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Cisplatin, Romidepsin and Nivolumab in Treating Patients with Locally Recurrent or Metastatic Triple Negative Breast Cancer

Trial Status: Active

This phase I / II trial studies the side effects and best dose of romidepsin when given together with cisplatin and nivolumab, to see how well they work in treating patients with triple negative breast cancer that has come back at or near the same place as the original (primary) tumor, usually after a period of time during which the cancer could not be detected or spread to other parts of the body. Romidepsin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Romidepsin may also help cisplatin work better. Monoclonal antibodies, such as nivolumab, may interfere with the ability of tumor cells to grow and spread. Giving romidepsin together with cisplatin and nivolumab may be a better treatment for tripe negative breast cancer.

Inclusion Criteria

  • Ability to understand and the willingness to sign a written informed consent (ICF)
  • Subjects must meet at least one of the following two criteria: * Histologically proven TNBC defined as estrogen receptor (ER) immunohistochemistry (IHC) =< 10%, progesterone receptor (PgR) IHC =< 10% and human epidermal growth factor receptor (HER)-2 negative disease per 2013 American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) HER testing guidelines (0 or 1+ by IHC; and/or HER2 ratio < 2.0 and HER2 copy number < 4 signals/cell by fluorescence in situ hybridization [FISH]) * Confirmed germline BRCA1 or BRCA2 mutation associated breast cancer regardless of the subtype of breast cancer
  • Breast cancer, which at the time of study entry is either stage III (locally advanced) disease not amenable to curative therapy or stage IV disease; histological confirmation of recurrent/metastatic disease is encouraged but not required if clinical evidence of stage IV disease is available
  • Have measurable lesion, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded), with minimum lesion size >= 2 cm on conventional measurement techniques or >= 1 cm on spiral computed tomography (CT) scan
  • Subjects may have had any number of prior chemotherapy, endocrine therapy, immunologic, or biologic regimens for metastatic breast cancer; treatment with prior platinum compounds (except cisplatin) is allowed as long as it has been 6 months or more since exposure to prior platinum; prior cisplatin treatment is allowed IF it was given in the adjuvant setting
  • All patients should have received at least one line of chemotherapy in either the advanced or neo/adjuvant setting and hormonal therapy (where appropriate); participants who have previously been treated with endocrine therapy only, and later develop triple negative disease are eligible as long as they have had one line of chemotherapy in either the advanced or neo/adjuvant setting
  • Performance status of 2 or better as per Eastern Cooperative Oncology Group (ECOG) criteria
  • Performed within 14 days of patient registration: Absolute neutrophil count >= 1,500/uL
  • Performed within 14 days of patient registration: Platelets >= 100,000/uL (no transfusion allowed within 2 weeks)
  • Performed within 14 days of patient registration: Hemoglobin > 9 g/dL(which may be reached by transfusion)
  • Performed within 14 days of patient registration: Total bilirubin within normal range or =< 1.5 x institutional upper limit of normal (IULN) if liver metastases are present or total bilirubin =< 3.0 x IULN with direct bilirubin within normal range in patients with well documented Gilbert’s syndrome, which is defined as presence of several episodes of unconjugated hyperbilirubinemia with normal results from complete blood count (CBC) (including normal reticulocyte count and blood smear), normal liver function test results, and absence of other contributing disease processes at the time of diagnosis
  • Performed within 14 days of patient registration: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x IULN or =< 5 x IULN if liver metastases are present
  • Performed within 14 days of patient registration: Serum creatinine =< 1.5 x IULN
  • Performed within 14 days of patient registration: International normalized ration (INR) =< 1.5
  • Performed within 14 days of patient registration: Serum potassium > 3.8 mmol/L (can be achieved with replacement)
  • Performed within 14 days of patient registration: Serum magnesium > 1.8 mg/dL(can be achieved with replacement) * NOTE: The package insert for the study drug, romidepsin, does not require subject blood levels of potassium (K) and magnesium (Mg) to be at a certain level; therefore in this study, we will require K > 3.8 and Mg > 1.8 for eligibility, but for the rest of the treatment parameters during the course of the study we will require these electrolytes to be within normal range (WNL)
  • Intravenous (IV) bisphosphonate and denosumab for bony metastatic disease will be allowed
  • Prior palliative radiation therapy to bony metastases will be allowed; there should be minimum of 14 days between the end of radiation treatment and start of study treatment
  • Subjects with previously treated brain metastasis who are free of central nervous system (CNS) symptoms and are >= 14 days from treatment of brain metastasis are eligible; there must also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration
  • Women of child-bearing potential (WOCBP) and their partners must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 5 months following last dose of investigational drug; after confirmation of negative pregnancy test at screening, should a WOCBP become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician and the investigator immediately; the outcome of the pregnancy will be followed and reported to Bristol-Myers Squibb (BMS) * WOCBP are any females (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meet the following criteria: ** Have not undergone a hysterectomy or bilateral oophorectomy; OR ** Have not been naturally postmenopausal for at least 12 consecutive months (i.e.: has had menses at any time in the preceding 12 consecutive months)

Exclusion Criteria

  • Subject has received any anti-cancer therapy including chemotherapy, immunotherapy, biologic, targeted therapy, or any investigational therapy within either 14 days or 5 half-lives (whichever is shorter), prior to study drug administration
  • Subjects who have not recovered to within one grade level (not to exceed grade 2) of their baseline following a significant adverse event or toxicity attributed to prior anti-cancer treatment are excluded
  • The presence of any other medical or psychiatric disorder that, in the opinion of the treating physician, would contraindicate the use of drugs in this protocol or place the subject at undue risk for treatment complications
  • Subject is pregnant or lactating
  • Subject has previously been treated with a HDAC inhibitor, PD-1 inhibitor, PD-L1 inhibitor, PD-L2 inhibitor, CTLA-4 inhibitor, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
  • Patients should be excluded if they have a positive test for hepatitis B virus surface antigen (hepatitis B surface antigen [HBV sAg]) or hepatitis C virus ribonucleic acid (hepatitis C virus [HCV] antibody) indicating acute or chronic infection
  • Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) (testing not mandatory)
  • Subject has inflammatory breast cancer
  • Subject has a known hypersensitivity to any of the excipients of nivolumab, cisplatin or romidepsin
  • Subject has a concurrent malignancy or malignancy within 3 years of study enrollment (with the exception of adequately treated, basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer or prior ovarian/breast cancer in patients with BRCA associated breast cancer)
  • Subject is classified into Child-Pugh class C
  • Subject has active, uncontrolled infection
  • Subject has symptomatic and untreated central nervous system (CNS) disease
  • Patients should be excluded if they have an active, known or suspected autoimmune disease; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Subject has active cardiac disease or a history of cardiac dysfunction including any of the following: * Congenital long QT syndrome * Corrected QT (QTc) interval >= 500 ms on the screening electrocardiogram (ECG) (using the corrected QT Fridericia [QTcF] formula) * Myocardial infarction within 6 months of course 1 day 1 (C1D1); subjects with a history of myocardial infarction between 6 and 12 months prior to C1D1 who are asymptomatic and have had a negative cardiac risk assessment (treadmill stress test, nuclear medicine stress test, or stress echocardiogram) since the event may participate * Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min) * Symptomatic coronary artery disease (CAD), e.g., angina Canadian class II-IV; in any subject in whom there is doubt, the subject should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present * An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the subject should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV definitions and/or ejection fraction < 40% by multi gated acquisition (MUGA) scan or < 50% by echocardiogram and/or magnetic resonance imaging (MRI) * A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD) * Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes * Uncontrolled hypertension, i.e., blood pressure (BP) of >= 160/95; subjects who have a history of hypertension controlled by medication must be on a stable dose (for at least one month) and meet all other inclusion criteria * Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers) * Subjects taking drugs leading to significant QT prolongation * Concomitant use of cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inhibitors
  • Subject has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects
  • Subject is currently receiving or has received systemic corticosteroids =< 2 weeks prior to starting study drug or who have not fully recovered from side effects of such treatment; inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
  • Subject is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzyme cytochrome P450 family 3, subfamily A (CYP3A); the subject must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the start of treatment
  • Subject is currently receiving warfarin or other Coumarin derived anti-coagulant for treatment; therapy with heparin, low molecular weight heparin (LMWH), factor Xa, or fondaparinux is allowed
  • Subjects with baseline peripheral neuropathy that exceeds grade 1


University of Kansas Clinical Research Center
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-945-7625
Kansas City
University of Kansas Cancer Center
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-588-6029
University of Kansas Cancer Center-West
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-574-2620
Overland Park
University of Kansas Cancer Center-Overland Park
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-574-2650
University of Kansas Hospital-Westwood Cancer Center
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-588-6029


Kansas City
The University of Kansas Cancer Center-South
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-574-2430
University of Kansas Cancer Center - North
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-574-2520
Lee's Summit
University of Kansas Cancer Center - Lee's Summit
Status: ACTIVE
Contact: Priyanka Sharma
Phone: 913-574-2350


Vanderbilt University / Ingram Cancer Center
Contact: Vandana Gupta Abramson


I. Determine the recommended phase II dose (RPTD) of romidepsin + cisplatin to be used in combination for treatment of advanced triple negative breast cancer (TNBC). (Phase I)

II. Assess objective response rate (ORR) with RPTD of romidepsin, plus cisplatin combined with nivolumab. (Phase II)


I. Assess pharmacokinetics of romidepsin when administered with cisplatin. (Phase I)

II. Assess pharmacokinetics of romidepsin when administered with cisplatin and nivolumab. (Phase II lead-in)

III. Determine clinical benefit rate (CBR) at 9 weeks of study treatment for subjects treated at the RPTD. (Phase II)

IV. Determine progression-free survival (PFS) and overall survival (OS). (Phase II)


I. Investigate the correlation of breast cancer (BRCA) deficiency/BRCAness with clinical response.

OUTLINE: This is a phase I dose-escalation study of romidepsin followed by a phase II study.

PHASE I: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and romidepsin IV over 4 hours on days 2 and 9. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive cisplatin and romidepsin as in phase I, and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with stable disease/partial response (PR)/complete response (CR) after 4 (for phase II patients) or 6 (for phase I patients) courses of treatment, patients can either continue all study drugs until disease progression/unacceptable toxicity or cisplatin can be stopped (at the discretion of the treating physician) with continuation of nivolumab and romidepsin until disease progression/unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months for 36 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
University of Kansas Cancer Center

Principal Investigator
Priyanka Sharma

  • Primary ID IIT-2014-PS-BRST-CISRomiTNBC
  • Secondary IDs NCI-2015-01524, STUDY00002219, RM-CL-BRST-PI-002783
  • ID NCT02393794