Clinical Trials /

A Trial of Obinutuzumab,GDC-0199 Plus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma Patients

NCT02558816

Description:

This is an open label, multicenter, fixed dose and dose escalation, phase I/II study. The study will be conducted into 3 steps. The first one 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 will be included in this first step (step A) with grouped inclusions of three patients (a safety evaluation will be performed at each inclusion of 3 patients). The second step (step B) will be conducted if no unacceptable toxicity is observed during the first step and 24 new patients will be included in the step B. The aim of the second step is to determine the MTD of the GDC-0199 in combination of GA101 and Ibrutinib (both respecting the previous doses) by using a Continual Reassessment Method. The third step (step C) will be conducted if no unacceptable toxicity is observed during the second step. The aim of the third step is to confirm the safety profile of the combination of GA101 + Ibrutininb + GDC-199 at dose determined according to step B result in patients with untreated Mantle Cell Lymphoma (MCL). 15 patients will be included in this step.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

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

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
Ibrutinib + GA101 +GDC-0199GA101 : Obinutuzumab, Ibrutinib, GDC-0199Ibrutinib - GA101 - GDC_0199

Purpose

This is an open label, multicenter, fixed dose and dose escalation, phase I/II study. The study will be conducted into 3 steps. The first one 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 will be included in this first step (step A) with grouped inclusions of three patients (a safety evaluation will be performed at each inclusion of 3 patients). The second step (step B) will be conducted if no unacceptable toxicity is observed during the first step and 24 new patients will be included in the step B. The aim of the second step is to determine the MTD of the GDC-0199 in combination of GA101 and Ibrutinib (both respecting the previous doses) by using a Continual Reassessment Method. The third step (step C) will be conducted if no unacceptable toxicity is observed during the second step. The aim of the third step is to confirm the safety profile of the combination of GA101 + Ibrutininb + GDC-199 at dose determined according to step B result in patients with untreated Mantle Cell Lymphoma (MCL). 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 :

      This study 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 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 will be conducted if no unacceptable toxicity is 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/d of Ibrutinib + 1000 mg of GA101, GDC-199 doses
      will be determinated according to step B result), 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

NameTypeDescriptionInterventions
Ibrutinib - GA101 - GDC_0199ExperimentalStep A : C1:Ibrutinib 560mg D2 28 / GA101 1000mg D1/2,8,15 ; C2-6:Ibrutinib 560mg day 1-28 / GA101 1000mg day 1 ; C7-C24 (maintenance):Ibrutinib 560mg D1-28 (until progression) / GA101 1000mg D1 every 2cycles (from C8) Step B : C1:Ibrutinib 560mg D2 - 28 / GA101 1000mg D/2,8,15 ; C1bis:Ibrutinib 560mg D1-28 / GA101 1000mg D1 / GDC-0199:20mg/d at W1, 50mg/d at W2, 100mg at W3 and 200 mg/d at W4 ; C2-6:Ibrutinib 560mg D1-28 / GA101 1000mg D1 / GDC199:400mg/d at W1 and 400, 600 or 800 mg/d at W2-3-4 and 400, 600 or 800 mg/d C3 to C6 ; C7-C23 (maintenance):Ibrutinib 560mg D1-28 (until progression) / GA101 1000mg D1 every 2 cycles (from C8) / GDC-0199 : 400, 600 or 800 mg D1-28 Step C : C1 to C2W1 : identical as step B. Then, dose of GDC-199 as recommended in step B at C2W2-3-4 and in C3 to C6. C7-C23:Ibrutinib 560mg D1-28 (until progression) / GA101 1000mg D1 every 2 cycles (from C8) / GDC-0199 as recommended in step B from D1 to D28
  • 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 3months before
             baseline). The initial diagnosishas 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

        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 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 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 .

          -  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 heighten months after completion of treatment for the
             women and six 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 : The 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:Recruiting
Lead Sponsor:Nantes University Hospital

Last Updated

August 10, 2017