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

• Sponsor: Dana-Farber Cancer Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT03316586
• Collaborator: Bristol-Myers Squibb (Industry), Exelixis (Industry)
• Enrollment: 18
• Location: 1
• Arm: 1
• Actual Duration (Months): 21
• Patients Per Site Per Month: 0.9

Study Details

Study Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• 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: Nov 30, 2017
• Actual Primary Completion Date: Aug 30, 2019
• Actual Study Completion Date: Aug 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nivolumab + Cabozantinib 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.	Drug: Nivolumab; Nivolumab is an experimental antibody drug that may make the immune response more active against cancer.; Other Names: Opdivo ; Drug: Cabozantinib; Cabozantinib may help to shrink or stabilize breast cancer; Other Names: Cabometyx

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [2 years]

   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.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [2 years]

   Toxicities will be defined according to NCI CTCAE, Version 4.0

2. Clinical Benefit Rate [2 years]

   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

3. Progression Free Survival Rate [5 years]

   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.

4. Overall Response Rate Per Immune Criteria [2 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Dana-Farber Cancer Institute
• Bristol-Myers Squibb
• Exelixis

Investigators

• Principal Investigator: Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 9, 2019

More Information

Publications

None provided.

• Responsible Party: Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT03316586
• Other Study ID Numbers: 17-324
• First Posted: Oct 20, 2017
• Last Update Posted: Dec 28, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• 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, Principal Investigator, Dana-Farber Cancer Institute: Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Nivolumab

Study Results

Participant Flow

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Period Title: Overall Study
STARTED	18
COMPLETED	0
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Overall Participants	18
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	18 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5.6%
White	15 83.3%
More than one race	1 5.6%
Unknown or Not Reported	1 5.6%
Region of Enrollment (Count of Participants)
United States	18 100%
ECOG (Count of Participants)
0	18 100%
1	0 0%
Stage at initial Diagnosis (Count of Participants)
I	3 16.7%
II	6 33.3%
III	2 11.1%
IV	5 27.8%
Unknown	2 11.1%
Disease free interval (Count of Participants)
De novo	5 27.8%
<=2 years	4 22.2%
>2 years	5 27.8%
Date missing	4 22.2%
Sites of disease -- lung pleural (Count of Participants)
Count of Participants [Participants]	6 33.3%
Sites of disease -- liver (Count of Participants)
Count of Participants [Participants]	7 38.9%
Sites of disease -- bone (Count of Participants)
Count of Participants [Participants]	8 44.4%
Sites of disease -- Breast/chest wall (Count of Participants)
Count of Participants [Participants]	7 38.9%
Sites of disease -- Lymph node (Count of Participants)
Count of Participants [Participants]	11 61.1%
Sites of disease -- Soft tissue (Count of Participants)
Count of Participants [Participants]	3 16.7%
Adjuvant or neoadjuvant hormonal therapy (Count of Participants)
Count of Participants [Participants]	1 5.6%
Adjuvant or or neoadjuvant anthracycline (Count of Participants)
Count of Participants [Participants]	12 66.7%
Adjuvant or neoadjuvant taxane (Count of Participants)
Count of Participants [Participants]	12 66.7%
Lines of chemotherapy for metastasis or recurrence (line) [Median (Full Range) ]
Median (Full Range) [line]	1
Lines of chemotherapy for metastasis or recurrence (Count of Participants)
0	5 27.8%
1	6 33.3%
2	5 27.8%
3	2 11.1%
Prior metastatic chemotherapy -- Anthracycline (Count of Participants)
Count of Participants [Participants]	4 22.2%
Prior metastatic chemotherapy -- Taxane (Count of Participants)
Count of Participants [Participants]	5 27.8%
Prior metastatic chemotherapy -- Platinum (Count of Participants)
Count of Participants [Participants]	11 61.1%
Prior metastatic chemotherapy -- Capecitabine (Count of Participants)
Count of Participants [Participants]	2 11.1%
Prior metastatic chemotherapy -- Eribulin (Count of Participants)
Count of Participants [Participants]	2 11.1%
Prior metastatic chemotherapy -- Other chemotherapy (Count of Participants)
Count of Participants [Participants]	6 33.3%
ER, PR, and HER2 status at study entry (Count of Participants)
ER and/or PR-positive (≤10%), HER2-negative	2 11.1%
ER and PR negative, HER2-negative	16 88.9%
PD-L1 positive cells (Count of Participants)
Count of Participants [Participants]	1 5.6%
TILs in metastatic samples (Count of Participants)
Count of Participants [Participants]	3 16.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

