Cabozantinib and Nivolumab for Carcinoid Tumors

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Brief Title

Cabozantinib and Nivolumab for Carcinoid Tumors

Official Title

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 Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective Response Rate (ORR)

Secondary Outcome

 Progression-free survival (PFS)

Condition

Carcinoid Tumor

Intervention

Nivolumab

Study Arms / Comparison Groups

 Nivolumab and Cabozantinib
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

35

Start Date

December 26, 2019

Completion Date

December 26, 2022

Primary Completion Date

December 26, 2021

Eligibility Criteria

        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.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Kimberly Perez, MD, 877-DF-TRIAL, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04197310

Organization ID

19-403


Responsible Party

Principal Investigator

Study Sponsor

Dana-Farber Cancer Institute

Collaborators

 Bristol-Myers Squibb

Study Sponsor

Kimberly Perez, MD, Principal Investigator, Dana-Farber Cancer Institute


Verification Date

January 2020