Carboplatin +/- Nivolumab in Metastatic Triple Negative Breast Cancer

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by progression-free survival (PFS), in patients with metastatic TNBC previously treated with 0 to 1 line of chemotherapy in the metastatic setting.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by progression-free survival (PFS), as first-line therapy in the metastatic setting for patients with unselected (by PD-L1 status)metastatic TNBC.

<p>Inclusion Criteria:</p><ul><li>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.</li><li>Estrogen-receptor and progesterone-receptor expression both ≤ 1% by immunohistochemistry (IHC), and HER2-negative status as determined by the current ASCO&#x2F;CAP guidelines.
If a patient has more than one histological result, the most recent sample will be considered for inclusion.</li><li>Participants must have measurable or evaluable disease by RECIST version 1.1.</li><li>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 monotherapy at time of progression, a mandatory biopsy will be required if tumor is safely accessible prior to initiating nivolumab; participants must also agree to undergo this biopsy, if applicable.</li><li>Prior chemotherapy: Participants may have received 0-1 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to registration.
No prior platinum in the metastatic setting is allowed.
Prior platinum in the neo&#x2F;adjuvant setting is permissible, if at least 12 months elapsed since the end of adjuvant 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 in 3.1.10.
If a patient recurs within 12 months of neoadjuvant or adjuvant chemotherapy, this will be counted as one line of therapy for metastatic disease.</li><li>Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days prior to registration.
Prior poly-ADP ribose polymerase (PARP) inhibitors are allowed in the metastatic setting.
Prior PARP inhibitors in the neo&#x2F;adjuvant setting are permissible.
All toxicities related to prior biologic therapy must have resolved to CTCAE v4.0 grade 1 or lower, unless otherwise specified in 3.1.10.</li><li>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 &gt;25% of their bone marrow radiated.</li><li>The subject is ≥18 years old.</li><li>ECOG performance status ≤1 (Karnofsky &gt;60%, see Appendix A).</li><li><p>Participants must have normal organ and marrow function as defined below:</p><ul><li>Absolute neutrophil count ≥1,500&#x2F;mcL</li><li>Platelets ≥100,000&#x2F;mcL</li><li>Hemoglobin ≥ 9.0 g&#x2F;dl</li><li>Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN in patients with documented Gilbert&#x27;s Syndrome)</li><li><p>AST(SGOT)&#x2F;ALT(SGPT) ≤2.5 × institutional ULN or</p><p>≤5 × institutional ULN for participants with documented liver metastases</p></li><li>Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 45 mL&#x2F;min&#x2F; 1.73m2 for participants with creatinine levels above institutional ULN.</li></ul></li><li>Supportive care (e.g.
transfusion of red blood cells) is allowed to meet eligibility criteria.</li><li>Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to registration.</li><li>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&#x2F;or uterus).</li><li>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 &lt; 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.</li><li>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.)</li><li>Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment.</li><li>The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document</li></ul><p>Exclusion Criteria:</p><ul><li>Concurrent administration of any other anti-cancer therapy within 14 days of starting protocol therapy and during the course of this study (bisphosphonates and RANK ligand inhibitors are allowed).</li><li>Prior hypersensitivity to platinum chemotherapy or to any of the excipients of platinum or nivolumab therapy.</li><li>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).</li><li>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 having no evidence of progression for ≥ 1 month after treatment, and no 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 ≥2 weeks prior to registration.
Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, surgery or a combination as deemed appropriate by the treating physician.</li><li>Major surgery within 2 weeks prior to registration.
Patients must have recovered from any effects of any major surgery.</li><li>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&#x2F;social situation that would limit compliance with study requirements in the opinion of the treating investigator.</li><li>Participant has a medical condition that requires chronic systemic steroid therapy (&gt; 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.</li><li>Participant has documented history of autoimmune disease or syndrome that currently requires systemic steroids or immunosuppressive agents.</li><li>History or evidence of active, non-infectious pneumonitis or interstitial lung disease.</li><li>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&#x2F;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.</li><li>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.</li><li>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&#x2F;zoster, yellow fever, rabies, BCG, and typhoid vaccine.
The use of the inactivated seasonal influenza vaccine is allowed.</li><li>Women who are pregnant or breastfeeding or adults of reproductive potential not employing an adequate method of contraception.</li><li>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&#x2F;or uterus)</li></ul>

