Subject Inclusion Criteria for Part 1: Safety Run-in study
1. Women diagnosed with pathologically confirmed metastatic triple negative invasive
breast cancer (centrally confirmed immunophenotype negative for all three receptors
ER, PR and HER2).
2. 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).
3. Have either Evaluable disease, or 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).
4. Age > 18 years.
5. Disease stage: Unresectable metastatic disease.
6. Patients received up to 2 prior regimens for their disease in the metastatic setting.
7. Patients are candidates for chemotherapy with carboplatin and gemcitabine.
8. ECOG performance status 0 - 2.
9. Adequate organ function tests and hematologic indices within 10 days of registration.
10. 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.
11. 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.
12. Signed written Informed Consent in accordance with regulatory and institutional
guidelines
Subject Exclusion Criteria for Part 1: Safety Run-in study
1. Patients participating in another trial of an investigational agent within 4 weeks of
the first dose of the study.
2. 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.
3. Patients with baseline grade 2 neuropathy.
4. 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).
5. Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive
therapy within 4 weeks of the study.
6. Active autoimmune disease or a documented history of autoimmune disease, or a syndrome
that has required systemic treatment in the past 2 years (ie, with use of
disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement
therapy (eg, thryoxine, 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 Sjögren's syndrome will not be
excluded from the study.
7. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
8. 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.
9. 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.
10. If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.
11. 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.
12. Life expectancy of less than 3 months.
13. Patients known to be carriers of Human Immunodeficiency Virus (HIV1/2).
14. Patients known to be carriers of hepatitis virus B and C.
15. 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.
16. 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.
17. Active infection requiring systemic therapy.
18. Active substance abuse or psychiatric disorders.
19. 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.
20. 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.
21. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
Subject Inclusion Criteria for Part 2 (Randomized Phase II Clinical Trial)
1. Women diagnosed with pathologically confirmed triple negative invasive breast cancer,
metastatic (locally confirmed immunophenotype negative for all three receptors ER, PR,
HER2).
2. 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).
3. Age > 18 years.
4. Disease stage IV, metastatic unresectable disease.
5. 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).
6. Patients received up to 3 prior regimens for their metastatic disease. Prior hormone
therapy will not be counted towards the line of therapies.
7. Patients are candidates for chemotherapy with carboplatin and gemcitabine.
8. ECOG performance status 0-2.
9. Adequate organ function tests and hematologic indices within 10 days of registration.
10. 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.
11. 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.
12. Signed written Informed Consent in accordance with regulatory and institutional
guidelines.
13. 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 and agreed to providing a second newly
obtained biopsy after completion of 2 cycles of the study drugs.
Subject Exclusion Criteria for Part 2 (Randomized Phase II Clinical Trial)
1. Patients participating in another trial of an investigational agent within 4 weeks of
the first dose of the study.
2. Patients with tumors that cannot be measured or clinically followed (i.e. evaluable
disease).
3. Patients with metastatic breast cancer who received prior therapy using
carboplatin/gemcitabine within 12months prior to their enrollment or subjects whose
tumor progressed while on treatment with carboplatin or cisplatin.
4. Patients with baseline grade 2 neuropathy.
5. 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).
6. Diagnosis of immunosuppression or receiving steroid therapy or other immunosuppressive
therapy within 4 weeks of the study.
7. Active autoimmune disease or a documented history of autoimmune disease, or a syndrome
that has required systemic treatment in the past 2 years (ie, with use of
disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement
therapy (eg, thryoxine, 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 Sjögren's syndrome will not be
excluded from the study.
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis.
9. 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.
10. 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.
11. If subject received major surgery, they must have recovered adequately from the
toxicity and/or complications from the intervention prior to starting therapy.
12. 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.
13. Life expectancy of less than 3 months.
14. Patients known to be carriers of Human Immunodeficiency Virus (HIV1/2).
15. Patients known to be carriers of hepatitis virus B and C .
16. 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.
17. 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.
18. Active infection requiring systemic therapy.
19. Active substance abuse or psychiatric disorders.
20. 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.
21. 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.
22. Has received a live vaccine within 30 days prior to the first dose of trial treatment.
23. 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.
