Carboplatin and Gemcitabine Hydrochloride with or without Pembrolizumab in Treating Patients with Metastatic Triple-Negative Breast Cancer

Inclusion Criteria

• SAFETY RUN-IN: Women diagnosed with pathologically confirmed metastatic triple negative invasive breast cancer (centrally confirmed immunophenotype negative for all three receptors estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2])
• SAFETY RUN-IN: Hormone receptor status (ER and PR) both =< 5% by immunohistochemistry, and HER2 status confirmed by means of immunohistochemistry (with 0 or 1+ indicating negative status) or fluorescence in situ hybridization (with amplification ratio < 2.0 indicating negative status)
• SAFETY RUN-IN: Have either evaluable disease, or have measurable clinical disease: measurable disease, defined as at least 1 unidimensionally measurable lesion on a computed tomography (CT) scan as defined by RECIST (version v1.1)
• SAFETY RUN-IN: Age >= 18 years
• SAFETY RUN-IN: Disease stage: unresectable metastatic disease
• SAFETY RUN-IN: Patients received up to 2 prior regimens for their disease in the metastatic setting
• SAFETY RUN-IN: Patients are candidates for chemotherapy with carboplatin and gemcitabine
• SAFETY RUN-IN: Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• SAFETY RUN-IN: Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days of registration)
• SAFETY RUN-IN: Platelets >= 100,000 / mcL (within 10 days of registration)
• SAFETY RUN-IN: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 10 days of registration)
• SAFETY RUN-IN: Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of registration)
• SAFETY RUN-IN: Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of registration)
• SAFETY RUN-IN: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of registration)
• SAFETY RUN-IN: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of registration)
• SAFETY RUN-IN: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of registration)
• SAFETY RUN-IN: Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registration; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• SAFETY RUN-IN: Female subjects of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• SAFETY RUN-IN: Signed written informed consent in accordance with regulatory and institutional guidelines
• RANDOMIZED PHASE II CLINICAL TRIAL: Women diagnosed with pathologically confirmed triple negative invasive breast cancer, metastatic (locally confirmed immunophenotype negative for all three receptors ER, PR, HER2)
• RANDOMIZED PHASE II CLINICAL TRIAL: Hormone receptor status (ER and PR) both =< 5% by immunohistochemistry, and HER2 status confirmed by means of immunohistochemistry (with 0 or 1+ indicating negative status) or fluorescence in situ hybridization (with amplification ratio < 2.0 indicating negative status)
• RANDOMIZED PHASE II CLINICAL TRIAL: Age > 18 years
• RANDOMIZED PHASE II CLINICAL TRIAL: Disease stage IV, metastatic unresectable disease
• RANDOMIZED PHASE II CLINICAL TRIAL: Have measurable clinical disease: Measurable disease, defined as at least 1 unidimensionally measurable lesion on a CT scan as defined by RECIST (version v1.1)
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients received up to 3 prior regimens for their metastatic disease; prior hormone therapy will not be counted towards the line of therapies
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients are candidates for chemotherapy with carboplatin and gemcitabine
• RANDOMIZED PHASE II CLINICAL TRIAL: ECOG performance status 0-2
• RANDOMIZED PHASE II CLINICAL TRIAL: Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Platelets >= 100,000 / mcL (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (GFR can also be used in place of CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: AST (SGOT) and ALT (SGPT) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: International normalized ratio (INR) or PT =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of registration)
• RANDOMIZED PHASE II CLINICAL TRIAL: Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to registration; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
• RANDOMIZED PHASE II CLINICAL TRIAL: Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
• RANDOMIZED PHASE II CLINICAL TRIAL: Signed written informed consent in accordance with regulatory and institutional guidelines
• RANDOMIZED PHASE II CLINICAL TRIAL: Have provided tissue from a newly obtained biopsy (an archival tissue sample may be substituted if new biopsy cannot be obtained and by discretion of principal investigator only) from a local or distant site at the time of screening and agreed to providing a second newly obtained biopsy after completion of 2 cycles of the study drugs. If the patient is found to have inadequate tumor burden or collecting second biopsy may place the patient at risk, decision to accrue the patient may rest with the sponsor investigator

Exclusion Criteria

• SAFETY RUN-IN: Patients participating in another trial of an investigational agent within 4 weeks of the first dose of the study
• SAFETY RUN-IN: Patients who received prior therapy using carboplatin/gemcitabine within 12 months prior to enrollment or subjects whose tumor progressed while on treatment with carboplatin or cisplatin
• SAFETY RUN-IN: Patients with baseline grade 2 neuropathy
• SAFETY RUN-IN: Patients with hormone-receptor positive breast cancer (ER and/or PR > 5%), and with HER-2 positive breast cancer (by means of immunohistochemistry with 3+ indicating positive status or fluorescence in situ hybridization with amplification ratio >= 2.0 indicating positive status)
• SAFETY RUN-IN: Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive therapy within 4 weeks of the study
• SAFETY RUN-IN: Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects who require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
• SAFETY RUN-IN: Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• SAFETY RUN-IN: Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• SAFETY RUN-IN: Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
• SAFETY RUN-IN: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• SAFETY RUN-IN: Known additional malignancy that progressed and/or required treatment in the last 5 years; except that for basal and squamous cell carcinoma of the skin or in situ cervical carcinoma that has completed potentially curative therapy
• SAFETY RUN-IN: Life expectancy of less than 3 months
• SAFETY RUN-IN: Patients known to be carriers of human immunodeficiency virus (HIV1/2)
• SAFETY RUN-IN: Patients known to be carriers of hepatitis virus B and C
• SAFETY RUN-IN: Prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand (PDL-1), anti-PD-L2, anti-cluster of differentiation 137 (CD137) antibody, or anti-cytotoxic T-lymphocyte –associated antigen-4 (CTLA-4) antibody
• SAFETY RUN-IN: Pregnant, breastfeeding, or expecting to conceive children within the projected time of the trial, starting with the pre-screening or screening visit and through 120 days after the last dose of trial treatment
• SAFETY RUN-IN: Active infection requiring systemic therapy
• SAFETY RUN-IN: Active substance abuse or psychiatric disorders
• SAFETY RUN-IN: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
• SAFETY RUN-IN: Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• SAFETY RUN-IN: Has received a live vaccine within 30 days prior to the first dose of trial treatment
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients participating in another trial of an investigational agent within 4 weeks of the first dose of the study
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients with tumors that cannot be measured or clinically followed (i.e. evaluable disease)
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients with metastatic breast cancer who received prior therapy using carboplatin/gemcitabine within 12 months prior to their enrollment or subjects whose tumor progressed while on treatment with carboplatin or cisplatin
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients with baseline grade 2 neuropathy
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients with hormone-receptor positive breast cancer (ER and/or PR > 5%), and with HER-2 positive breast cancer (by means of immunohistochemistry with 3+ indicating positive status or fluorescence in situ hybridization with amplification ratio >= 2.0 indicating positive status)
• RANDOMIZED PHASE II CLINICAL TRIAL: Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive therapy within 4 weeks of first dose of treatment
• RANDOMIZED PHASE II CLINICAL TRIAL: Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects who require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study
• RANDOMIZED PHASE II CLINICAL TRIAL: Has evidence of interstitial lung disease or active, non-infectious pneumonitis
• RANDOMIZED PHASE II CLINICAL TRIAL: Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
• RANDOMIZED PHASE II CLINICAL TRIAL: Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
• RANDOMIZED PHASE II CLINICAL TRIAL: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• RANDOMIZED PHASE II CLINICAL TRIAL: Known additional malignancy that progressed and/or required treatment in the last 5 years; except that for basal and squamous cell carcinoma of the skin or in situ cervical carcinoma that has completed potentially curative therapy
• RANDOMIZED PHASE II CLINICAL TRIAL: Life expectancy of less than 3 months
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients known to be carriers of human immunodeficiency virus (HIV1/2)
• RANDOMIZED PHASE II CLINICAL TRIAL: Patients known to be carriers of hepatitis virus B and C
• RANDOMIZED PHASE II CLINICAL TRIAL: Prior therapy with an anti-programmed cell death 1 (PD-1), anti-programmed cell death 1 ligand (PDL-1), anti-PD-L2, anti-CD137 antibody, or anti-cytotoxic T-lymphocyte –associated antigen-4 (CTLA-4) antibody
• RANDOMIZED PHASE II CLINICAL TRIAL: Pregnant, breastfeeding, or expecting to conceive children within the projected time of the trial, starting with the pre-screening or screening visit and through 120 days after the last dose of trial treatment
• RANDOMIZED PHASE II CLINICAL TRIAL: Active infection requiring systemic therapy
• RANDOMIZED PHASE II CLINICAL TRIAL: Active substance abuse or psychiatric disorders
• RANDOMIZED PHASE II CLINICAL TRIAL: Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
• RANDOMIZED PHASE II CLINICAL TRIAL: Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• RANDOMIZED PHASE II CLINICAL TRIAL: Has received a live vaccine within 30 days prior to the first dose of trial treatment
• RANDOMIZED PHASE II CLINICAL TRIAL: Subjects who do not consent to providing pre and post treatment tissue sample for future research would not be eligible to participate in the trial