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

Primary Purpose

Neuroendocrine Carcinoma

Status
Active
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Nivolumab
Ipilimumab
Sponsored by
Intergroupe Francophone de Cancerologie Thoracique
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuroendocrine Carcinoma focused on measuring IFCT, NIPINEC, Neuroendocrine, FFCD, GERCOR

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. WHO Performance status 0 - 1
  3. Life expectancy > 12 weeks
  4. 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
  5. Tumor progression after one or two lines of treatment, including at least one line of platin-based chemotherapy
  6. Unresectable locally advanced or metastatic stage
  7. Measurable disease according to RECIST 1.1 guidelines for solid tumors
  8. 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
  9. 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
  10. Availability of tumor material for central review processes and translational research projects
  11. 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.
  12. Before patient inclusion, written informed consent must be given according to ICH/GCP, and national/local regulations.
  13. 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.
  14. Patient must be affiliated to or a beneficiary of social security insurance.

Exclusion Criteria:

  1. Patients <18 years old
  2. 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)
  3. Small cell lung NEC (except as a minor <30% component in mixed tumors)
  4. Known EGFR activating mutation or ALK or ROS1 rearrangement for lung NEC
  5. Brain metastasis, except if surgically resected or treated with stereotaxic radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic patient
  6. 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.
  7. 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.
  8. 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.
  9. Live attenuated vaccination administered within 30 days prior to randomization.
  10. Known history of interstitial lung disease or CT-scan signs of interstitial lung disease.
  11. 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.

  12. 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.
  13. 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;
    • known acute or chronic B or C hepatitis by serological evaluation. Patients with serological sequelae of hepatitis (antibodies test serologically positive for virus) without hepatitis could be included.
    • known Human immunodeficiency virus infection.
  14. Concurrent administration of any anti-cancer therapies (e.g., chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study
  15. 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 checkpoint pathways
  16. The last dose of prior chemotherapy or radiation therapy (with the exception of palliative radiotherapy) was received less than 3 weeks prior to randomization;
  17. Patients with a psychiatric history that hinders the comprehension of the information leaflet
  18. Individual deprived of liberty or placed under the authority of a tutor.
  19. Unwillingness to practice effective birth control. Pregnant or lactating women.
  20. Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study

Sites / Locations

  • Centre Hospitalier du Pays d'Aix
  • CHU d'Amiens-Picardie
  • CHU d'Angers
  • Auxerre - CH
  • Avignon - CH
  • Lyon - Hôpital Edouard Herriot
  • Paris - Curie

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm A : monotherapy arm

Arm B : combination arm

Arm Description

Nivolumab administered IV

Nivolumab administered IV followed by ipilimumab administered IV

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Objective response rate assessed by independent central review
Number of patients with a best overall response of complete response (CR) or partial response (PR) assessed by independent central review using validated criteria (i.e. RECIST 1.1) divided by the number of eligible patients.
Disease control rate assessed by independent central review
Percentage of patients who will achieve complete response, partial response or stable disease
Response duration
Time between the date of the best overall response of partial or complete response until the date of progressive disease or death due to any cause.
Time to symptom deterioration
Time between the date of treatment start and the date of event defined as the first documented symptom deterioration
Progression-free survival
Time between the date of treatment start and the date of event defined as the first documented disease progression or death from any cause.
Overall Survival
Time between the date of treatment start and the date of death from any cause.
Frequency of adverse events

Full Information

First Posted
July 9, 2018
Last Updated
March 10, 2023
Sponsor
Intergroupe Francophone de Cancerologie Thoracique
Collaborators
Federation Francophone de Cancerologie Digestive, GERCOR - Multidisciplinary Oncology Cooperative Group
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1. Study Identification

Unique Protocol Identification Number
NCT03591731
Brief Title
Nivolumab +/- Ipilimumab in Patients With Advanced, Refractory Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Tumors (NECs)
Acronym
NIPINEC
Official Title
A GCO Trial Exploring the Efficacy and Safety of Nivolumab Monotherapy or Nivolumab Plus Ipilimumab in Pre-treated Patients With Advanced, Refractory Pulmonary or Gastroenteropancreatic Poorly Differentiated Neuroendocrine Tumors (NECs)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2, 2019 (Actual)
Primary Completion Date
July 9, 2021 (Actual)
Study Completion Date
September 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Intergroupe Francophone de Cancerologie Thoracique
Collaborators
Federation Francophone de Cancerologie Digestive, GERCOR - Multidisciplinary Oncology Cooperative Group

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuroendocrine Carcinoma
Keywords
IFCT, NIPINEC, Neuroendocrine, FFCD, GERCOR

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
185 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A : monotherapy arm
Arm Type
Experimental
Arm Description
Nivolumab administered IV
Arm Title
Arm B : combination arm
Arm Type
Experimental
Arm Description
Nivolumab administered IV followed by ipilimumab administered IV
Intervention Type
Drug
Intervention Name(s)
Nivolumab
Intervention Description
Nivolumab 3 mg/kg every 2 weeks
Intervention Type
Drug
Intervention Name(s)
Ipilimumab
Intervention Description
Ipilimumab 1 mg/kg every 6 weeks
Primary Outcome Measure Information:
Title
Objective response rate
Description
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.
Time Frame
8 weeks after randomization
Secondary Outcome Measure Information:
Title
Objective response rate assessed by independent central review
Description
Number of patients with a best overall response of complete response (CR) or partial response (PR) assessed by independent central review using validated criteria (i.e. RECIST 1.1) divided by the number of eligible patients.
Time Frame
8 weeks after randomization
Title
Disease control rate assessed by independent central review
Description
Percentage of patients who will achieve complete response, partial response or stable disease
Time Frame
8 weeks after randomization
Title
Response duration
Description
Time between the date of the best overall response of partial or complete response until the date of progressive disease or death due to any cause.
Time Frame
24 months after randomization of the last subject
Title
Time to symptom deterioration
Description
Time between the date of treatment start and the date of event defined as the first documented symptom deterioration
Time Frame
24 months after randomization of the last subject
Title
Progression-free survival
Description
Time between the date of treatment start and the date of event defined as the first documented disease progression or death from any cause.
Time Frame
24 months after randomization of the last subject
Title
Overall Survival
Description
Time between the date of treatment start and the date of death from any cause.
Time Frame
24 months after randomization of the last subject
Title
Frequency of adverse events
Time Frame
24 months after randomization of the last subject

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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. Before patient inclusion, written informed consent must be given according to ICH/GCP, and national/local regulations. 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. Exclusion Criteria: 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 Brain metastasis, except if surgically resected or treated with stereotaxic radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic patient 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; known acute or chronic B or C hepatitis by serological evaluation. Patients with serological sequelae of hepatitis (antibodies test serologically positive for virus) without hepatitis could be included. known Human immunodeficiency virus infection. Concurrent administration of any anti-cancer therapies (e.g., chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study 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 checkpoint pathways The last dose of prior chemotherapy or radiation therapy (with the exception of palliative radiotherapy) was received less than 3 weeks prior to randomization; Patients with a psychiatric history that hinders the comprehension of the information leaflet Individual deprived of liberty or placed under the authority of a tutor. Unwillingness to practice effective birth control. Pregnant or lactating women. Patients with other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicolas GIRARD, Pr
Organizational Affiliation
Institut Curie Paris
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Thomas WALTER, Pr
Organizational Affiliation
Hôpital Herriot
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre Hospitalier du Pays d'Aix
City
Aix-en-Provence
Country
France
Facility Name
CHU d'Amiens-Picardie
City
Amiens
Country
France
Facility Name
CHU d'Angers
City
Angers
Country
France
Facility Name
Auxerre - CH
City
Auxerre
ZIP/Postal Code
89011
Country
France
Facility Name
Avignon - CH
City
Avignon
Country
France
Facility Name
Lyon - Hôpital Edouard Herriot
City
Lyon
Country
France
Facility Name
Paris - Curie
City
Paris
Country
France

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Links:
URL
https://www.ifct.fr/etudes-cliniques/149-gco-001
Description
IFCT website

Learn more about this trial

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

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