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Clinical Trial 20885

Cancer Type: Gastrointestinal Tumor
Study Type: Treatment
NCT#: NCT04079712

Phase: Phase II
Prinicipal Investigator: Jonathan Strosberg

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Study Title

A Phase 2 Study of XL184 (Cabozantinib) in Combination with Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas


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.


Primary Objectives 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 - To evaluate progression-free survival (PFS). - To measure the safety and tolerability of the combination of XL184 (cabozantinib), nivolumab, and ipilimumab in patients with advanced, poorly differentiated NECs. - To evaluate disease control rate (DCR). - To measure duration of response (DOR). - To describe the tumor molecular profile using whole exome sequencing (WES) and correlate it with treatment outcome. - To describe the tumor molecular profile using RNA sequencing (RNAseq) and correlate it with treatment outcome. Exploratory Objectives - To measure the tumor-infiltrating CD8+ T lymphocytes in pre- and on-treatment biopsies. - To measure tumor-infiltrating myeloid derived suppressor cells (MDSCs) in pre- and on treatment biopsies. - To measure tumor-infiltrating tumor-associated macrophages (TAM) in the pre and on treatment biopsies. - To measure the expression of programmed death-ligand 1 (PD-L1) in tumor cells and infiltrating immune cells.




BMS-936558 (Nivolumab); Cabozantinib (XL 184); Ipilimumab (); Nivolumab (Opdivo); Yervoy (Ipilimumab)

Inclusion Criteria

Inclusion Criteria:

  • 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
  • Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • 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 == 60%)
  • Adequate organ function as outlined per protocol
  • 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.
  • 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 will also be eligible.

  • Exclusion Criteria

    Exclusion Criteria:

  • 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. A brief course of corticosteroids for prophylaxis or for treatment of non-autoimmune conditions is permitted, as is steroid pre-medication for contrast allergy
  • 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
  • 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
  • Must not have received radiation therapy to any part of the body within 28 days
  • 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
  • Must not require concomitant treatment with oral anticoagulants (e.g., warfarin, direct thrombin, and factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel). Allowed anti-coagulants are outlined in protocol.
  • 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
  • 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 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
  • 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, 2 additional EKGs at intervals of approximately 3 mins must be performed within 30 minutes after the initial EKG, and the average of these 3 consecutve results for QTcF will be used to determine eligibility.
  • 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 even
  • Other exclusions apply

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