For this Phase II trial, the efficacy evaluable population is a modified intent-to-treat (ITT) population. The modified ITT population consists of all patients who initiate protocol therapy, even if there are major protocol therapy deviations.

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Measure Participants	18
Count of Participants [Participants]	1 5.6%

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Toxicities will be defined according to NCI CTCAE, Version 4.0
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

For this Phase II trial, the efficacy evaluable population is a modified intent-to-treat (ITT) population. The modified ITT population consists of all patients who initiate protocol therapy, even if there are major protocol therapy deviations.

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Measure Participants	18
Count of Participants [Participants]	18 100%

3. Secondary Outcome

Title	Clinical Benefit Rate
Description	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
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

For this Phase II trial, the efficacy evaluable population is a modified intent-to-treat (ITT) population. The modified ITT population consists of all patients who initiate protocol therapy, even if there are major protocol therapy deviations.

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Measure Participants	18
Count of Participants [Participants]	3 16.7%

4. Secondary Outcome

Title	Progression Free Survival Rate
Description	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.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

For this Phase II trial, the efficacy evaluable population is a modified intent-to-treat (ITT) population. The modified ITT population consists of all patients who initiate protocol therapy, even if there are major protocol therapy deviations.

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Measure Participants	18
Median (95% Confidence Interval) [months]	3.6

5. Secondary Outcome

Title	Overall Response Rate Per Immune Criteria
Description	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.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

For this Phase II trial, the efficacy evaluable population is a modified intent-to-treat (ITT) population. The modified ITT population consists of all patients who initiate protocol therapy, even if there are major protocol therapy deviations.

Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
Measure Participants	18
irPR	1 5.6%
irSD	14 77.8%
irPD	2 11.1%
not evaluable	1 5.6%