<p>Inclusion Criteria:</p><ul><li>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.</li><li>Estrogen-receptor and progesterone-receptor expression both ≤ 1% by immunohistochemistry (IHC), and HER2-negative status as determined by the current ASCO&#x2F;CAP guidelines.
If a patient has more than one histological result, the most recent sample will be considered for inclusion.</li><li>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.</li><li>Participants must have measurable or evaluable disease by RECIST version 1.1.</li><li>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.</li><li>Prior chemotherapy: Participants must have received 0 prior chemotherapeutic regimens for metastatic breast cancer.
Prior platinum in the neo&#x2F;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.</li><li>Prior biologic therapy: Prior poly-ADP ribose polymerase (PARP) inhibitors are not allowed in the metastatic setting.
Prior PARP inhibitors in the neo&#x2F;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.</li><li>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 &gt;25% of their bone marrow radiated.</li><li>The subject is ≥18 years old.</li><li>ECOG performance status ≤1 (Karnofsky &gt;60%, see Appendix A).</li><li><p>Participants must have normal organ and marrow function as defined below:</p><ul><li>Absolute neutrophil count ≥1,500&#x2F;mcL</li><li>Platelets ≥100,000&#x2F;mcL</li><li>Hemoglobin ≥ 9.0 g&#x2F;dl</li><li>Total bilirubin ≤1.5 × institutional upper limit of normal (ULN) (or ≤2.0 x ULN in patients with documented Gilbert&#x27;s Syndrome)</li><li><p>AST(SGOT)&#x2F;ALT(SGPT) ≤2.5 × institutional ULN or</p><p>≤5 × institutional ULN for participants with documented liver metastases</p></li><li>Serum creatinine ≤1.5 × institutional ULN OR creatinine clearance ≥ 45 mL&#x2F;min&#x2F; 1.73m2 for participants with creatinine levels above institutional ULN.</li></ul></li><li>Supportive care (e.g.
transfusion of red blood cells) is allowed to meet eligibility criteria.</li><li>Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 2 weeks prior to registration.</li><li>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&#x2F;or uterus).</li><li>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 &lt; 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.</li><li>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.)</li><li>Participants on bisphosphonates or RANK ligand inhibitors may continue receiving therapy during study treatment.</li><li>The participant must be capable of understanding and complying with the protocol and willing to sign a written informed consent document</li></ul><p>Exclusion Criteria:</p><ul><li>Concurrent administration of any other anti-cancer therapy during the course of this study (bisphosphonates and RANK ligand inhibitors are allowed).</li><li>Prior hypersensitivity to platinum chemotherapy or to any of the excipients of platinum or nivolumab therapy.</li><li>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).</li><li>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</li><li>Major surgery within 2 weeks prior to registration.
Patients must have recovered from any effects of any major surgery.</li><li>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&#x2F;social situation that would limit compliance with study requirements in the opinion of the treating investigator.</li><li>Participant has a medical condition that requires chronic systemic steroid therapy (&gt; 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.</li><li>Participant has documented history of autoimmune disease or syndrome that currently requires systemic steroids or immunosuppressive agents.</li><li>History or evidence of active, non-infectious pneumonitis or interstitial lung disease.</li><li>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&#x2F;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.</li><li>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.</li><li>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&#x2F;zoster, yellow fever, rabies, BCG, and typhoid vaccine.
The use of the inactivated seasonal influenza vaccine is allowed.</li><li>Women who are pregnant or breastfeeding or adults of reproductive potential not employing an adequate method of contraception.</li><li>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&#x2F;or uterus)</li></ul>

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall response rate (ORR) according to RECIST 1.1 and immune-related response criteria (irRC), in patients with metastatic TNBC.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall response rate (ORR) according to RECIST 1.1 and immune-related response criteria (irRC), in patients with unselected metastatic TNBC.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall survival (OS), in patients with metastatic TNBC.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by overall survival (OS), in patients with unselected metastatic TNBC.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by clinical benefit rate (CBR) according to RECIST 1.1, in patients with metastatic TNBC.

To compare the efficacy of carboplatin in combination with nivolumab versus carboplatin alone, as defined by clinical benefit rate (CBR) according to RECIST 1.1, in patients with unselected metastatic TNBC.

To evaluate the duration of response (DOR) of carboplatin in combination with nivolumab versus carboplatin alone, in patients with metastatic TNBC.

To evaluate the duration of response (DOR) of carboplatin in combination with nivolumab versus carboplatin alone, in patients with unselected metastatic TNBC.

To evaluate the time to objective response (TTOR) of carboplatin in combination with nivolumab versus carboplatin alone, in patients with metastatic TNBC.

To evaluate the time to objective response (TTOR) of carboplatin in combination with nivolumab versus carboplatin alone, in patients with unselected metastatic TNBC.

2018-10

2019-11

2018-10-01

2019-11-06

2018-10-02

2019-11-08

A Randomized Phase II Trial of Carboplatin With or Without Nivolumab in First- or Second-line Metastatic Triple-negative Breast Cancer

A Randomized Phase II Trial of Carboplatin With or Without Nivolumab in First-line Metastatic Triple-negative Breast Cancer