Carboplatin +/- Nivolumab in Metastatic Triple Negative Breast Cancer

Conditions:Breast Cancer, Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:January 30, 2018
End Date:June 30, 2025
Contact:Paulina Lange

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

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

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being

The FDA (the U.S. Food and Drug Administration) has not approved nivolumab for your specific
disease but it has been approved for other uses. The FDA has approved carboplatin as a
treatment option for your disease.

The purpose of this research study is to determine how well carboplatin, by itself, or
together with nivolumab, works in treating breast cancer that has spread to other parts of
the body. Nivolumab is a recently discovered human monoclonal antibody. An antibody is a type
of protein that your immune system (the system that defends your body against potentially
harmful particles) uses to find and destroy foreign molecules (particles not typically found
in your body, such as bacteria and viruses). Scientists can now make antibodies in the
laboratory and produce them for the treatment of many different diseases.

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 cell.
Nivolumab has been shown in research studies to prevent PD-1 from shutting down the immune
system, thus allowing it to recognize and help your body destroy the cancer cells. You are
being asked to participate in this study because triple-negative breast cancer has shown
elevated rates of PD-L1 expression.

Nivolumab has been used in other research studies and information from those research studies
suggests that nivolumab may help shrink or stabilize your triple negative breast cancer in
this study

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 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
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.

- 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/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.

- 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/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.

- 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

- 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

- 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 within 14 days of starting
protocol therapy and 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 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.

- 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

- 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

- 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)
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