A phase I/II trial of Obinutuzumab, ABT-199 (GDC-0199) plus Ibrutinib in Relapsed / Refractory Mantle Cell Lymphoma patients (OAsIs)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Nantes

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Oct 2015 → 13 May 2025

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Roche · Janssen

External identifiers

EU CT number

2024-516750-21-00

EudraCT number

2014-003740-13

ClinicalTrials.gov

NCT02558816

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

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).
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)
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 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 3

1. - 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.
2. - To describe the safety and tolerability of the novel combination of GDC-0199, GA101 and Ibrutinib
3. - To establish a bio-bank to explore biomarkers and mechanism of action including resistance

Conditions and MedDRA coding

Patients with relapsed / refractory Mantle Cell Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. • Age ≥18 for French patients, Age ≥16 for English patients
2. • Step A and B : Relapsed / refractory disease 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
3. • Step C : Untreated patients with histologically confirmed mantle cell lymphoma (within 3 months before baseline). The initial diagnosis has to be confirmed according to WHO classification.
4. • Stage II-IV in need of treatment (see Appendix 12 : Ann Arbor Staging)
5. • ECOG performance status of 0 – 2
6. • Hematology values must be within the following limits: a. Absolute neutrophil count (ANC) ≥1000/mm3 independent of growth factor support b. Platelets≥75,000/mm3 or ≥ 50,000/mm3 if bone marrow involvement and independent of transfusion support in either situation
7. • Biochemical values within the following limits: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN) b. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin c. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault11) ≥ 50 mL/min/1.73m2
8. • HIV, anti-HBc, HbsAg test negative
9. • Life expectancy of more than 3 months.
10. • 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.
11. • 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.
12. • Written signed informed consent form.

Exclusion criteria 20

1. • 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.
2. • Major surgery within 4 weeks of inclusion
3. • Known central nervous system lymphoma
4. • History of stroke or intracranial hemorrhage within 6 months prior to inclusion
5. • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon)
6. • Impaired liver, renal (GFR<50ml/min) or other organ function which will interfere with the treatment
7. • Requires treatment with strong CYP3A inhibitors
8. • Vaccinated with live, attenuated vaccines within 4 weeks of inclusion
9. • 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)
10. • 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 ibrutinib capsules, or put the study outcomes at undue risk
11. • Known hypersensitivity to study treatment (GA101, Ibrutinib, GDC-0199) or to any of the excipients
12. • Known allergy to xanthine oxidase inhibitors and rasburicase
13. • Severe prior reactions to monoclonal antibodies or with prior significant toxicity (other than thrombocytopenia) from Bcl-2 inhibitor
14. • 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
15. • Other cancers not specified above which have been curatively treated and from which subject is disease-free for <5 years
16. • Allografted patients
17. • Psychiatric illness or condition which could interfere with their ability to understand the requirements of the study
18. • Pregnancy/lactation
19. • 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
20. • Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Step A : The occurrence of unacceptable toxicity (definition p35) of the combination of GA101 and Ibrutinib during the first cycle of treatment. Step B : The occurrence of unacceptable toxicity (definition p35) of the combination of GA101 and Ibrutinib plus GDC-0199 during the cycle 2 in terms of Dose-Limiting Toxicities (DLTs). Step C : The occurrence of unacceptable toxicity of the combination of GA101 and Ibrutinib plus GDC-199 at the end of the cycle 2

Secondary endpoints 5

1. • Safety (type, frequency, severity, and relationship of adverse events to study treatment)
2. • Incidence of Serious Adverse Event (SAE), Adverse Event (AE) and laboratory abnormalities.
3. • Incidence and severity of tumor lysis syndrome
4. • Time to progression and overall survival
5. • Response (CR, PR, SD, PD) and overall response (CR+ PR) rates

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Nantes

Sponsor organisation

Centre Hospitalier Universitaire De Nantes

Address

5 Allee De L Ile Gloriette, Cs 69301 Cs 69301

City

Nantes Cedex 1

Postcode

44093

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Maëlle NINGRE

Public contact point

Organisation

Centre Hospitalier Universitaire De Nantes

Contact name

Maëlle NINGRE

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 8 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications