Bruton's Tyrosine Kinase (BTK) Inhibition in B-cell Lymphomas (BIBLOS)
This is an open label, multicenter, dose escalation, phase Ib study to determine the recommended dose by assessing the maximum tolerated dose (MTD), safety and efficacy of ibrutinib in combination with R-DHAP (Group A/Abis) or R-DHAOx (Group B/Bbis) for patients with B-cell malignancies. This dose escalation will be followed by an exploratory expansion phase in 3 groups of 12 patients each (Group A/Abis, Group B/B bis and Group C).
During Part 1 Dose Escalation, the "3+3" design will be applied. Three doses of ibrutinib (280, 420 and 560 mg) will be examined sequentially in each cohort by the Dose Escalation Committee. Dose escalation will begin at dose level 1 = 420 mg.
The dose escalation will be performed for two types of associations in four separate groups :
- Group A : ibrutinib D1-D21+ R-DHAP
- Group B : ibrutinib D1-D21 R-DHAOx
- Group Abis : ibrutinib D5-D18+ R-DHAP
- Group Bbis : ibrutinib D5-D18 R-DHAOx
This dose escalation will be followed by an exploratory expansion phase in the same 2 groups A/Abis and B/Bbis plus a third one including only mantle cell lymphoma (MCL) in first line patients: group C. Patients included in the Group C will receive ibrutinib in combination with R-DHAP or R-DHAOx according to the choice of the local investigator at time of inclusion of each patient.
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase Ib Study of Ibrutinib Combined With R-DHAP or R-DHAOx in Patients With B-cell Lymphomas|
- The primary endpoint is the incidence rate of DLTs at each dose level on cycle 1 [ Time Frame: 21 days ]Determine the recommended phase II dose (RP2D) of ibrutinib when administered in combination with R-DHAP (rituximab + dexamethasone + cytarabine + cisplatin) or with R-DHAOx (rituximab + dexamethasone + cytarabine + oxaliplatin) in patients with relapsed or refractory B-cell malignancies eligible for autologous stem cell transplantation (ASCT) by assessing the maximum tolerated dose (MTD) observed during the dose escalation part of the study. Assessment of the MTD will be performed by the analysis of the dose-limiting toxicities (DLTs).
- Secondary safety endpoints [ Time Frame: 84 days ]Study drug administration including treatment duration, average dose, dose reduction; Treatment discontinuation, study discontinuation; Adverse events, vital sign measurements, clinical laboratory measurements, and concomitant therapies.
- Response Rate [ Time Frame: 30 days after the last dose of study drug is administered ]Disease response evaluation at 3 cycles (or 4 cycles for patients with mantle cell lymphoma in first line in the expansion phase) will be used to determine the Response Rate. Response after 3 cycles (or 4 cycles) will be assessed at the end of completion of the cycles if patient received all cycles or at withdrawal
- Duration of response (DoR) [ Time Frame: from first evidence of response to the date of first documented disease progression, relapse or death from any cause, assessed up to 52 months ]Duration of response is defined as the time from first evidence of response (PR or better) to first documented disease progression, relapse or death from any cause. Patients alive and free of progression at data cut-off will be censored at the last adequate tumor assessment indicating no disease progression
- Progression-Free Survival (PFS) [ Time Frame: from the date of inclusion to the date of first observation of documented disease progression or death due to any cause, assessed up to 52 months ]PFS is defined as the time from inclusion into the study to the first observation of documented disease progression or death due to any cause. If a patient has not progressed or died, PFS will be censored at the time of last visit with adequate assessment. Patients without documented event at the time of analysis will be censored at their last follow-up date.
- Time to Next Anti-Lymphoma Treatment (TTNLT) [ Time Frame: from the date of inclusion to the date of first documented administration of any new anti-lymphoma treatment, assessed up to 52 months ]TTNLT is defined as the time from the date of inclusion to the date of first documented administration of any new anti-lymphoma treatment (chemotherapy, radiotherapy, radio-immunotherapy, immunotherapy). Patients continuing in response or who are lost to follow-up will be censored on their last visit date. Patients who died (due to any cause) before having received a new anti-lymphoma treatment will be included in the statistical analysis with death being counted as an event.
- Overall Survival (OS) [ Time Frame: from the date of inclusion to the date of death from any cause, assessed up to 52 months ]Overall survival is defined as the time from the date of inclusion to the date of death from any cause. Patients who did not die will be censored at their last follow-up date.
- Pharmacokinetics profile of ibrutinib in Groups A bis and B bis [ Time Frame: During dose escalation part, on first day of ibrutinib administration (Day 5) and on Day 15 of cycle 1 and cycle 2 ]The objective is to assess the pharmacokinetic profile of ibrutinib in the presence of R-DHA(P/Ox) for groups A bis and B bis during the dose escalation part.
|Study Start Date:||May 2014|
|Estimated Study Completion Date:||November 2019|
|Estimated Primary Completion Date:||October 2018 (Final data collection date for primary outcome measure)|
Experimental: Ibrutinib and immunochemotherapies
Combination of immunochemotherapies (R-DHAP or R-DHAOx) and ibrutinib
Drug: Ibrutinib and immunochemotherapies
Combination of immunochemotherapies (R-DHAP or R-DHAOx) and ibrutinib
Please refer to this study by its ClinicalTrials.gov identifier: NCT02055924
|Contact: Christelle Seigne||04 72 66 93 33|
|CHU de Liège||Recruiting|
|Liège, Belgium, 04000|
|Contact: Christophe Bonnet, Dr 0032 43 66 84 20|
|Sub-Investigator: Christophe Bonnet, Dr|
|Centre François Baclesse||Recruiting|
|Caen, France, 14076|
|Contact: Christophe Fruchart, Dr 02 31 45 50 93|
|Principal Investigator: Christophe Fruchart, Dr|
|Hôpital Henri Mondor||Recruiting|
|Créteil, France, 94010|
|Contact: Jehan Dupuis, Dr 01 49 81 21 71|
|Principal Investigator: Jehan Dupuis, Dr|
|CHU de Nantes||Recruiting|
|Nantes, France, 44093|
|Contact: Steven Le Gouill, Pr 02 40 08 32 71|
|Principal Investigator: Steven Le Gouill, Pr|
|Centre Hospitalier Lyon Sud||Recruiting|
|Pierre Bénite, France, 69495|
|Contact: Gilles Salles, Pr 04 78 86 43 01|
|Principal Investigator: Gilles Salles, Pr|
|Rennes, France, 35003|
|Contact: Thierry Lamy, Pr 02 99 28 42 91|
|Principal Investigator: Thierry Lamy, Pr|
|Centre Henri Becquerel||Recruiting|
|Rouen, France, 76038|
|Contact: Hervé Tilly, Pr 02 32 08 22 02|
|Principal Investigator: Hervé Tilly, Pr|
|Study Chair:||Gilles SALLES, PhD||CHU Lyon - Sud - LYSA|
|Study Chair:||Christophe BONNET, MD||CHU Liège - LYSA|