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

NCT04079712 | Active Not Recruiting Phase 2 Results FDA Drug

• 4 other identifiers: NCI-2019-0586410315UM1CA186689UM1CA186691
• Study Type: interventional
• Target: 17
• Locations: 2 countries
• Sites: 46

Brief Summary

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.

Conditions

Metastatic Small Cell Neuroendocrine Carcinoma; Metastatic Neuroendocrine Carcinoma; Metastatic Neuroendocrine Neoplasm; Metastatic Large Cell Neuroendocrine Carcinoma

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Response

  Participants who are considered to have a response are those with either a complete response (CR) (disappearance of all target lesions) or a partial response (PR) (\>=30% decrease in the sum of the longest diameter of target lesions) using Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and assessed by CT or MRI scan.

  Up to 3.5 years

Secondary Outcomes (4)

• Progression Free Survival (PFS)

  Up to 3.5 years

• Number of Participants Reporting Adverse Events

  Up to 3.5 years

• Disease Control Rate (DCR)

  Up to 3.5 years

• Duration of Response (DOR)

  Up to 3.5 years

Other Outcomes (3)

• CD8+ T Lymphocytes

  Up to Day 35

• Myeloid-Derived Suppressor Cells

  Up to Day 35

• Tumor-associated Macrophages

  Up to Day 35

Study Arms (1)

Treatment (cabozantinib s-malate, nivolumab, ipilimumab)

EXPERIMENTAL

Patients receive cabozantinib s-malate 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.

Drug: Cabozantinib S-malate; Biological: Ipilimumab; Biological: Nivolumab

Interventions

Cabozantinib S-malate DRUG

Given PO

Also known as: BMS-907351, Cabometyx, Cometriq, XL 184, XL-184, XL184

Treatment (cabozantinib s-malate, nivolumab, ipilimumab)

Ipilimumab BIOLOGICAL

Given IV

Also known as: Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016, Ipilimumab Biosimilar CS1002, MDX 010, MDX-010, MDX-CTLA4, MDX010, Yervoy

Treatment (cabozantinib s-malate, nivolumab, ipilimumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: ABP 206, BCD-263, BMS 936558, BMS-936558, BMS936558, CMAB819, MDX 1106, MDX-1106, MDX1106, NIVO, Nivolumab Biosimilar ABP 206, Nivolumab Biosimilar BCD-263, Nivolumab Biosimilar CMAB819, ONO 4538, ONO-4538, ONO4538, Opdivo

Treatment (cabozantinib s-malate, nivolumab, ipilimumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have metastatic, histologically confirmed poorly-differentiated neuroendocrine neoplasms per 2018 World Health Organization (WHO) classification, with the exception of small cell lung cancer and Merkel cell carcinoma. 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 have lesions that can be safely biopsied and 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (46)

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, 35233, United States

Location

Banner University Medical Center - Tucson

Tucson, Arizona, 85719, United States

Location

University of Arizona Cancer Center-North Campus

Tucson, Arizona, 85719, United States

Location

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

UF Health Cancer Institute - Gainesville

Gainesville, Florida, 32610, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

University of Kansas Clinical Research Center

Fairway, Kansas, 66205, United States

Location

HaysMed

Hays, Kansas, 67601, United States

Location

Lawrence Memorial Hospital

Lawrence, Kansas, 66044, United States

Location

The University of Kansas Cancer Center - Olathe

Olathe, Kansas, 66061, United States

Location

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas, 66210, United States

Location

Mercy Hospital Pittsburg

Pittsburg, Kansas, 66762, United States

Location

Salina Regional Health Center

Salina, Kansas, 67401, United States

Location

University of Kansas Health System Saint Francis Campus

Topeka, Kansas, 66606, United States

Location

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas, 66205, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Wayne State University/Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Weisberg Cancer Treatment Center

Farmington Hills, Michigan, 48334, United States

Location

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri, 63376, United States

Location

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri, 63141, United States

Location

University Health Truman Medical Center

Kansas City, Missouri, 64108, United States

Location

University of Kansas Cancer Center - North

Kansas City, Missouri, 64154, United States

Location

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri, 64064, United States

Location

University of Kansas Cancer Center at North Kansas City Hospital

North Kansas City, Missouri, 64116, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Siteman Cancer Center-South County

St Louis, Missouri, 63129, United States

Location

Siteman Cancer Center at Christian Hospital

St Louis, Missouri, 63136, United States

Location

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire, 03756, United States

Location

Wake Forest University at Clemmons

Clemmons, North Carolina, 27012, United States

Location

Wake Forest Baptist Health - Wilkes Medical Center

Wilkesboro, North Carolina, 28659, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

Farmington Health Center

Farmington, Utah, 84025, United States

Location

University of Utah Sugarhouse Health Center

Salt Lake City, Utah, 84106, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

VCU Massey Comprehensive Cancer Center

Richmond, Virginia, 23298, United States

Location

University Health Network-Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Related Publications (1)

• Mandl A, Chen R, Das S, Strosberg JR, Kasi A, Konda B, Li D, Burns TF, Chauhan A, Ciombor KK, Dayyani F, Dorff T, Ohr JP, Patel BB, Sukrithan V, Soares HP, Chen K, Liu SV, Tesfaye AA, Carducci MA, Beumer JH. Phase 2 Study of Cabozantinib (XL184) with Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas (ETCTN10315). Oncologist. 2026 Apr 10:oyag140. doi: 10.1093/oncolo/oyag140. Online ahead of print.

  PMID: 41968073 DERIVED

MeSH Terms

Conditions

Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Small Cell Lung Carcinoma

Interventions

cabozantinib; Ipilimumab; CTLA-4 Antigen; Nivolumab

Condition Hierarchy (Ancestors)

Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immune Checkpoint Proteins; Costimulatory and Inhibitory T-Cell Receptors; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens, Differentiation, T-Lymphocyte; Antigens, Differentiation; Antigens, Surface; Antigens; Biological Factors; Biomarkers

Results Point of Contact

• Title: Grants Administrative Manager
• Organization: Johns Hopkins University/SKCCC

jmurra33@jhmi.edu

4439273568

Study Officials

• Adel Mandl

  Yale University Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2019
• First Posted: September 6, 2019
• Study Start: August 6, 2020
• Primary Completion: January 10, 2025
• Study Completion (Estimated): August 19, 2026
• Last Updated: April 13, 2026
• Results First Posted: December 12, 2025

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); US (45)