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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02558816
Recruitment Status : Active, not recruiting
First Posted : September 24, 2015
Last Update Posted : March 13, 2020
Sponsor:
Collaborators:
Janssen, LP
Roche Pharma AG
Information provided by (Responsible Party):
Nantes University Hospital

Tracking Information
First Submitted Date  ICMJE August 27, 2015
First Posted Date  ICMJE September 24, 2015
Last Update Posted Date March 13, 2020
Actual Study Start Date  ICMJE October 14, 2015
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 11, 2020)
  • Step A : occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib during the first cycle of treatment [ Time Frame: week 4 ]
    4 weeks after initiation of treatment.
  • 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) [ Time Frame: 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 C : occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib and GDC-0199 at the end of the cycle 2 [ Time Frame: 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
Original Primary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • The occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib during the first cycle of treatment in step A [ Time Frame: week 4 ]
    4 weeks after initiation of treatment.
  • 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 in step B [ Time Frame: week 8 ]
    This step will be performed conditionally to the observation of no unacceptable toxicity in patients included in the step A.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2017)
  • Response (CR, PR, SD, PD) and overall response (CR+ PR) rates [ Time Frame: 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
  • Time to progression [ Time Frame: 48 months ]
  • Overall survival [ Time Frame: 48 months ]
  • Safety measured by type, frequency, severity of related treatment adverse event as Assessed by CTCAE v4.0. [ Time Frame: 48 months ]
  • Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities. [ Time Frame: 48 months ]
  • Incidence and severity of tumor lysis syndrome [ Time Frame: 48 months ]
Original Secondary Outcome Measures  ICMJE
 (submitted: September 23, 2015)
  • Overall response rate [ Time Frame: 48 months ]
    overall response rate assessed by Cheson 99 and 07 criteria and Working Group Revised Response Criteria for Malignant Lymphomas 14
  • Complete response rate [ Time Frame: 48 months ]
    complete response rate, assessed by Cheson 99 and 07 criteria and Working Group Revised Response Criteria for Malignant Lymphomas 14
  • Partial response rate [ Time Frame: 48 months ]
    Partial response rate assessed by Cheson 99 and 07 criteria and Working Group Revised Response Criteria for Malignant Lymphomas 14
  • overall survival [ Time Frame: 48 months ]
  • Time to progression [ Time Frame: 48 months ]
  • Safety (measured by type, frequency, severity of related treatment adverse event as Assessed by CTCAE v4.0.) [ Time Frame: 48 months ]
  • Incidence of serious adverse events [ Time Frame: 48 months ]
  • Incidence of adverse events [ Time Frame: 48 months ]
  • Incidence of laboratory abnormalities [ Time Frame: 48 months ]
  • Incidence and severity of tumor lysis syndrome [ Time Frame: 48 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial of Obinutuzumab,GDC-0199 Plus Ibrutinib in Relapsed/Refractory Mantle Cell Lymphoma Patients
Official Title  ICMJE A Phase I/II Trial of Obinutuzumab, ABT-199 (GDC-0199) Plus Ibrutinib in Relapsed / Refractory Mantle Cell Lymphoma Patients
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mantle Cell Lymphoma
Intervention  ICMJE Drug: Ibrutinib + GA101 +GDC-0199
Step A : 9 patients receive the combination of Ibrutinib + GA101 Step B : 24 patients receive the combination of Ibrutinib + GA101 + GDC-0199 Step C : 15 untreated patients receive the combination of Ibrutinib + GA101 + GDC-0199
Other Names:
  • GA101 : Obinutuzumab
  • Ibrutinib
  • GDC-0199
Study Arms  ICMJE Experimental: 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
Intervention: Drug: Ibrutinib + GA101 +GDC-0199
Publications * Le Gouill S, Morschhauser F, Chiron D, Bouabdallah K, Cartron G, Casasnovas O, Bodet-Milin C, Ragot S, Bossard C, Nadal N, Herbaux C, Tessoulin B, Tchernonog E, Rossi C, McCulloch R, Gastinne T, Callanan MB, Rule S. Ibrutinib, obinutuzumab, and venetoclax in relapsed and untreated patients with mantle cell lymphoma: a phase 1/2 trial. Blood. 2021 Feb 18;137(7):877-887. doi: 10.1182/blood.2020008727.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 10, 2017)
48
Original Estimated Enrollment  ICMJE
 (submitted: September 23, 2015)
33
Estimated Study Completion Date  ICMJE October 2025
Actual Primary Completion Date April 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02558816
Other Study ID Numbers  ICMJE RC14_0048
2014-003740-13 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Nantes University Hospital
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Nantes University Hospital
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • Janssen, LP
  • Roche Pharma AG
Investigators  ICMJE
Principal Investigator: Steven LE GOUILL, Pr CHU de Nantes
PRS Account Nantes University Hospital
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP