Mantle Cell Lymphoma MedDRA version: 18.0 Level: PT Classification code 10061275 Term: Mantle cell lymphoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: IMBRUVICA
Product Name: IBRUTINIB
Product Code: PRD2480669
Pharmaceutical Form: Capsule
Trade Name: GAZIVARO
Product Name: OBINUTUZUMAB
Product Code: PRD2480532
Pharmaceutical Form: Conce
Sponsors
CHU de Nantes
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: •Age =18 and =80 for French patients, Age =16 and =80 for English patients •Relapse or refractory histologically confirmed (according to the ECOG classification) MCL within 3 months before C1D1. The diagnosis has to be confirmed by phenotypic expression of CD5, CD20 and cyclin D1 or the t(11;14) translocation. •Relapsed / refractory disease after at least one line of treatment (an additional cohort of 15 untreated MCL patients will be discussed with DSMC after completion of step 2) •Stage II-IV in need of treatment •ECOG performance status of 0 – 2. •Hematology values must be within the following limits: a. Absolute neutrophil count (ANC) =1000/mm3 independent of growth factor support b. Platelets=100,000/mm3 or = 50,000/mm3 if bone marrow involvement and independent of transfusion support in either situation •Biochemical values within the following limits: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) = 3 x upper limit of normal (ULN) b. Total bilirubin = 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin c. Serum creatinine = 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault11) = 50 mL/min/1.73m2 •HIV, anti-HBc, HbsAg test negative •Life expectancy of more than 3 months. •Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 18 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug. •Women of childbearing potential must have a negative serum or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study. •Written signed informed consent form. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: •Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification. •Major surgery within 4 weeks of randomization. •Known central nervous system lymphoma. •History of stroke or intracranial hemorrhage within 6 months prior to randomization. •Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon). •Impaired liver, renal (GFR<50ml/min) or other organ function which will interfere with the treatment. •Requires treatment with strong CYP3A inhibitors. •Vaccinated with live, attenuated vaccines within 4 weeks of randomization. •Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. (patients HbsAg+and/or antiHBc+ and/or HIV+ are excluded) •Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk. •Known hypersensitivity to study treatment (GA101, Ibrutinib, GDC-0199) or to any of the excipients. •Known allergy to xanthine oxidase inhibitors and rasburicase •Severe prior reactions to monoclonal antibodies or with prior significant toxicity (other than thrombocytopenia) from Bcl-2 inhibitor •History of prior other malignancy with the exception of: Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study •Other cancers not specified above which have been curatively treated by surgery alone and from which subject is disease-free for =5 years without further treatment. •Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study. •Pregnancy/lactation •Men or women of reproductive potential not agreeing to use acceptable method of birth control during treatment and for six months after completion of treatment. •Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Step A : To evaluate the safety of the combination of GA101 + Ibrutinib at fixed doses (560 mg per day of Ibrutinib + 1000 mg of GA101), in patients with relapsed or refractory Mantle Cell Lymphoma (MCL). Step B : This step will be performed conditionally to the observation of no unacceptable toxicity in patients included in the step A. The primary objective of this step is to determine the maximal tolerated dose (MTD) of the GDC-0199 in addition to the GA101 and Ibrutinib in relapsed refractory MCL patients by using a Continual Reassessment Method (CRM). ;Secondary Objective: -To describe the efficacy of the combination GA101 and Ibrutinib (step A) and combination GA101, Ibrutinib, GDC-0199 (step B) in terms of clinical benefits response (overall response rate, complete response rate, partial response rate cheson 99 and 07 criteria and Working Group Revised Response Criteria for Malignant Lymphomas 14), overall survival, progression-free survival. -To describe the safety and tolerability of the combination of GA101 and Ibrutinib (Step A) and combination GA101, Ibrutinib, GDC-0199 (step B) -To establish a bio-bank to explore biomarkers and mechanism of action including resistance. ;Primary end point(s): Step A : The occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib during the first cycle of treatment. Step B : The occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib plus GDC-0199 during the first two cycles of treatment in terms of Dose-Limiting Toxicities (DLTs) of the studied combination to establish the Recommended Phase 2 Dose (RP2D). ;Timepoint(s) of evaluation of this end point: Step A : end of cycle 1 Step B : end of cycle 2 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •Safety (type, frequency, severity, and relationship of adverse events to study treatment). •Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities. •Incidence and severity of tumor lysis syndrome •Time to progression and overall survival •Response (CR, PR, SD, PD) and overall response (CR+ PR) rates ;Timepoint(s) of evaluation of this end point: 4 years | — |
Countries
France, United Kingdom
Contacts
Public ContactSandrine Cussonneau
CHU de Nantes
Outcome results
None listed