Adverse Events

Time Frame	AE data were collected every cycle from the time of the first dose of the study treatment, through the end of the treatment. Vital status was followed even after patients were off treatment. AEs, including overall mortality, were observed up to 60 months.
Adverse Event Reporting Description	Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
Arm/Group Title	Nivolumab + Cabozantinib
Arm/Group Description	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. Nivolumab: Nivolumab is an experimental antibody drug that may make the immune response more active against cancer. Cabozantinib: Cabozantinib may help to shrink or stabilize breast cancer
All Cause Mortality
	Nivolumab + Cabozantinib
	Affected / at Risk (%)	# Events
Total	3/18 (16.7%)
Serious Adverse Events
	Nivolumab + Cabozantinib
	Affected / at Risk (%)	# Events
Total	13/18 (72.2%)
Blood and lymphatic system disorders
Anemia	1/18 (5.6%)
Endocrine disorders
Endocrine disorders - Other, specify	1/18 (5.6%)
Gastrointestinal disorders
Small intestinal perforation	1/18 (5.6%)
General disorders
Edema trunk	1/18 (5.6%)
Fatigue	2/18 (11.1%)
Infections and infestations
Appendicitis	1/18 (5.6%)
Investigations
Alanine aminotransferase increased	2/18 (11.1%)
Aspartate aminotransferase increased	3/18 (16.7%)
Metabolism and nutrition disorders
Dehydration	1/18 (5.6%)
Hypokalemia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	1/18 (5.6%)
Nervous system disorders
Syncope	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/18 (5.6%)
Hypoxia	1/18 (5.6%)
Pneumonitis	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	3/18 (16.7%)
Vascular disorders
Hypertension	2/18 (11.1%)
Thromboembolic event	2/18 (11.1%)
Other (Not Including Serious) Adverse Events
	Nivolumab + Cabozantinib
	Affected / at Risk (%)	# Events
Total	17/18 (94.4%)
Blood and lymphatic system disorders
Anemia	1/18 (5.6%)
Lymph node pain	1/18 (5.6%)
Cardiac disorders
Palpitations	1/18 (5.6%)
Endocrine disorders
Endocrine disorders - Other, specify	1/18 (5.6%)
Hyperthyroidism	3/18 (16.7%)
Hypothyroidism	7/18 (38.9%)
Gastrointestinal disorders
Abdominal pain	1/18 (5.6%)
Constipation	2/18 (11.1%)
Diarrhea	5/18 (27.8%)
Dry mouth	3/18 (16.7%)
Dyspepsia	1/18 (5.6%)
Dysphagia	1/18 (5.6%)
Flatulence	1/18 (5.6%)
Gastroesophageal reflux disease	1/18 (5.6%)
Mucositis oral	3/18 (16.7%)
Nausea	2/18 (11.1%)
Oral pain	2/18 (11.1%)
Vomiting	2/18 (11.1%)
General disorders
Death NOS	1/18 (5.6%)
Edema face	1/18 (5.6%)
Edema limbs	4/18 (22.2%)
Edema trunk	1/18 (5.6%)
Fatigue	7/18 (38.9%)
Pain	2/18 (11.1%)
Immune system disorders
Allergic reaction	1/18 (5.6%)
Infections and infestations
Infections and infestations - Other, specify	1/18 (5.6%)
Skin infection	1/18 (5.6%)
Upper respiratory infection	1/18 (5.6%)
Injury, poisoning and procedural complications
Spinal fracture	1/18 (5.6%)
Wound complication	1/18 (5.6%)
Investigations
Alanine aminotransferase increased	6/18 (33.3%)
Aspartate aminotransferase increased	9/18 (50%)
Creatinine increased	1/18 (5.6%)
Neutrophil count decreased	4/18 (22.2%)
Platelet count decreased	1/18 (5.6%)
Weight loss	1/18 (5.6%)
Metabolism and nutrition disorders
Anorexia	7/18 (38.9%)
Dehydration	1/18 (5.6%)
Hyponatremia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Back pain	5/18 (27.8%)
Chest wall pain	1/18 (5.6%)
Generalized muscle weakness	1/18 (5.6%)
Muscle weakness lower limb	1/18 (5.6%)
Musculoskeletal and connective tissue disorder - Other, specify	1/18 (5.6%)
Myalgia	6/18 (33.3%)
Neck pain	2/18 (11.1%)
Nervous system disorders
Dysgeusia	4/18 (22.2%)
Headache	2/18 (11.1%)
Peripheral sensory neuropathy	1/18 (5.6%)
Presyncope	1/18 (5.6%)
Psychiatric disorders
Anxiety	1/18 (5.6%)
Depression	1/18 (5.6%)
Renal and urinary disorders
Chronic kidney disease	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/18 (5.6%)
Cough	4/18 (22.2%)
Dyspnea	3/18 (16.7%)
Hypoxia	1/18 (5.6%)
Pleural effusion	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders - Other, specify	1/18 (5.6%)
Sore throat	1/18 (5.6%)
Voice alteration	4/18 (22.2%)
Skin and subcutaneous tissue disorders
Alopecia	2/18 (11.1%)
Dry skin	2/18 (11.1%)
Palmar-plantar erythrodysesthesia syndrome	7/18 (38.9%)
Pruritus	2/18 (11.1%)
Rash maculo-papular	1/18 (5.6%)
Vascular disorders
Hypertension	5/18 (27.8%)
Thromboembolic event	1/18 (5.6%)

Limitations/Caveats

Only one of the first 18 patients had a PR. The study therefore did not meet the prespecified criteria to proceed to the second stage of the trial, and it was closed to further accrual.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.