Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Cabozantinib and Nivolumab for Carcinoid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04197310
Recruitment Status : Recruiting
First Posted : December 13, 2019
Last Update Posted : January 6, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Exelixis
Information provided by (Responsible Party):
Kimberly Perez, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE December 11, 2019
First Posted Date  ICMJE December 13, 2019
Last Update Posted Date January 6, 2020
Actual Study Start Date  ICMJE December 26, 2019
Estimated Primary Completion Date December 26, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
Objective Response Rate (ORR) [ Time Frame: 2 years ]
Determine the number of patients who demonstrated a clinical response assessed by RECIST 1.1 criteria on imaging to the combination of Cabozantinib and Nivolumab
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 13, 2019)
  • Progression-free survival (PFS) [ Time Frame: 2 years ]
    Determine the progression free survival, by using RECIST 1.1, derived from the combination of Cabozantinib and Nivolumab.
  • Overall Response Rate (ORR) per immune-related response criteria [ Time Frame: 2 years ]
    ORR will be determined according to immune-related response criteria (irRC).
  • Overall survival (OS) [ Time Frame: 2 years ]
    Evaluate OS in patients receiving the combination of Cabozantinib and Nivolumab.
  • Number of Participants with Treatment Related Adverse Events [ Time Frame: 2 years ]
    Toxicities will be defined according to NCI CTCAE version 5.0
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2019)
  • Progression-free survival (PFS) [ Time Frame: 2 years ]
    Determine the progression free survival, by using RECIST 1.1, derived from the combination of Cabozantinib and Nivolumab.
  • Overall Response Rate (ORR) per immune-related response criteria [ Time Frame: 2 years ]
    ORR will be deterined according to immune-related response criteria (irRC).
  • Overall survival (OS) [ Time Frame: 2 years ]
    Evaluate OS in patients receiving the combination of Cabozantinib and Nivolumab.
  • Number of Participants with Treatment Related Adverse Events [ Time Frame: 2 years ]
    Toxicities will be defined according to NCI CTCAE version 5.0
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cabozantinib and Nivolumab for Carcinoid Tumors
Official Title  ICMJE Phase II Trial of Cabozantinib in Combination With Nivolumab for Advanced Carcinoid Tumors
Brief Summary

This research study, is studying the combination of cabozantinib and nivolumab in treating advanced carcinoid tumors.

- Carcinoid tumor is another term used to refer to neuroendocrine tumors that arise in organs such as the gastrointestinal tract, lungs, or thymus.

Detailed Description

This is open-label, single-arm, phase II research study, studying the combination of cabozantinib and nivolumab in treating advanced carcinoid tumors. Carcinoid tumor is another term used to refer to neuroendocrine tumors that arise in organs such as the gastrointestinal tract, lungs, or thymus.

  • The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.
  • Cabozantinib will be administered orally, once daily
  • Nivolumab will be administered intravenously, every two weeks
  • The target enrollment for this study is 35 participants.
  • The U.S. Food and Drug Administration (FDA) has not approved cabozantinib or nivolumab for treating carcinoid tumors.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Carcinoid Tumor
  • Carcinoid Tumor of GI System
  • Neuroendocrine Tumors
Intervention  ICMJE
  • Drug: Nivolumab
    240mg, intravenously, Day 1 and 15 of a 28 day cycle
    Other Name: Opdivo
  • Drug: Cabozantinib
    40mg, orally, Daily for a 28 day cycle
    Other Names:
    • Cometriq
    • Cabometyx
Study Arms  ICMJE Experimental: Nivolumab and Cabozantinib

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

  • Cabozantinib will be administered at a dose of 40mg orally, once daily
  • Nivolumab will be given at a dose of 240mg every 14 days, intravenously

Retreat Phase (Optional)

  • Participants may elect to stop nivolumab and cabozantinib with confirmed CR after at least 24 weeks of treatment.
  • Participants who elect to stop and then the condition progresses after stopping study treatment may be eligible to resume nivolumab and cabozantinib therapy.
  • This resumption will be termed as a retreatment second course phase and is available only while the study remains open and the subject meets specified criteria.
Interventions:
  • Drug: Nivolumab
  • Drug: Cabozantinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 11, 2019)
35
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 26, 2022
Estimated Primary Completion Date December 26, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with locally unresectable or metastatic well-differentiated neuroendocrine tumor of non-pancreatic (ie, carcinoid) origin
  • Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. See Section 11 for the evaluation of measurable disease.
  • Patients must have evidence of radiographic disease progression within the past 12 months.
  • Patients who have received at least one line of therapy, which can include somatostatin analog therapy. Participants should be adequately recovered from acute toxicities of prior treatment.

