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A Phase II Study of Nivolumab in Combination With Cabozantinib for Metastatic Triple-negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT03316586
Recruitment Status : Recruiting
First Posted : October 20, 2017
Last Update Posted : August 28, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
Exelixis
Information provided by (Responsible Party):
Sara Tolaney, Dana-Farber Cancer Institute

Brief Summary:

This research study is studying a combination of drugs as a possible treatment for metastatic triple-negative breast cancer.

The drugs involved in this study are:

  • Cabozantinib (XL184)
  • Nivolumab

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Nivolumab Drug: Cabozantinib Phase 2

Detailed Description:

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 studied.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of Nivolumab and Cabozantinib as a treatment for any disease.

The FDA has not approved Cabozantinib for this specific disease but it has been approved for other uses. The FDA (the U.S. Food and Drug Administration) has not approved nivolumab for this specific disease but it has been approved for other uses.

Cabozantinib has been used in some phase I studies and information from those other research studies suggests that cabozantinib may help to shrink or stabilize breast cancer.

Cancers are recognized by the immune system, and under some circumstances, the immune system may control or even eliminate tumors. An antibody is a natural protein made by the immune system that binds other proteins and molecules to fight infection and its ill effects. Antibodies stimulating the immune system have been developed for treatment of human cancers. Nivolumab is an experimental antibody drug that may make the immune response more active against cancer.

In this research study, the investigators are looking at how the participant's type of breast cancer responds to the combination of cabozantinib and nivolumab.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Nivolumab in Combination With Cabozantinib for Metastatic Triple-negative Breast Cancer
Actual Study Start Date : November 30, 2017
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Nivolumab + Cabozantinib
  • Nivolumab given every 4 weeks intravenously
  • Cabozantinib given orally once daily
Drug: Nivolumab
Nivolumab is an experimental antibody drug that may make the immune response more active against cancer.
Other Name: Opdivo

Drug: Cabozantinib
Cabozantinib may help to shrink or stabilize breast cancer
Other Name: Cabometyx




Primary Outcome Measures :
  1. Overall Response Rate [ Time Frame: 2 years ]
    Will be defined according to RECIST 1.1


Secondary Outcome Measures :
  1. Number of participants with adverse events [ Time Frame: 2 years ]
    Toxicities will be defined according to NCI CTCAE, Version 4.0

  2. Clinical Benefit Rate [ Time Frame: 2 years ]
    CBR will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 24 weeks, per RECIST 1.1

  3. Progression Free Survival Rate [ Time Frame: 5 years ]
    PFS will be determined by using RECIST 1.1

  4. Overall Response Rate per Immune Criteria [ Time Frame: 2 years ]
    ORR will be determined according to immune-related response criteria (irRC)



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Participants must have histologically or cytologically confirmed invasive breast cancer, with 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 <10% by immunohistochemistry (IHC) and HER2 negative by IHC or non-amplified as determined by the current ASCO-CAP criteria. If patient has more than one histological result, the most recent one has to be considered for inclusion.
  • Participants must have measurable disease by RECIST version 1.1
  • Participants must agree to undergo a research biopsy, if tumor is safely accessible, at baseline and 7-14 days prior to C3D1. Participants for whom newly-obtained samples cannot be provided (e.g. inaccessible or participant safety concern) may submit an archived specimen.

Note: After the first 6 participants undergo biopsy on cabozantinib, we will review their adverse event profiles to ensure no more than a 20% rate of grade 3 or higher bleeding or wound healing complications occur. If more than 2 patients (>20%) have safety concerns, we will reassess the safety of collecting the research biopsies. Full review of all grade (including grade 1 and 2) may also prompt changes and will be reviewed by the study team. Exelixis may be consulted if necessary.

