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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)

NCT03591731

Description:

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.

Related Conditions:
  • Large Cell Lung Neuroendocrine Carcinoma
  • Neuroendocrine Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief 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)
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: GCO-001
  • NCT ID: NCT03591731

Conditions

  • Neuroendocrine Carcinoma

Interventions

DrugSynonymsArms
NivolumabArm A : monotherapy arm
IpilimumabArm B : combination arm

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Arm A : monotherapy armExperimentalNivolumab administered IV
  • Nivolumab
Arm B : combination armExperimentalNivolumab administered IV followed by ipilimumab administered IV
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥ 18 years.

          2. WHO Performance status 0 - 2

          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. Subjects with type I diabetes
             mellitis, or hypothyroidism only requiring hormone replacement, or 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate
Time Frame:8 weeks after randomization
Safety Issue:
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.

Secondary Outcome Measures

Measure:Objective response rate assessed by independent central review
Time Frame:8 weeks after randomization
Safety Issue:
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.
Measure:Disease control rate assessed by independent central review
Time Frame:8 weeks after randomization
Safety Issue:
Description:Percentage of patients who will achieve complete response, partial response or stable disease
Measure:Objective response rate using iRECIST criteria
Time Frame:8 weeks after randomization
Safety Issue:
Description:Percentage of patients with a best overall response of complete response (CR) or partial response (PR) using criteria iRECIST
Measure:Disease control rate using iRECIST criteria
Time Frame:8 weeks after randomization
Safety Issue:
Description:Percentage of patients who will achieve complete response, partial response or stable disease using criteria iRECIST
Measure:Response duration
Time Frame:24 months after randomization of the last subject
Safety Issue:
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.
Measure:Time to symptom deterioration
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description:Time between the date of treatment start and the date of event defined as the first documented symptom deterioration
Measure:Progression-free survival
Time Frame:24 months after randomization of the last subject
Safety Issue:
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.
Measure:Overall Survival
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description:Time between the date of treatment start and the date of death from any cause.
Measure:Frequency of adverse events
Time Frame:24 months after randomization of the last subject
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Intergroupe Francophone de Cancerologie Thoracique

Trial Keywords

  • IFCT
  • NIPINEC
  • Neuroendocrine
  • FFCD
  • GERCOR

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