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Breast CancerPhase 2NCT03316586

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

A Phase 2 study testing Nivolumab and Cabozantinib in people with Breast Cancer, run by Dana-Farber Cancer Institute at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
Nivolumab and Cabozantinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
18 participants
Where
1 siteUnited States
Study dates
30 Nov 2017to 30 Aug 2019
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

Other trials in United States

About this study

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
Read the 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.

Conditions
Breast Cancer
Being tested
Nivolumab, Cabozantinib
Keywords
Breast Cancer
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NivolumabDrug

    Also called Opdivo

    Nivolumab is an experimental antibody drug that may make the immune response more active against cancer.

  • CabozantinibDrug

    Also called Cabometyx

    Cabozantinib may help to shrink or stabilize breast cancer

Study groups in NCT03316586
Study groupRoleWhat they receive
Nivolumab + CabozantinibExperimental* Nivolumab was administered every 28 days at a dose of 480mg given intravenously over 30 minutes (+/- 10 minutes) using a volumetric pump with 0.2 to 1.2 micron pore size, low protein binding polyethersulfone membrane in-line filter * Cabozantinib was administered orally, once daily for 28 days at a dose of 40 mg.
Receives: Drug: Nivolumab; Drug: Cabozantinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response Rate

    Overall response rate (ORR) is defined as the percentage of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    Measured: 2 years

Secondary outcomes (4)

  1. Number of Participants With Adverse Events

    Toxicities will be defined according to NCI CTCAE, Version 4.0

    Measured: 2 years

  2. Clinical Benefit Rate

    Clinical Benefit Rate (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

    Measured: 2 years

  3. Progression Free Survival Rate

    Progression free survival is defined from the study entry to first documented evidence of disease progression by RECIST 1.1 or death of any cause, whichever occurs first. Patients alive with no progression are censored at the last disease assessment.

    Measured: 5 years

  4. Overall Response Rate Per Immune Criteria

    ORR will be determined according to immune-related response criteria (irRC). Per irRC, irComplete Response (irCR) refers to complete disappearance of all target lesions. irPartial Response (irPR) refers to decrease, relative to baseline, of 50% or greater in the sum of the products of the two largest perpendicular diameters of all target and all new measurable target lesions (i.e., Percentage Change in Tumor Burden). ORR per irRC is irCR + irPR.

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Oct 2017
  2. Study start30 Nov 2017
  3. Primary completion30 Aug 2019
  4. Study completion30 Aug 2019

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
18 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03316586
Sponsor's protocol ID
17-324
Status last verified
Nov 2021
First submitted
18 Oct 2017
Last updated
28 Dec 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and Cabozantinib in people with Breast Cancer, run by Dana-Farber Cancer Institute at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 38 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Dec 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 28 Dec 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (time frame: 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03316586.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Dec 2021.

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