Description:
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.
Title
- Brief Title: A Trial of Obinutuzumab,GDC-0199 Plus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma Patients
- Official Title: A Phase I/II Trial of Obinutuzumab, ABT-199 (GDC-0199) Plus Ibrutinib in Relapsed / Refractory Mantle Cell Lymphoma Patients
Clinical Trial IDs
- ORG STUDY ID:
RC14_0048
- SECONDARY ID:
2014-003740-13
- NCT ID:
NCT02558816
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Ibrutinib + GA101 +GDC-0199 | GA101 : Obinutuzumab, Ibrutinib, GDC-0199 | Ibrutinib - GA101 - GDC_0199 |
Purpose
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
Trial Arms
Name | Type | Description | Interventions |
---|
Ibrutinib - GA101 - GDC_0199 | Experimental | 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 | - Ibrutinib + GA101 +GDC-0199
|
Eligibility Criteria
Inclusion criteria :
- Age ≥18 for French patients and Age ≥16 for UK patients
- Step A + B : Relapsed / refractory MCL after at least one line of treatment. The
relapse diagnosis (within 3 months before baseline), needs to be histologically
confirmed (tumor biopsy or bone marrow biopsy) or confirmed by the presence
(immunuphenotype) of circulating tumor cells on peripheral blood and/or bone marrow
aspirate.
- Step C : Untreated patients with histologically confirmed MCL (within 3 months before
baseline). The initial diagnosis has to be confirmed according to WHO classification.
- Stage II-IV in need of treatment
- ECOG performance status of 0 - 2.
- Haematology values must be within the following limits:
1. Absolute neutrophil count (ANC)≥ 1000/mm3 independent of growth factor support
2. Platelets ≥75,000/mm3 or ≥ 50,000/mm3 if bone marrow involvement and independent
of transfusion support in either situation
- Biochemical values within the following limits:
1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper
limit of normal (ULN)
2. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or
of non-hepatic origin
3. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft
Gault 11) ≥ 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 at least 30 days after the last
dose of venetoclax or 18 months after the last dose of obinutuzumab, whichever is
longer. For males, these restrictions apply for 6 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.
Non-Inclusion 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 inclusion.
- Known central nervous system lymphoma.
- History of stroke or intracranial haemorrhage within 6 months prior to inclusion.
- 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 6 months of inclusion.
- Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus 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 study treatment (ibrutinib, GA101, GDC-0199) 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 and from which
subject is disease-free for < 5 years .
- Allografted patient
- 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 18 months after completion of treatment for the women
and 6 months for the men.
- Use of any standard or experimental anti-cancer drug therapy within 28 days prior to
the first dose of study drug.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 16 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Step A : occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib during the first cycle of treatment |
Time Frame: | week 4 |
Safety Issue: | |
Description: | 4 weeks after initiation of treatment. |
Secondary Outcome Measures
Measure: | Response (CR, PR, SD, PD) and overall response (CR+ PR) rates |
Time Frame: | 48 months |
Safety Issue: | |
Description: | 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 |
Measure: | Time to progression |
Time Frame: | 48 months |
Safety Issue: | |
Description: | |
Measure: | Overall survival |
Time Frame: | 48 months |
Safety Issue: | |
Description: | |
Measure: | Safety measured by type, frequency, severity of related treatment adverse event as Assessed by CTCAE v4.0. |
Time Frame: | 48 months |
Safety Issue: | |
Description: | |
Measure: | Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities. |
Time Frame: | 48 months |
Safety Issue: | |
Description: | |
Measure: | Incidence and severity of tumor lysis syndrome |
Time Frame: | 48 months |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Nantes University Hospital |
Last Updated
March 13, 2020