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

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ClinicalTrials.gov Identifier: NCT02558816
Recruitment Status : Recruiting
First Posted : September 24, 2015
Last Update Posted : August 14, 2017
Sponsor:
Collaborators:
Janssen, LP
Roche Pharma AG
Information provided by (Responsible Party):
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 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.


Condition or disease Intervention/treatment Phase
Mantle Cell Lymphoma Drug: Ibrutinib + GA101 +GDC-0199 Phase 1 Phase 2

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Obinutuzumab, ABT-199 (GDC-0199) Plus Ibrutinib in Relapsed / Refractory Mantle Cell Lymphoma Patients
Actual Study Start Date : October 14, 2015
Estimated Primary Completion Date : April 2018
Estimated Study Completion Date : October 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Ibrutinib - GA101 - GDC_0199

Step 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

Drug: Ibrutinib + GA101 +GDC-0199
Step A : 9 patients will receive the combination of Ibrutinib + GA101, as soon as the step A patients are recruited and if no toxicity observed the step B will be initiated, Step B : 24 new patients will receive the combination of Ibrutinib + GA101 + GDC-0199
Other Names:
  • GA101 : Obinutuzumab
  • Ibrutinib
  • GDC-0199




Primary Outcome Measures :
  1. Step A : The 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.

  2. Step B : The occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib plus GDC-0199 during the cycle 2 in terms of Dose-Limiting Toxicities (DLTs) of the studied combination to establish the Recommended Phase 2 Dose (RP2D). [ Time Frame: At the end of cycle 2 (each cycle is 28 days) ]
    This step will be performed conditionally to the observation of no unacceptable toxicity in patients included in the step A.

  3. Step C : The 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 will be conducted if no unacceptable toxicity is observed during the second step


Secondary Outcome Measures :
  1. 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

  2. Time to progression [ Time Frame: 48 months ]
  3. Overall survival [ Time Frame: 48 months ]
  4. Safety measured by type, frequency, severity of related treatment adverse event as Assessed by CTCAE v4.0. [ Time Frame: 48 months ]
  5. Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities. [ Time Frame: 48 months ]
  6. Incidence and severity of tumor lysis syndrome [ Time Frame: 48 months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02558816


Contacts
Contact: Steven LE GOUILL, Pr steven.legouill@chu-nantes.fr
Contact: Simon RULE, Pr simon.rule@nhs.net

Locations
France
CHU Angers Not yet recruiting
Angers, France, 49033
Contact: Marie-Pierre MOLES-MOREAU    +33 2 41 35 45 82    mpmoles@chu-angers.fr   
CHU de Dijon Not yet recruiting
Dijon, France, 21000
Contact: René-Olivier Casasnovas, Pr       olivier.casasnovas@chu-dijon.fr   
Hôpital Claude Huriez - CHRU de Lille Recruiting
Lille, France, 59037
Contact: Franck Morschhauser, Pr    00 33 3 20 44 60 68    franck.morschhauser@chru-lille.fr   
Hôpital Saint Eloi Recruiting
Montpellier, France, 34295
Contact: Guillaume Cartron, Pr       g-cartron@chu-montpellier.fr   
CHU de Nantes Recruiting
Nantes, France, 44093
Contact: Steven LE GOUILL, Pr         
Hôpital du Haut Lévêque Recruiting
Pessac, France, 33604
Contact: Krimo BOUABDALLAH, Pr       krimo.bouabdallah@chu-bordeaux.fr   
CHU Rennes Not yet recruiting
Rennes, France, 35033
Contact: LAMY DE LA CHAPELLE Thierry    + 33 2 99 28 42 91    thierry.lamy@chu-rennes.fr   
United Kingdom
Derriford Hospital _ Plymouth Hospitals NHS Trust Not yet recruiting
Plymouth, Devon, United Kingdom, PL6 8DH
Contact: Simon RULE, Pr       simon.rule@nhs.net   
University of Southampton Not yet recruiting
Southampton, United Kingdom, SO16 6YD
Contact: Andrew DAVIES, Dr       a.davies@southampton.ac.uk   
Sponsors and Collaborators
Nantes University Hospital
Janssen, LP
Roche Pharma AG
Investigators
Principal Investigator: Steven LE GOUILL, Pr CHU de Nantes

Responsible Party: Nantes University Hospital
ClinicalTrials.gov Identifier: NCT02558816     History of Changes
Other Study ID Numbers: RC14_0048
2014-003740-13 ( EudraCT Number )
First Posted: September 24, 2015    Key Record Dates
Last Update Posted: August 14, 2017
Last Verified: August 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Obinutuzumab
Venetoclax
Antineoplastic Agents