical removal
             of their reproductive organs. Pregnant women are excluded from this study because
             birinapant may have potential for teratogenic or abortifacient effects. Because there
             is an unknown but potential risk for adverse events in nursing infants secondary to
             treatment of the mother with birinapant, breastfeeding should be discontinued prior to
             enrollment.

        EXCLUSION CRITERIA:

          1. Known or suspected diagnosis of human immunodeficiency virus or chronic active
             hepatitis B or C. Viral testing is not required. The reason for exclusion is
             insufficient evidence demonstrating safety of administration of birinapant in patients
             with human immunodeficiency virus (HIV), hepatitis B or C due to theoretical risk of
             unmasking or exacerbating these serious viral illnesses since birinapant may impair
             immunological function. Data are not currently available on risk of interaction with
             antiretroviral drugs. HIV-positive patients on combination antiretroviral therapy are
             ineligible because of the potential for pharmacokinetic interactions with birinapant.
             The potential immune suppressive effects and T-cell depletion associated with
             birinapant pose an additional increased risk to these patients. Appropriate studies
             will be undertaken in patients receiving combination antiretroviral therapy when
             indicated.

          2. Symptomatic or uncontrolled brain metastases requiring current treatment (< 8 weeks
             from last cranial radiation or < 4 weeks from last steroids). (Patients with abnormal
             clinical exam or history will require a head CT or MRI to rule out or confirm brain
             metastases).

          3. Impaired cardiac function or clinically significant cardiac disease including the
             following:

               1. New York Heart Association grade III or IV congestive heart failure.

               2. Myocardial infarction within the last 12 months prior to dosing with birinapant.

               3. Subjects known to have impaired left ventricular ejection fraction (LVEF)
                  according to institutional standards must be excluded.

          4. Lack of recovery of prior adverse events to Grade less than or equal to1 severity
             (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]
             v 4.03) (except alopecia) due to therapy administered prior to the initiation of study
             drug dosing. Stable persistent grade 2 peripheral neuropathy may be allowed as
             determined on a case-by-case basis at the discretion of the Investigator as birinapant
             has not been shown to cause or exacerbate peripheral neuropathy.

          5. Known allergy to any of the formulation components of birinapant including citric acid
             monohydrate, sodium citrate dehydrate, and sodium chloride.

          6. Any concurrent disease and/or medical condition that in the opinion of the
             Investigator would prevent the subjects participation, render the subject at excessive
             risk or limit the subjects compliance with the protocols required evaluations.

          7. Patients with active infection will not be eligible, but may become eligible once
             infection has resolved and they are at least 7 days from completion of antibiotics.

          8. Another previous or current malignancy within the last 5 years, with the exception of
             non-melanoma skin cancer, cervical carcinoma in situ curatively treated, ductal or
             lobular carcinoma in situ curatively treated and without ongoing therapeutic
             intervention. Patients with breast cancer (BRCA) 1 or 2 mutation, who have had a
             previous diagnosis of breast cancer are eligible if the breast cancer was diagnosed 5
             years previously and distant or local recurrence of breast cancer has been outruled.

          9. Concomitant chronic (daily or almost daily for greater than or equal to1 month prior)
             use of steroids or non-steroidal anti-inflammatory drugs (NSAIDS). Intermittent use of
             steroids as pre-medications is allowed. Based on research to date the tumor and tumor
             microenvironment production of tumor necrosis factor (TNF) alpha could promote
             anti-tumor activity. Theoretically, anti-inflammatories could blunt local production,
             limiting this possibly positive cofactor.

         10. No concomitant use of complementary or alternative medication or other agents
             (investigational therapeutic agents) will be allowed without approval of a principal
             investigator (PI) or associate investigator (AI). Every effort will be made to
             maximize patient safety and minimize changes in chronic medications.

         11. Patients with a recent history (within last 5 years) of autoimmune disease or
             inflammatory diseases will be excluded, for example, active rheumatoid
             arthritis,active inflammatory bowel disease or any chronic inflammatory conditions
             because birinapant synergizes with TNF in vitro.

        INCLUSION OF MINORITIES:

        Women from all racial/ethnic groups are eligible for this study if they meet the
        eligibility criteria.

        To date, there is no information that suggests that differences in drug metabolism or
        disease response would be expected in one group compared to another. Efforts will be made
        to extend accrual to a representative population, but in this preliminary study, a balance
        must be struck between patient safety considerations and limitations on the number of
        individuals exposed to potentially toxic and/or ineffective treatments on the one hand and
        the need to explore ethnic aspects of clinical research on the other hand. If differences
        in outcome that correlate to ethnic identity are noted, accrual may be expanded or a
        follow-up study may be written to investigate those differences more fully. This study will
        be recruited through internal referral, our local physician referral base, and through
        Cancer Hotline information.