Nivolumab +/- Ipilimumab in Patients With Advanced, Refractory Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Tumors (NECs)

NCT03591731 | Completed Phase 2

• 1 other identifier: GCO-001
• Study Type: interventional
• Target: 185
• Locations: 1 country
• Sites: 7

Brief Summary

Neuroendocrine tumors of the lung include the small cell carcinoma (SCLC), and large cell neuroendocrine carcinoma (LCNEC) and represent 20% of lung cancer. One of the only studies reported to date is reporting on a progression-free survival (PFS) and overall survival (OS) of 5.2 months and 7.7 months, respectively. Poorly differentiated gastroentero-pancreatic neuroendocrine carcinomas (GEP-NEC) represent a small sub-group of digestive NENs, according to the studies, 7 to 21% of patients. However, their prognosis is more negative, with the 5-year survival at less than 20%. Many Phase III trials showed superiority in terms of efficacy and tolerance of nivolumab+/-ipilimumab versus standard chemotherapy in second-line treatment in metastatic solid tumors. Neuroendocrine tumors are considered as rare disease without therapeutic guidelines in this setting. The French academic oncology groups (IFCT, FFCD and GERCOR) have the opportunity to recruit a sufficient number of patients, in a reasonable period of time, to provide a proof-of-concept of the safety and efficacy of nivolumab+/-ipilimumab in this population.

Conditions

Neuroendocrine Carcinoma

Keywords

IFCT; NIPINEC; Neuroendocrine; FFCD; GERCOR

Outcome Measures

Primary Outcomes (1)

• Objective response rate

  Number of patients with a best overall response of complete response (CR) or partial response (PR) assessed by investigators using validated criteria (i.e. RECIST 1.1) divided by the number of eligible patients.

  8 weeks after randomization

Secondary Outcomes (7)

• Objective response rate assessed by independent central review

  8 weeks after randomization

• Disease control rate assessed by independent central review

  8 weeks after randomization

• Response duration

  24 months after randomization of the last subject

• Time to symptom deterioration

  24 months after randomization of the last subject

• Progression-free survival

  24 months after randomization of the last subject

Study Arms (2)

Arm A : monotherapy arm

EXPERIMENTAL

Nivolumab administered IV

Drug: Nivolumab

Arm B : combination arm

EXPERIMENTAL

Nivolumab administered IV followed by ipilimumab administered IV

Drug: Nivolumab; Drug: Ipilimumab

Interventions

Nivolumab DRUG

Nivolumab 3 mg/kg every 2 weeks

Arm A : monotherapy arm; Arm B : combination arm

Ipilimumab DRUG

Ipilimumab 1 mg/kg every 6 weeks

Arm B : combination arm

Eligibility Criteria

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

You may qualify if:

• Age ≥ 18 years.
• WHO Performance status 0 - 1
• Life expectancy \> 12 weeks
• Poorly differentiated neuroendocrine carcinoma (NEC): large and small cells for gastroenteropancreatic NEC (WHO 2010 classification) and only large cells for lung NEC (WHO 2015 classification), independently from PD-L1 expression status by tumor cells; mixed tumors with a prominent (\>70%) NEC component are eligible
• Tumor progression after one or two lines of treatment, including at least one line of platin-based chemotherapy
• Unresectable locally advanced or metastatic stage
• Measurable disease according to RECIST 1.1 guidelines for solid tumors
• Patients must have adequate organ function: creatinine clearance \> 50 mL/min (Cockcroft formula), Neutrophiles count ≥ 1500/mm3; Platelets \> 100 000/mm3 ; Hemoglobin \> 9 g/dL; hepatic enzymes \< 3 x ULN (upper limit of normal) with total bilirubin ≤ 2 × ULN except subjects with documented Gilbert's syndrome (≤ 5 × ULN) or liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL
• Patients must have recovered from all toxicities associated with prior treatment, to acceptable baseline status, or a National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE v4.0) Grade of 0 or 1, except for toxicities not considered a safety risk, such as alopecia or vitiligo
• Availability of tumor material for central review processes and translational research projects
• Absence of any unstable systemic disease and any psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule.
• Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception for 28 days prior to the first dose of investigational product, and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. They must also refrain from egg cell donation for 6 months after the final dose of investigational product. Men receiving nivolumab and who are sexually active with women of childbearing potential will be instructed to adhere to contraception for a period of 31 weeks after the last dose of nivolumab.
• Patient must be affiliated to or a beneficiary of social security insurance.

You may not qualify if:

• Patients \<18 years old
• Well-differentiated neuroendocrine tumor (NET G1 and G2 according to digestive WHO 2010 classification or typical/atypical carcinoid tumor according to lung WHO 2015 classification)
• Small cell lung NEC (except as a minor \<30% component in mixed tumors)
• Known EGFR activating mutation or ALK or ROS1 rearrangement for lung NEC
• Patients with a recent history of other malignancies except adequately treated non-melanoma skin cancer, and curatively treated in-situ cancer. Patients with history of solid tumors, including adenocarcinoma, treated in a curative way with or without chemotherapy and without any evidence of disease \>2 years before randomisation can be included as well.
• History of primary immunodeficiency, history of organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of randomization or a prior history of severe (grade 3 or 4) immune mediated toxicity from other immune therapy.
• Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Intranasal/inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
• Live attenuated vaccination administered within 30 days prior to randomization.
• Known history of interstitial lung disease or CT-scan signs of interstitial lung disease.
• Subjects with an active, known or suspected autoimmune disease, including systemic lupus erythematosis or Wegener's granulomatosis.
• Note : Subjects with type I diabetes mellitis, or hypothyroidism are eligible if only requiring hormone replacement therapy.
• Subjects with skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, are permitted to enroll.
• Active or history of inflammatory or irritable bowel disease (eg, diverticulitis, colitis, Crohn's), irritable bowel disease, celiac disease or other serious gastrointestinal chronic conditions associated with diarrhea. Note that diverticulosis is permitted.
• Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. This includes but is not limited to:
• known prior history of active tuberculosis-disease;

Sponsors & Collaborators

• Intergroupe Francophone de Cancerologie Thoracique: lead
• GERCOR - Multidisciplinary Oncology Cooperative Group: collaborator
• Federation Francophone de Cancerologie Digestive: collaborator

Study Sites (7)

Centre Hospitalier du Pays d'Aix

Aix-en-Provence, France

Location

CHU d'Amiens-Picardie

Amiens, France

Location

CHU d'Angers

Angers, France

Location

Auxerre - CH

Auxerre, 89011, France

Location

Avignon - CH

Avignon, France

Location

Lyon - Hôpital Edouard Herriot

Lyon, France

Location

Paris - Curie

Paris, France

Location

Related Links

• IFCT website

MeSH Terms

Conditions

Carcinoma, Neuroendocrine

Interventions

Nivolumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Nicolas GIRARD, Pr

  Institut Curie Paris

  PRINCIPAL INVESTIGATOR

• Thomas WALTER, Pr

  Hôpital Herriot

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 9, 2018
• First Posted: July 19, 2018
• Study Start: January 2, 2019
• Primary Completion: July 9, 2021
• Study Completion: December 15, 2024
• Last Updated: April 1, 2025

Record last verified: 2025-03

Locations

FR (7)