A Phase II Study of Nivolumab in Combination With Cabozantinib for Metastatic Triple-negative Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms
Intervention: Nivolumab; Cabozantinib
Intervention description: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer.; Cabozantinib may help to shrink or stabilize breast cancer
Intervention MeSH terms: Nivolumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer

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
    

Eligibility 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 human epidermal growth factor receptor 2 (HER2)
             negative by IHC or non-amplified as determined by the current American Society of
             Clinical Oncology (ASCO)/CAP (College of American Pathologists) 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 Cycle 3 Day 1. 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 (Eastern Cooperative Oncology Group) performance status ≤1(Karnofsky ≥60%, see
             Appendix A)

          -  Participants must have normal organ and marrow function as defined below:

               -  absolute neutrophil count ≥1,000/microliter (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)

               -  Aspartate aminotransferase (AST) / Alanine transaminase (ALT) ≤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 eligible.

          -  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-programmed cell death-1 (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, Note: Complete healing of an
                  intra-abdominal abscess must be confirmed prior to randomization

          -  Other clinically significant disorders that would preclude safe study participation;

          -  Corrected Fridericia's QT interval (QTcF) interval >500 msec Note: 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.

        Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose
        low molecular weight heparin (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).

        Note: 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. For example, participants with
             autoimmune disease that requires systemic steroids or immunosuppression agents should
             be excluded. Replacement therapy (eg., thyroxine, insulin, or physiologic
             corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is
             not considered a form of systemic treatment.

          -  The participant is known to be positive for the human immunodeficiency virus (HIV),
             HepBsAg, or Hepatitis C virus (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, bacille Calmette-Guerin (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

               -  Clinically significant hemoptysis within 3 months of 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