Carboplatin +/- Nivolumab in Metastatic Triple Negative Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Carboplatin; Nivolumab
Intervention description: Carboplatin interferes with the development of the genetic material in a cell, which will cause the cancer cells to die.; Nivolumab works by attaching to and blocking a molecule called PD-1. PD-1 is a different molecule that can turn off the immune system by interacting with PD-L1 on the cancer cells
Intervention MeSH terms: Carboplatin; Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer

Summary:

      This research study is studying a drug called Carboplatin with or without another study drug,
      Nivolumab as a possible treatment for triple-negative breast cancer that has spread to other
      parts of the body.

      The interventions involved in this study are:

        -  Carboplatin

        -  Nivolumab
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed invasive breast
             cancer, with unresectable locally advanced or metastatic disease. Participants without
             pathologic or cytologic confirmation of metastatic disease should have unequivocal
             evidence of metastasis from physical examination or radiologic evaluation.

          -  Estrogen-receptor and progesterone-receptor expression both ≤ 1% by
             immunohistochemistry (IHC), and HER2-negative status as determined by the current
             ASCO/CAP guidelines. If a patient has more than one histological result, the most
             recent sample will be considered for inclusion.

          -  Participants must have PD-L1 status available at the time of registration. Standard
             local testing with any PD-L1 antibody that has been validated in a CLIA-certified
             environment will be acceptable for including patients on trial.. Primary or metastatic
             samples may be tested for PD-L1 status.

          -  Participants must have measurable or evaluable disease by RECIST version 1.1.

          -  Participants must agree to undergo a research biopsy, if tumor is safely accessible,
             at baseline. Previously collected archival tissue will also be obtained on all
             participants. For participants for whom newly-obtained samples cannot be provided
             (e.g. inaccessible or participant safety concern) the archival tissue alone will be
             acceptable. Tissue needs to be located and availability confirmed at time of
             registration (See Section 9 for more details). Participants must agree to a mandatory
             repeat biopsy 3-6 weeks after starting treatment, if tumor is safely accessible. For
             patients randomized to carboplatin alone who decide to crossover to nivolumab and
             nab-paclitaxel at time of progression, a mandatory biopsy will be required if tumor is
             safely accessible prior to initiating crossover treatment; participants must also
             agree to undergo this biopsy, if applicable.

          -  Prior chemotherapy: Participants must have received 0 prior chemotherapeutic regimens
             for metastatic breast cancer. Prior platinum in the neo/adjuvant setting is
             permissible, if at least 6 months elapsed since the end of adjuvant systemic therapy
             to the development of metastatic disease. All toxicities related to prior chemotherapy
             must have resolved to CTCAE v4.0 grade 1 or lower, unless otherwise specified.

          -  Prior biologic therapy: Prior poly-ADP ribose polymerase (PARP) inhibitors are not
             allowed in the metastatic setting. Prior PARP inhibitors in the neo/adjuvant setting
             are permissible, if at least 6 months elapsed since the end of adjuvant systemic
             therapy to the development of metastatic disease. All toxicities related to prior
             biologic therapy must have resolved to CTCAE v4.0 grade 1 or lower, unless otherwise
             specified.

          -  Prior radiation therapy: Patients may have received prior radiation therapy. Radiation
             therapy must be completed at least 14 days prior to registration, and all toxicities
             related to prior radiation therapy must have resolved to CTCAE v4.0 grade 1 or lower,
             unless otherwise specified in 3.1.10. Patients may not have had >25% of their bone
             marrow radiated.

          -  The subject is ≥18 years old.

          -  ECOG performance status ≤1 (Karnofsky >60%, see Appendix A).

          -  Participants must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥1,500/mcL

               -  Platelets ≥100,000/mcL

               -  Hemoglobin ≥ 9.0 g/dl

               -  Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN
                  in patients with documented Gilbert's Syndrome)

               -  AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN or

                  ≤5 × institutional ULN for participants with documented liver metastases

               -  Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 45 mL/min/
                  1.73m2 for participants with creatinine levels above institutional ULN.

          -  Supportive care (e.g. transfusion of red blood cells) is allowed to meet eligibility
             criteria.

          -  Female subjects of childbearing potential must have a negative serum or urine
             pregnancy test within 2 weeks prior to registration.

          -  Childbearing potential is defined as: participants who have not reached a
             postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause
             other than menopause) and have not undergone surgical sterilization (removal of
             ovaries and/or uterus).

          -  Women of childbearing potential (WOCBP) must agree to use an adequate method of
             contraception. Contraception is required starting with the first dose of study
             medication through 150 days (5 months) after the last dose of study medication.
             Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal ligation, male sterilization, established and proper use of hormonal
             contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and
             copper intrauterine devices. Periodic abstinence (e.g., calendar, ovulation,
             symptothermal, or postovulation methods) and withdrawal are not acceptable methods of
             contraception.

          -  Males who are sexually active with WOCBP must agree to follow instructions for
             method(s) of contraception for the duration of study treatment with nivolumab and 7
             months after the last dose of study treatment (i.e., 90 days (duration of sperm
             turnover) plus the time required for the investigational drug to undergo approximately
             five half-lives.)

          -  Participants on bisphosphonates or RANK ligand inhibitors may continue receiving
             therapy during study treatment.

          -  The participant must be capable of understanding and complying with the protocol and
             willing to sign a written informed consent document

        Exclusion Criteria:

          -  Concurrent administration of any other anti-cancer therapy during the course of this
             study (bisphosphonates and RANK ligand inhibitors are allowed).

          -  Prior hypersensitivity to platinum chemotherapy or to any of the excipients of
             platinum or nivolumab therapy.

          -  Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including pembrolizumab,
             ipilimumab, and any other antibody or drug specifically targeting T-cell
             co-stimulation or checkpoint pathways).

          -  Known brain metastases that are untreated, symptomatic, or require therapy to control
             symptoms. Participants with a history of treated central nervous system (CNS)
             metastases are eligible. Treated brain metastases are defined as those without ongoing
             requirement for corticosteroids, as ascertained by clinical examination and brain
             imaging (magnetic resonance imaging or CT scan) completed during screening. Any
             corticosteroid use for brain metastases must have been discontinued without the
             subsequent appearance of symptoms for ≥7 days prior to registration. Treatment for
             brain metastases may include whole brain radiotherapy, radiosurgery, surgery or a
             combination as deemed appropriate by the treating physician. Radiation therapy must be
             completed at least 7 days prior to registration

          -  Major surgery within 2 weeks prior to registration. Patients must have recovered from
             any effects of any major surgery.

          -  Uncontrolled, significant intercurrent or recent illness including, but not limited
             to, ongoing or active infection, uncontrolled non-malignant systemic disease,
             uncontrolled seizures, or psychiatric illness/social situation that would limit
             compliance with study requirements in the opinion of the treating investigator.

          -  Participant has a medical condition that requires chronic systemic steroid therapy (>
             10 mg of prednisone daily or equivalent) or any other form of immunosuppressive
             medication (including disease modifying agents) and has required such therapy in the
             last 2 years. Replacement therapy (eg., thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
             not considered a form of systemic therapy.

          -  Participant has documented history of autoimmune disease or syndrome that currently
             requires systemic steroids or immunosuppressive agents.

          -  History or evidence of active, non-infectious pneumonitis or interstitial lung
             disease.

          -  Individuals with a history of a second malignancy are ineligible except for the
             following circumstances. Individuals with a history of other malignancies are eligible
             if they have been disease-free for at least 3 years or are deemed by the investigator
             to be at low risk for recurrence of that malignancy. Individuals with the following
             cancers that have been diagnosed and treated within the past 3 years are eligible:
             cervical/prostate carcinoma in situ, superficial bladder cancer, non-melanoma cancer
             of the skin. Patients with other cancers diagnosed within the past 3 years and felt to
             be at low risk of recurrence should be discussed with the study sponsor to determine
             eligibility.

          -  Participant is known to be positive for the human immunodeficiency virus (HIV),
             HepBsAg, or HCV RNA. HIV-positive participants are ineligible because of the potential
             for pharmacokinetic interactions of combination antiretroviral therapy with study
             drugs. In addition, these participants are at increased risk of fatal infections when
             treated with marrow-suppressive therapy.

          -  The participant has received a live vaccine within 28 days prior to registration.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. The
             use of the inactivated seasonal influenza vaccine is allowed.

          -  Women who are pregnant or breastfeeding or adults of reproductive potential not
             employing an adequate method of contraception.

          -  Childbearing potential is defined as: participants who have not reached a
             postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause
             other than menopause) and have not undergone surgical sterilization (removal of
             ovaries and/or uterus)