MAPS2: Nivolumab Monotherapy or Nivolumab Plus Ipilimumab, for Unresectable Malignant Pleural Mesothelioma (MPM) Patients

Sponsor

Intergroupe Francophone de Cancerologie Thoracique (Other)

Overall Status

Completed

CT.gov ID

NCT02716272

Collaborator

(none)

125

Enrollment

Locations

Arms

38.9

Actual Duration (Months)

5.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The sponsor raise the hypothesis that inhibition of immune PD-1+/- CTLA-4 check-point(s) would delay tumor progression in patients with unresectable MPM, experiencing disease progression after one or two lines of chemotherapy including at least first-line with pemetrexed and platinum, without altering significantly the quality of life of patients.

Condition or Disease	Intervention/Treatment	Phase
Mesothelioma	Drug: Nivolumab Drug: Nivolumab + Ipilimumab	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

125 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase II Study Evaluating Efficacy and Safety of 2nd or 3rd Line Treatment by Nivolumab Monotherapy or Nivolumab Plus Ipilimumab, for Unresectable Malignant Pleural Mesothelioma (MPM) Patients

Actual Study Start Date :

Mar 24, 2016

Actual Primary Completion Date :

Feb 1, 2018

Actual Study Completion Date :

Jun 22, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MONOTHERAPY ARM Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks	Drug: Nivolumab Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks
Experimental: COMBINATION ARM Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks, combined with Ipilimumab administered IV over 90 minutes at 1mg/Kg every 6 weeks	Drug: Nivolumab + Ipilimumab Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks, combined with Ipilimumab administered IV over 90 minutes at 1mg/Kg every 6 weeks

Arm

Intervention/Treatment

Experimental: MONOTHERAPY ARM

Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks

Drug: Nivolumab

Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks

Experimental: COMBINATION ARM

Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks, combined with Ipilimumab administered IV over 90 minutes at 1mg/Kg every 6 weeks

Drug: Nivolumab + Ipilimumab

Nivolumab administered IV over 60 minutes at 3mg/kg every 2 weeks, combined with Ipilimumab administered IV over 90 minutes at 1mg/Kg every 6 weeks

Outcome Measures

Primary Outcome Measures

Disease Control rate assessed by CT scan [3-months]
Tumor assessment (modified RECIST1.0 for mesothelioma)

Secondary Outcome Measures

Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [3-months]
NCI CTC AE 4.0
Progression-Free Survival [3-month]
Overall Survival [3-months]
Quality of Life [3-months]
LCSS ( Lawrence County School System) Scale
prognosis impact of blood biomarkers (exploratory studies) [3-months]
dosage in blood of numerous biomarkers and analysis of their prognosis impact

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically proved diagnosis of unresectable malignant pleural Mesothelioma (MPM)
Available (archival and/or fresh) pathological samples for centralized PD-L1 expression assessment by immunohistochemistry
Age ≥ 18 years old; male and female
ECOG Performance status 0-1
Weight loss < 10% during last 3 months
Life expectancy > 12 weeks
Documented progression of the MPM, assessed by computed tomography (CT) -Scan.
Measurable disease, defined as at least 1 lesion (measurable) that can be accurately assessed at baseline by CT-Scan and is suitable for repeated assessment using modified Response Evaluation Criteria in Solid Tumors [RECIST] for pleural mesothelioma (Byrne 2004; Therasse 2006).
Previous treatment by 1 or 2 systemic chemotherapy lines (1 line of chemotherapy considered if the patient received ≥2 cycles of this chemotherapy), including at least one line with pemetrexed in combination with platinum agent (i.e. "gold standard chemotherapy in MPM; triplet including bevacizumab also accepted)
Written informed consent
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 < 3N with total bilirubin ≤ 1.5 × ULN (upper limit of normal) except subjects with documented Gilbert's syndrome (≤ 5 × ULN) or liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL
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
Females of childbearing potential who are sexually active with a nonsterilized 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.

Exclusion Criteria:

Patients with primitive peritoneal, pericardial, testis or tunica vaginalis mesothelioma
Patients with a recent history of other malignancies except adequately treated non-melanoma skin cancer, and curatively treated in-situ cancer. Patients with prostate adenocarcinoma diagnosed less than 5 years could be included in case of localized prostate cancer with good outcome according the Amico classification: ≤ T2a and Gleason Score ≤6 and PSA blood level ≤10 ng/ml, and treated with curative intent (surgery or radiotherapy) without chemotherapy. Patients with history of solid tumors, including adenocarcinoma, treated with curative intent and without any evidence of disease >5 years can be included as well.
Brain metastasis, except if surgically resected or treated with stereotaxic radiotherapy with no evolution within the 3 months before inclusion, and asymptomatic patient
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 (asbestosis…) 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. 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.
Active or history of inflammatory 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.

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Angers - CHU	Angers	France	49000
2	Avignon - Institut Sainte-Catherine	Avignon	France	84918
3	CHU	Clermont-Ferrand	France
4	Dijon - CHU	Dijon	France	63000
5	Grenoble - CHU	Grenoble	France	38000
6	Centre Hospitalier - Pneumologie	Le Havre	France	76600
7	Centre Hospitalier - Pneumologie	Le Mans	France	72000
8	CHRU Lille - Hopital Calmette	Lille	France
9	AP-HM Hôpital Nord	Marseille	France
10	Mulhouse - CH	Mulhouse	France	68000
11	AP-HP Hopital Tenon - Pneumologie	Paris	France	75020
12	AP-HP Hôpital Bichat	Paris	France
13	HCL Lyon Sud	Pierre Bénite	France	69495
14	Pontoise - CH	Pontoise	France
15	Rennes - CHU	Rennes	France
16	Rouen - CHU	Rouen	France	76000
17	Centre Etienne Dolet	Saint-Nazaire	France
18	CHU Strasbourg	Strasbourg	France
19	Toulon - CHI	Toulon	France	83000
20	Toulouse - CHU Larrey	Toulouse	France
21	CHU Tours - Pneumologie	Tours	France
22	Gustave Roussy	Villejuif	France	94800

Sponsors and Collaborators

Intergroupe Francophone de Cancerologie Thoracique

Investigators

Principal Investigator: Arnaud Scherpereel, MD, PhD, Intergroupe Francophone de Cancerologie Thoracique
Principal Investigator: Gérard Zalcman, MD, PhD, Intergroupe Francophone de Cancerologie Thoracique