Clinical Trials /

Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors

NCT04079712

Description:

This phase II trial studies how well the combination of XL184 (cabozantinib), nivolumab, and ipilimumab work in treating patients with poorly differentiated neuroendocrine tumors (i.e., neuroendocrine tumor that does not look like the normal tissue it arose from). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib, nivolumab and ipilimumab may shrink the cancer.

Related Conditions:
  • Neuroendocrine Neoplasm
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of XL184 (Cabozantinib), Nivolumab, and Ipilimumab for Poorly Differentiated Neuroendocrine Tumors
  • Official Title: A Phase 2 Study of XL184 (Cabozantinib) in Combination With Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-05864
  • SECONDARY ID: NCI-2019-05864
  • SECONDARY ID: 10315
  • SECONDARY ID: 10315
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT04079712

Conditions

  • Metastatic Large Cell Neuroendocrine Carcinoma
  • Metastatic Neuroendocrine Carcinoma
  • Metastatic Neuroendocrine Neoplasm
  • Metastatic Small Cell Carcinoma

Interventions

DrugSynonymsArms
CabozantinibTreatment (cabozantinib, nivolumab, ipilimumab)
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib, nivolumab, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (cabozantinib, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (cabozantinib, nivolumab, ipilimumab)

Purpose

This phase II trial studies how well the combination of XL184 (cabozantinib), nivolumab, and ipilimumab work in treating patients with poorly differentiated neuroendocrine tumors (i.e., neuroendocrine tumor that does not look like the normal tissue it arose from). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib, nivolumab and ipilimumab may shrink the cancer.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the overall response rate (ORR) associated with the combination of XL184
      (cabozantinib), nivolumab, and ipilimumab in patients with advanced poorly-differentiated
      neuroendocrine carcinomas (NECs), after the failure of at least one line of prior therapy.

      SECONDARY OBJECTIVES:

      I. To evaluate progression-free survival (PFS). II. To measure the safety and tolerability of
      the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced,
      poorly-differentiated NECs.

      III. To evaluate disease control rate (DCR). IV. To measure duration of response (DOR). V. To
      describe the tumor molecular profile using whole exome sequencing (WES) and correlate it with
      treatment outcome.

      VI. To describe the tumor molecular profile using ribonucleic acid (RNA) sequencing (RNAseq)
      and correlate it with treatment outcome.

      EXPLORATORY OBJECTIVES:

      I. To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment biopsies.

      II. To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and
      on-treatment biopsies.

      III. To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and
      on-treatment biopsies.

      IV. To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and
      infiltrating immune cells.

      OUTLINE:

      Patients receive cabozantinib orally (PO) once daily (QD) on days 1-21 of cycles 1-4 and days
      1-28 of subsequent cycles, nivolumab intravenously (IV) over 30 minutes on day 1, and
      ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4
      cycles then every 28 days for subsequent cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 4 weeks, and then every 3
      months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib, nivolumab, ipilimumab)ExperimentalPatients receive cabozantinib PO QD on days 1-21 of cycles 1-4 and days 1-28 of subsequent cycles, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 90 minutes on day 1 of cycles 1-4 only. Treatment repeats every 21 for 4 cycles then every 28 days for subsequent cycles in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib
  • Cabozantinib S-malate
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have metastatic, histologically confirmed poorly-differentiated
             neuroendocrine neoplasms per 2018 World Health Organization (WHO) classification. All
             variations of poorly differentiated neuroendocrine carcinoma (small cell, large cell
             and mixed cells) are eligible

          -  Failure of only one line of prior systemic cancer treatment

          -  Patients must have measurable disease as defined by Response Evaluation Criteria in
             Solid Tumors (RECIST) version (v)1.1

          -  Patients must be willing to have a pre-treatment and an on-treatment biopsy (after 1
             month of treatment with the combination regimen) and a blood collection at baseline

          -  Prior systemic cancer therapy must have been completed at least 4 weeks prior to cycle
             1 day 1 of treatment with the combination regimen

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

          -  Leukocytes >= 3,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL without granulocyte-colony stimulating (GCSF)
             factor support

          -  Hemoglobin >= 9 g/dL

          -  Serum thyroid stimulating hormone (TSH) within institutional normal limits

          -  Platelets >= 100,000/mcL

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN); =< 3.0 x ULN for
             patients with Gilbert's syndrome

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3.0 x institutional ULN

          -  Alkaline phosphatase =< 3.0 x institutional ULN; =< 5.0 x ULN with documented bone
             metastases

          -  Creatinine =< institutional ULN OR creatinine clearance (CrCl) >= 50 mL/min/1.73 m^2
             (using the Cockcroft-Gault formula)

          -  Serum albumin >= 2.8 g/dL

          -  Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

          -  Urine protein/creatinine ratio (UPCR) =< 1 mg protein/mg creatinine

          -  Serum phosphorus, calcium, magnesium, and potassium within institutional normal limits

          -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
             time (PTT) test < 1.3 x ULN

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy utilizing agents that do not strongly induce or inhibit cytochrome P450 (CYP)
             3A4 with undetectable viral load within 6 months prior to study registration are
             eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression and are
             off steroid support for at least 4 weeks after treatment for metastases is complete
             and within 28 days prior to the first dose of study treatment. Radiotherapy should
             have been stopped at least 4 weeks prior to study registration. Brain surgery should
             not have occurred within 3 months of study registration to be eligible

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  The effects of XL184 (cabozantinib), nivolumab, and ipilimumab on the developing human
             fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men
             must agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry and for the duration of study participation. WOCBP
             should use an adequate method to avoid pregnancy for 5 months after the last dose of
             study therapy. Women of childbearing potential must have a negative serum or urine
             pregnancy test (minimum sensitivity: 25 IU/L or equivalent units of human chorionic
             gonadotropin [hCG]) within 24 hours prior to the start of study therapy. Women must
             not be breastfeeding. Men who are sexually active with WOCBP must use any
             contraceptive method with a failure rate of < 1% per year. Men who receive study
             therapy 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 study therapy. Women who
             are not of childbearing potential (i.e., who are postmenopausal or surgically sterile)
             as well as azoospermic men do not require contraception. WOCBP is defined as any
             female who has experienced menarche and who has not undergone surgical sterilization
             (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is
             defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of
             other biological or physiological causes. In addition, women under the age of 55 must
             have a documented serum follicle stimulating hormone (FSH) level < 40 mIU/mL. WOCBP
             and men who are sexually active with WOCBP will be instructed to adhere to
             contraception for a period of 5 and 7 months, respectively, after the last dose of
             study therapy. These durations have been calculated using the upper limit of the
             half-life for nivolumab (25 days) and are based on the protocol requirement that WOCBP
             use contraception for 5 half-lives plus 30 days and men who are sexually active with
             WOCBP use contraception for 5 half-lives plus 90 days. Should a woman become pregnant
             or suspect she is pregnant while she or her partner is participating in this study,
             she (or the participating partner) must inform the treating physician immediately

          -  Patients must be able to swallow tablets

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients must not require systemic corticosteroids treatment (>= 10 mg/day prednisone
             equivalents) or other immunosuppressive medications within 28 days prior to study drug
             administration. Inhaled or topical steroids and adrenal replacement doses < 10 mg/day
             prednisone equivalents are permitted in the absence of active autoimmune disease.
             Patients are permitted to use topical, ocular, intra-articular, intranasal, and
             inhalational corticosteroids (with minimal systemic absorption). Physiologic
             replacement doses of systemic corticosteroids in patients with adrenal insufficiency
             are permitted, even if >= 10 mg/day prednisone equivalents. A brief course of
             corticosteroids for prophylaxis or for treatment of non-autoimmune conditions (e.g.,
             delayed-type hypersensitivity reaction caused by contact allergen) is permitted, as is
             steroid pre-medication for contrast allergy

          -  Patients must not have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2,
             anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T cell
             co-stimulation or immune checkpoint pathways

          -  Patients must not have had prior treatment with XL184 (cabozantinib), or any
             MET-targeting tyrosine kinase inhibitor (TKI), or any MET-targeting monoclonal
             antibody (MetMAb), such as onartuzumab

          -  Patients must not have received radiation therapy to any part of the body within 28
             days

          -  Patients must not have clinically relevant, ongoing complications from prior radiation
             therapy. No radiation therapy is allowed while the patient is on study. Palliative
             radiation therapy, if needed, should be completed at least 28 days prior to enrollment
             into the study as described above

          -  Patients must not require concomitant treatment with oral anticoagulants (e.g.,
             warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (e.g.,
             clopidogrel). The following anticoagulants are allowed:

               -  Low-dose aspirin for cardioprotection (per local applicable guidelines),

               -  Low-dose low molecular weight heparins (LMWH),

               -  Therapeutic doses of LMWH are allowed in patients without known brain metastases
                  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

          -  Patients must not have had major surgery (e.g., gastrointestinal [GI] surgery or
             removal or biopsy of brain metastasis) within 4 weeks before first dose of study
             treatment. Complete wound healing from major surgery must have occurred 1 month before
             the first dose of study treatment and from minor surgery (e.g., simple excision or
             tooth extraction) at least 10 days before the first dose. Patients with clinically
             relevant ongoing complications from prior surgery are not eligible

          -  Patients must not have received cytotoxic chemotherapy (including investigational
             cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 4
             weeks, or nitrosoureas/ mitomycin C within 4 weeks, before the first dose of study
             treatment. Patients may continue on bone-modifying agents (denosumab or
             bisphosphonates) with caution

          -  Patients who have not recovered to baseline from adverse events due to prior
             anti-cancer therapy (i.e., have residual toxicities > grade 1) according to Common
             Terminology Criteria for Adverse Events (CTCAE) version (v)0.5 unless the adverse
             events (AEs) are clinically nonsignificant and/or stable on supportive therapy, with
             the exception of alopecia

          -  Patients who are receiving any other investigational agents. Patients must not have
             received any other type of investigational agent within 4 weeks before the first dose
             of study treatment to be eligible

          -  Patients must not have a corrected QT interval calculated by the Fridericia formula
             (QTcF) > 500 msec by electrocardiogram (EKG) within 28 days before the first dose of
             study treatment

               -  Note: If a single EKG shows a QTcF with an absolute value > 500 msec, two
                  additional EKGs at intervals of approximately 3 min must be performed within 30
                  min after the initial EKG, and the average of these three consecutive results for
                  QTcF will be used to determine eligibility

          -  Patients should not have known, untreated brain metastases or leptomeningeal
             metastases because of poor prognosis and concerns that progressive neurologic
             dysfunction could confound the evaluation of neurologic and other adverse events

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to agents used in study

          -  Patients must not have a history of severe hypersensitivity reactions to any
             monoclonal antibodies

          -  Patients must not require concomitant treatment with strong CYP3A4 inducers (e.g.,
             dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
             phenobarbital, or St. John's wort). Because lists of these agents are constantly
             changing, it is important to regularly consult a frequently-updated medical reference.
             As part of the enrollment/informed consent procedures, patients will be counseled on
             the risk of interactions with other agents, and what to do if new medications need to
             be prescribed or if the patient is considering a new over-the-counter medicine or
             herbal product

          -  Patients must not have uncontrolled, significant intercurrent or recent illness
             including, but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Congestive heart failure New York Heart Association (NYHA) Class 3 or 4,
                       unstable angina pectoris, serious cardiac arrhythmias.

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
                       Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
                       treatment within seven days prior to the first dose of study treatment.

                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
                       (MI), or other ischemic event, or thromboembolic event (e.g., deep venous
                       thrombosis [DVT], pulmonary embolism [PE]) within 6 months before first
                       dose.

               -  GI disorders including those associated with a high risk of perforation or
                  fistula formation:

                    -  The patient has evidence of tumor invading the GI tract, active peptic ulcer
                       disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
                       cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
                       acute obstruction of the pancreatic duct or common bile duct, or gastric
                       outlet obstruction.

                    -  Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
                       abscess within 6 months before first dose. Complete healing of an
                       intra-abdominal abscess must be confirmed before first dose.

               -  Clinically significant hematuria, hematemesis, or hemoptysis or other history of
                  significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before first
                  dose.

               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
                  manifestation.

               -  Lesions invading or encasing any major blood vessels.

               -  Other clinically significant disorders that would preclude safe study
                  participation.

                    -  Serious non-healing wound/ulcer/bone fracture.

                    -  Uncompensated/symptomatic hypothyroidism.

                    -  Moderate to severe hepatic impairment (Child-Pugh B or C).

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because XL184 (cabozantinib) has the
             potential for teratogenic or abortifacient effects, and the effects of nivolumab and
             ipilimumab on the developing fetus are not well known. Because there is an unknown but
             potential risk for AEs in nursing infants secondary to treatment of the mother,
             breastfeeding must be discontinued if the mother is treated with XL184 (cabozantinib),
             nivolumab, or ipilimumab

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including high dose systemic corticosteroids, should be excluded. These include but
             are not limited to: immune-related neurologic disease, such as multiple sclerosis,
             autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, or myasthenia gravis;
             systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective
             tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative
             colitis, or autoimmune hepatitis. Patients with a history of toxic epidermal
             necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be
             excluded because of the risk of recurrence or exacerbation of disease. Patients with
             vitiligo, type I diabetes mellitus (DM), or endocrine deficiencies (e.g., thyroiditis)
             managed with replacement hormones, including physiologic corticosteroids, are
             eligible. Patients with rheumatoid arthritis and other arthropathies, Sjogren's
             syndrome and psoriasis controlled with topical medication,
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Within 6 months of treatment initiation
Safety Issue:
Description:Defined as complete responses (CR) plus partial responses (PR). Responses will be determined via Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR+PR rate will be summarized with a point estimate and a 2-sided Wilson type confidence interval (CI) estimate.

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:Analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored PFS will be analyzed for all registered patients.
Measure:Incidence of adverse events
Time Frame:Up to 1 year
Safety Issue:
Description:Safety including specific toxicity types, grades, and attributions will be evaluated and summarized. Toxicity will be assessed in all toxicity-evaluable (t-e) patients using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. The t-e population is defined as all patients who have received the study treatment. The resulting binary endpoints of each toxicity type at a specific grade(s), will all be summarized with point estimates and 2-sided Wilson type CI estimates. The grade of each type of toxicity will also be summarized with 1-way frequency distributions.
Measure:Disease control rate (DCR)
Time Frame:Up to 1 year
Safety Issue:
Description:The binary endpoint of DCR will be defined as the achievement of either CR, or PR, or stable disease (SD) (yes/no). The resulting binary endpoints of DCR will all be summarized with point estimates and 2-sided Wilson type CI estimates.
Measure:Duration of response (DOR)
Time Frame:From the time measurement criteria are met for CR/PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 1 year
Safety Issue:
Description:The censored time-to-event distributions of DOR will be analyzed with standard Kaplan-Meier methodology. Point and CI estimates of the median and various time point-specific rates will be derived from the Kaplan-Meier life table. Censored DOR will be analyzed for the combination of all patients who achieve either a CR or a PR.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 9, 2020