A Trial of Obinutuzumab,GDC-0199 Plus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma Patients
- Conditions
- Mantle Cell Lymphoma
- Interventions
- Registration Number
- NCT02558816
- Lead Sponsor
- Nantes University Hospital
- Brief Summary
This is an open label, multicenter, fixed dose and dose escalation, phase I/II study.
The study will be conducted in 3 steps. The first one (step A) will be to ensure the safety of the combination of Obinutuzumab (GA101) and Ibrutinib at fixed doses in patients with relapsed or refractory Mantle Cell Lymphoma (MCL).
A total of 9 patients have been included in the first step with grouped inclusions of three patients (safety evaluation performed at each inclusion of 3 patients).
No unacceptable toxicity has been observed during step A, thefore the second step (step B) was initiated. The aim of the second step was to determine the MTD of the GDC-0199 (400-600-800mg/d) in combination of GA101 and Ibrutinib (both respecting the previous doses) by using a Continual Reassessment Method. This dose escalation method was used until the 12th patient (3 patients included at 400mg/d of GDC-0199-(no DLT), 3 at 600mg/d- (no DLT) and 6 at 800mg/d, (not DLT reported so far). Once the last patient of the 800mg cohort is evaluated for DLT, all other patients will be treated at the dose of 400mg/d of GDC-0199.
The third step (step C) for untreated patients will be conducted at the dose of 400mg/d of GDC-0199. The aim of step C is to confirm the safety profile of the GA101 + Ibrutininb + GDC-199 combination according to step B result. 15 patients will be included in this step.
- Detailed Description
The study will be conducted into 3 steps for respecting the optimal safety of the OASIS trial:
Step A :
The primary objective of step A is 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).
Secondary objectives:
* To describe the efficacy of the combination of GA101 and Ibrutinib 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
* To establish a bio-bank to explore biomarkers and mechanisms of action including resistance
Step B : Step B started because no unacceptable toxicity occurred 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), used up to the 12th enrolled patients. No DLT occured for the first 12 patients. Based on the most recent publications, the dose of 400mg/d will be used from the 13th to the 24th patients (no CRM used).
Secondary objectives:
* To describe the efficacy of the combination GA101, Ibrutinib and GDC-0199 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 novel combination of GDC-0199, GA101 and Ibrutinib
* To establish a bio-bank to explore biomarkers and mechanism of action including resistance
Step C :
This step has started because no unacceptable toxicity was observed during the second step.
The primary objective of this step is to confirm the safety of the combination of GA101 + Ibrutinib + GDC-199 at fixed doses (560 mg per day of Ibrutinib + 1000 mg of GA101, 400mg/d of GDC-199 ), in patients with untreated Mantle Cell Lymphoma (MCL), at end of Cycle 2.
Secondary objectives :
* To describe the efficacy of the combination GA101, Ibrutinib and GDC-0199 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 novel combination of GDC-0199, GA101 and Ibrutinib
* To establish a bio-bank to explore biomarkers and mechanism of action including resistance
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 48
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Ibrutinib - GA101 - GDC_0199 Ibrutinib + GA101 +GDC-0199 STEP A:C1:Ibrutinib 560mg D2-28;GA101 1000mg day 1/2,8,15;C2-6:Ibrutinib 560mg D 1-28;GA101 1000mg D1 / C7 (Maintenance phase)-C24:Ibrutinib 560mg D1-28 (until progression);GA101 1000mg D1 every 2cycles (from C8) STEP B:C1:Ibrutinib 560mg D2-28;GA101 1000mg D1/2,8,15 / C1bis : Ibrutinib 560mg day 1-28 ; GA101 1000mg D 1 ; GDC-0199 20mg/d at W1, 50mg/d at W2, 100mg at W3, 200 mg/d at W4 / C2-6:Ibrutinib 560mg D1-28;GA101 1000mg D1;GDC-0199:400mg/d W1 and 400, 600 or 800mg/d W2-3-4 + 400, 600 or 800 mg/d C3-C6 (patients 1-12).Patients 13-24:GDC-199 400mg/d / C7(Maintenance phase)-C23:Ibrutinib 560mg D1-28 (until progression);GA101 1000mg D1 every 2 cycles (from C8);GDC:400, 600 or 800 mg D1-28 (patient 1-12).Patients 13-24 : 400mg/d STEP C:C1-C1bis=Step B; C2-6:Ibrutinib 560mg D1-28;GA101 1000mg D1;GDC:400mg/d C7 (Maintenance phase)-C23 : Ibrutinib 560mg D1-28 (--\>progression);GA101 1000mg D1/2 cycles (from C8);GDC-0199 400mg/d
- Primary Outcome Measures
Name Time Method Step B : occurrence of unacceptable toxicity (definition p3) of the combination of GA101 and Ibrutinib plus GDC-0199 during the cycle 2 in terms of Dose-Limiting Toxicities (DLTs) At the end of cycle 2 (each cycle is 28 days) No unacceptable toxicity has been observed during step A, thefore the second step (step B) was initiated
Step A : occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib during the first cycle of treatment week 4 4 weeks after initiation of treatment.
Step C : occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib and GDC-0199 at the end of the cycle 2 At the end of cycle 2 (each cycle is 28 days) The third step started, because no unacceptable toxicity has been observed during the second step
- Secondary Outcome Measures
Name Time Method Overall survival 48 months Time to progression 48 months Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities. 48 months Incidence and severity of tumor lysis syndrome 48 months Response (CR, PR, SD, PD) and overall response (CR+ PR) rates 48 months Response (CR, PR, SD, PD) and overall response (CR+ PR) rates assessed by Cheson 99 and 07 criteria and Working Group Revised Response Criteria for Malignant Lymphomas 14
Safety measured by type, frequency, severity of related treatment adverse event as Assessed by CTCAE v4.0. 48 months
Trial Locations
- Locations (9)
CHU de Dijon
🇫🇷Dijon, France
University of Southampton
🇬🇧Southampton, United Kingdom
CHU de Nantes
🇫🇷Nantes, France
CHU Angers
🇫🇷Angers, France
Hôpital du Haut Lévêque
🇫🇷Pessac, France
Hôpital Claude Huriez - CHRU de Lille
🇫🇷Lille, France
Hôpital Saint Eloi
🇫🇷Montpellier, France
CHU Rennes
🇫🇷Rennes, France
Derriford Hospital _ Plymouth Hospitals NHS Trust
🇬🇧Plymouth, Devon, United Kingdom