    • Prior somatostatin analog therapy is allowed. Continuation of somatostatin analog therapy is allowed provided that the dose has been stable for 2 months.
    • Prior chemotherapy: Participants must have been off treatment with cytotoxic chemotherapy for at least 14 days prior to registration.
    • Prior biologic therapy: Patients must have discontinued all biologic therapy at least 28 days prior to registration. Duration may be shorted to 14 days for agents with short half-lives.
    • Prior radiolabeled somatostatin analog therapy: Participants must have completed radiolabeled somatostatin analog therapy at least 6 weeks prior to registration.
    • Prior hepatic artery embolization or ablative therapies is allowed if measurable disease remains outside the treated area or there is documented disease progression in a treated site. Prior liver-directed or ablative treatment must be completed at least 28 days prior to registration.
    • Prior radiation therapy: Radiation therapy must be completed per the following timelines

      • i) Radiotherapy to the thoracic cavity or abdomen within 4 weeks prior to registration.
      • ii) Radiotherapy to bone lesions within 2 weeks prior to registration.
      • iii) Radiotherapy to any other site within 4 weeks prior to registration.
      • NOTE: In all cases, there must be complete recovery and no ongoing complications from prior radiotherapy.
  • Age ≥ 18 years.
  • ECOG performance status ≤1 (Karnofsky ≥60%, see Appendix A)
  • Participants must have normal organ and marrow function as defined below:

    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • 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 × ULN or ≤ 3 × ULN for participants with documented liver metastases
    • creatinine <1.5 × ULN Or creatinine clearance ≥40 mL/min (using Cockcroft-Gault formula) for participants with creatinine levels above institutional normal
    • Urine protein/creatinine ratio (UPCR) ≤ 1
    • PT/INR or partial thromboplastin time (PTT) test < 1.3 the laboratory ULN within 7 days before the first dose of study treatment.
  • Negative urine pregnancy test for women of childbearing potential.
  • Participant must be able to swallow pills.
  • The participant is capable of understanding and complying with the protocol and has signed the informed consent document.

Exclusion Criteria:

  • Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment. Complete wound healing from major surgery must have occurred 1 month before first dose and from minor surgery (eg, simple excision, tooth extraction) at least 10 days before first dose. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  • Participants who are receiving any other investigational agents.
  • Participants who have received a prior cabozantinib.
  • Participants who have 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 nivolumab, pembrolizumab, ipilimumab, and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
  • Participants with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • The participant has tumor in contact with, invading, or encasing major blood vessels or radiographic evidence of significant cavitary pulmonary lesions.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to cabozantinib or nivolumab.
  • Participants receiving any strong inhibitors or inducers of CYP3A4 within 14 days prior to registration are ineligible. Chronic treatment with strong inhibitors or inducers of CYP3A4 is not allowed.
  • 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;
    • QTcF interval >500 msec
    • 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 screening
  • Thromboembolic events within 6 months of registration.

    • Note: Low dose aspirin ≤ 81 mg/day is allowed. Anticoagulation with therapeutic doses of LMWH is allowed in patients who are on a stable dose of LMWH for at least 6 weeks prior to registration. Treatment with warfarin is not allowed.
  • The subject has experienced any significant bleeding episodes, including:

    • Clinically significant gastrointestinal bleeding within 6 months before the first dose of study treatment
    • Clinically significant hemoptysis (> 0.5 teaspoon) 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
    • 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
  • Any active, known, or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (e.g. celiac disease) are permitted to enroll.
  • Patient has a medical condition that requires chronic systemic steroid therapy or on any other form of immunosuppressive medication. Adrenal replacement steroid disease are permitted in the absence of autoimmune disease.
  • The participant is known to be positive for the human immunodeficiency virus (HIV), HepBsAg, or HCV RNA. HIV-positive participants with non-detectable viral loads on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cabozantinib and 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.
  • Pregnant or lactating females are excluded from this study because cabozantinib and nivolumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib and nivolumab, breastfeeding should be discontinued if the mother is treated with cabozantinib and nivolumab. These potential risks may also apply to other agents used in this study.
  • Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and following treatment. Women of childbearing potential receiving nivolumab will be instructed to adhere to contraception for a period of 5 months after the last dose of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 7 months after the last dose of nivolumab. Contraception must be used for 4 months after last dose of cabozantinib.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kimberly Perez, MD 877-DF-TRIAL Kimberly_perez@dfci.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04197310
Other Study ID Numbers  ICMJE 19-403
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data can be shared no earlier than 1 year following the date of publication
Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu
Responsible Party Kimberly Perez, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Exelixis
Investigators  ICMJE
Principal Investigator: Kimberly Perez, MD Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP