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NCT04079712

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

Active, enrolled Phase 2 Results posted Last updated 13 April 2026
What this trial tests

Phase 2 trial testing Cabozantinib S-malate in Metastatic Large Cell Neuroendocrine Carcinoma in 17 participants. Participants enrolled and being followed up; not accepting new ones.

Timeline
6 August 2020
Primary endpoint
10 January 2025
19 August 2026

Quick facts

Lead sponsorNational Cancer Institute (NCI)
PhasePhase 2
StatusActive, enrolled
Study typeINTERVENTIONAL
Allocationna
Designsingle group
Maskingnone
Primary purposetreatment
Enrollment17
Start date6 August 2020
Primary completion10 January 2025
Estimated completion19 August 2026
Sites46 locations across Canada, United States

Drugs / interventions tested

Conditions studied

Sponsor

National Cancer Institute (NCI)

Who can join

18 and older, any sex, with Metastatic Large Cell Neuroendocrine Carcinoma or Metastatic Neuroendocrine Carcinoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With a Response Primary · Up to 3.5 years

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.

GroupValue95% CI
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)2
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)14
Progression Free Survival (PFS) Secondary · Up to 3.5 years

Progression is defined as a \>= 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) and assessed by CT or MRI scan. The duration is from the date of registration to the time of progression or death, whichever occurs first.

GroupValue95% CI
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)8523 – 902
Number of Participants Reporting Adverse Events Secondary · Up to 3.5 years

Adverse events will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) 5.0 criteria. The population is defined as all patients who have received the study treatment. The highest grade is reported.

GroupValue95% CI
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)0
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)3
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)7
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)6
Disease Control Rate (DCR) Secondary · Up to 3.5 years

DCR will be defined as the achievement of Complete Response (CR) (disappearance of all target lesions), Partial Response (PR) (\>=30% decrease in the sum of the longest diameter of target lesions), or Stable Disease (SD) (between \< 30% decrease and \>20% increase in the sum of the longest diameter of target lesions) using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT or MRI scan.

GroupValue95% CI
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)9
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)7
Duration of Response (DOR) Secondary · Up to 3.5 years

The time when measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented.

GroupValue95% CI
Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)664504 – 824

Adverse events — posted to ClinicalTrials.gov

Time frame: About 3.5 years. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Treatment (Cabozantinib S-malate, Nivolumab, Ipilimumab)
Serious: 10/17 (59%)
Deaths: 13/17

Serious adverse events (16 terms)

ReactionSystemTreatment (Cabozantinib S-…
Hepatic failureHepatobiliary disorders
Pericardial effusionCardiac disorders
MalaiseGeneral disorders
Non-cardiac chest painGeneral disorders
AppendicitisInfections and infestations
CholangitisInfections and infestations
SepsisInfections and infestations
Stoma site infectionInfections and infestations
TracheitisInfections and infestations
FallInjury, poisoning and procedural complications
HyponatremiaMetabolism and nutrition disorders
Generalized muscle weaknessMusculoskeletal and connective tissue disorders
Acute kidney injuryRenal and urinary disorders
Urinary retentionRenal and urinary disorders
HypotensionVascular disorders
Thromboembolic eventVascular disorders
Other adverse events (113 terms — click to expand)

ReactionSystemTreatment (Cabozantinib S-…
Alanine aminotransferase increasedInvestigations
FatigueGeneral disorders
Aspartate aminotransferase increasedInvestigations
DiarrheaGastrointestinal disorders
HypoalbuminemiaMetabolism and nutrition disorders
HyponatremiaMetabolism and nutrition disorders
NauseaGastrointestinal disorders
Platelet count decreasedInvestigations
HypophosphatemiaMetabolism and nutrition disorders
AnemiaBlood and lymphatic system disorders
Abdominal painGastrointestinal disorders
Alkaline phosphatase increasedInvestigations
Weight lossInvestigations
White blood cell decreasedInvestigations
DyspneaRespiratory, thoracic and mediastinal disorders
HypertensionVascular disorders
HypothyroidismEndocrine disorders
ConstipationGastrointestinal disorders
Edema limbsGeneral disorders
Mucositis oralGastrointestinal disorders
VomitingGastrointestinal disorders
Blood bilirubin increasedInvestigations
Creatinine increasedInvestigations
Lipase increasedInvestigations
Lymphocyte count decreasedInvestigations
Neutrophil count decreasedInvestigations
AnorexiaMetabolism and nutrition disorders
HypocalcemiaMetabolism and nutrition disorders
HypokalemiaMetabolism and nutrition disorders
HypomagnesemiaMetabolism and nutrition disorders
Generalized muscle weaknessMusculoskeletal and connective tissue disorders
HeadacheNervous system disorders
Sinus bradycardiaCardiac disorders
HyperthyroidismEndocrine disorders
ChillsGeneral disorders
PainGeneral disorders
BruisingInjury, poisoning and procedural complications
HyperglycemiaMetabolism and nutrition disorders
Back painMusculoskeletal and connective tissue disorders
Muscle crampMusculoskeletal and connective tissue disorders

Most-reported serious reactions: Hepatic failure, Pericardial effusion, Malaise, Non-cardiac chest pain, Appendicitis, Cholangitis, Sepsis, Stoma site infection.

Data from ClinicalTrials.gov NCT04079712 adverse events section.

Sponsor's own 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer.
    Li K, Shi H, Zhang B, Ou X, et al · · 2021 · cited 687× · PMID 34620838 · DOI 10.1038/s41392-021-00670-9
  2. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors.
    Apolo AB, Nadal R, Girardi DM, Niglio SA, et al · · 2020 · cited 96× · PMID 32915679 · DOI 10.1200/jco.20.01652
  3. BDNF and its signaling in cancer.
    Malekan M, Nezamabadi SS, Samami E, Mohebalizadeh M, et al · · 2023 · cited 48× · PMID 36173463 · DOI 10.1007/s00432-022-04365-8
  4. Functionalized Nanoparticles Targeting Tumor-Associated Macrophages as Cancer Therapy.
    He Y, de Araújo Júnior RF, Cruz LJ, Eich C. · · 2021 · cited 48× · PMID 34683963 · DOI 10.3390/pharmaceutics13101670
  5. "Present and future of immunotherapy in Neuroendocrine Tumors".
    Albertelli M, Dotto A, Nista F, Veresani A, et al · · 2021 · cited 36× · PMID 33851319 · DOI 10.1007/s11154-021-09647-z
  6. Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma.
    Frizziero M, Kilgour E, Simpson KL, Rothwell DG, et al · · 2022 · cited 30× · PMID 35091446 · DOI 10.1158/1078-0432.ccr-21-3058
  7. Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia.
    Maggio I, Manuzzi L, Lamberti G, Ricci AD, et al · · 2020 · cited 30× · PMID 32235636 · DOI 10.3390/cancers12040832
  8. Myeloid-Derived Suppressor Cells: Implications in the Resistance of Malignant Tumors to T Cell-Based Immunotherapy.
    Shi H, Li K, Ni Y, Liang X, et al · · 2021 · cited 26× · PMID 34336860 · DOI 10.3389/fcell.2021.707198

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