  • Prior chemotherapy: Participants may have received 0-3 prior chemotherapeutic regimens for metastatic breast cancer and must have been off treatment with chemotherapy for at least 14 days prior to registration. Participants should also be adequately recovered from acute toxicities of prior treatment.
  • Prior biologic therapy: Patients must have discontinued all biologic therapy at least 14 days prior to registration.
  • Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed per the following timelines:

    • Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior to registration.
    • Radiotherapy to bone lesions within 2 weeks prior to registration.
    • Radiotherapy to any other site within 4 weeks prior to registration.
  • In all cases, there must be complete recovery and no ongoing complications from prior radiotherapy.
  • 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 ≥1,000/mcL
    • platelets ≥100,000/mcL
    • hemoglobin ≥ 9 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

      ≤ 3 × institutional ULN for participants with documented liver metastases

    • creatinine <1.5 ×institutional ULN OR creatinine clearance ≥40 mL/min (using Cockcroft-Gault formula) for participants with creatinine levels above institutional ULN.
    • Urine protein/creatinine ratio (UPCR) ≤1
  • Female subjects of childbearing potential must have a negative pregnancy test at screening
  • 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 has not undergone surgical sterilization (removal of ovaries and/or uterus).
  • Female and male participants of childbearing potential 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. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
  • Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment.
  • The participant is capable of understanding and complying with the protocol and has signed the informed consent document

Exclusion Criteria:

  • Major surgery within 12 weeks before the first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment. No clinically relevant ongoing complications from prior surgery are not eligibile.
  • The participant has tumor in contact with, invading, or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions.
  • The subject has pathologic evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib;
  • Concurrent administration of other anti-cancer therapy within 14 days of starting protocol therapy and during the course of this study.
  • The participant has received another investigational agent within 14 days of the first dose of study drug.
  • The participant has received a prior c-Met inhibitor
  • Has received 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, or a combination as deemed appropriate by the treating physician. Participants with CNS metastases treated by neurosurgical resection or brain biopsy performed within 2 months before day 1 will be excluded.
  • The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    • Cardiovascular disorders including:
    • Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening;
    • Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment;
    • Any history of congenital long QT syndrome;
    • Any of the following within 6 months before the first dose of study treatment:
    • unstable angina pectoris;
    • clinically-significant cardiac arrhythmias;
    • stroke (including transient ischemic attack (TIA), or other ischemic event);
    • myocardial infarction;
    • GI disorders particularly those associated with a high risk of perforation or fistula formation including:
    • Tumors invading the GI tract, active peptic ulcer disease, active inflammatory bowel disease (eg, Crohn's disease), active diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
    • Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal abscess within 6 months before randomization,
  • Complete healing of an intra-abdominal abscess must be confirmed prior to randomization
  • Other clinically significant disorders that would preclude safe study participation;
  • QTcF interval >500 msec
  • Three ECGs must be performed for eligibility determination. If the average of these three consecutive results for QTcF is ≤ 500 msec, the subject meets eligibility in this regard.
  • Thromboembolic events requiring therapeutic anticoagulation. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors), platelet inhibitors (eg, clopidogrel) are prohibited.
  • Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose LMWH are permitted (in subjects who are on a stable dose of LMWH for at least 6 weeks before the first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor).
  • Subjects with a venous filter (eg vena cava filter) are not eligible for this study).
  • Individuals with a history of different 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.
  • Participant has an active infection requiring IV antibiotics
  • Patient has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication.
  • The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants on combination antiretroviral therapy are ineligible.
  • Known hypersensitivity to any of the components of cabozantinib or nivolumab.
  • The participant has received a live vaccine within 28 days prior to the first dose of trial treatment and while participating in the trial. 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 (Fluzone®) is allowed.
  • The subject has experienced any of the following:

    • Clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment
    • Hemoptysis of >0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment
    • Any other signs indicative of pulmonary hemorrhage within 3 months before the start of study treatment
  • The participant is unable to swallow oral dosage forms.
  • The participant is pregnant or breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03316586


Contacts
Contact: Sara Tolaney, MD 617-632-3800 sara_tolaney@dfci.harvard.edu
Contact: Chelsea Andrews 617-632-6210 chelseap_andrews@dfci.harvard.edy

Locations
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Kelley Cassidy    617-632-3548    ckelley14@partners.org   
Principal Investigator: Sara Tolaney, MD         
Sponsors and Collaborators
Dana-Farber Cancer Institute
Bristol-Myers Squibb
Exelixis
Investigators
Principal Investigator: Sara Tolaney, MD Dana-Farber Cancer Institute

Responsible Party: Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT03316586     History of Changes
Other Study ID Numbers: 17-324
First Posted: October 20, 2017    Key Record Dates
Last Update Posted: August 28, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Sara Tolaney, Dana-Farber Cancer Institute:
Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs