Bruton's Tyrosine Kinase (BTK) Inhibition in B-cell Lymphomas

NCT02055924 | Terminated Phase 1

• 1 other identifier: BIBLOS
• Study Type: interventional
• Target: 85
• Locations: 2 countries
• Sites: 15

Brief Summary

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 five 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 group Bbis plus a new group 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.

Conditions

B-cell Lymphoma

Keywords

Bruton's tyrosine kinase (BTK) Inhibition in B-cell Lymphomas

Outcome Measures

Primary Outcomes (1)

• The primary endpoint is the incidence rate of DLTs at each dose level on cycle 1

  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).

  21 days

Secondary Outcomes (7)

• Secondary safety endpoints

  84 days

• Response Rate

  30 days after the last dose of study drug is administered

• Duration of response (DoR)

  from first evidence of response to the date of first documented disease progression, relapse or death from any cause, assessed up to 52 months

• Progression-Free Survival (PFS)

  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

• Time to Next Anti-Lymphoma Treatment (TTNLT)

  from the date of inclusion to the date of first documented administration of any new anti-lymphoma treatment, assessed up to 52 months

Study Arms (1)

Ibrutinib and immunochemotherapies

EXPERIMENTAL

Combination of immunochemotherapies (R-DHAP or R-DHAOx) and ibrutinib

Drug: Ibrutinib and immunochemotherapies

Interventions

Ibrutinib and immunochemotherapies DRUG

Combination of immunochemotherapies (R-DHAP or R-DHAOx) and ibrutinib

Also known as: Ibrutinib + R-DHAP, Ibrutinib + R-DHAOx

Ibrutinib and immunochemotherapies

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with any type of relapsed or refractory B-cell lymphoma will be eligible in groups A, A bis, B and B bis (during the dose escalation and the expansion parts of the study) and untreated patients with mantle cell lymphoma will be eligible for group C (only during the expansion part of the study)
• Each patient (or their legally acceptable representative) must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study
• Patients eligible for autologous stem cell transplantation (ASCT) for whom R-DHAP or R-DHAOx is an acceptable therapy regarding the investigator's opinion
• Measurable disease defined by at least one single node or tumor lesion \> 1.5 cm
• Patients who received prior therapy with at least one but no more than two lines therapies for B-Cell Lymphoma (except for patients included in group C during the expansion part of the study)
• Aged between 18 years and 70 years (included)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Absolute neutrophil count (ANC) \> 1,000 cells/mm3 (1.0 x 109/L) unless if bone marrow infiltration from lymphoma
• Spontaneous Platelets count \> 75,000 cells/mm3 (75 x 109/L) within 7 days of any platelet transfusion (allowed up to 50 x 109/L if due to bone marrow infiltration from lymphoma)
• Patients assessed as being able to receive full doses of R-DHA(P/Ox) for 3 cycles or 4 cycles for patients included in group C of the expansion phase
• Life expectancy of ≥ 90 days (3 months)
• Women of childbearing potential\* and men who are sexually active must be practicing a highly effective method of birth control during the study and during 12 months after the end of treatments. Men must agree to not donate sperm during the study and during 12 months after the end of treatments
• Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) or urine pregnancy test at Screening

You may not qualify if:

• Previous treatment with a BTK inhibitor
• Patients who progressed or became refractory while on treatment with a phosphoinositide 3-kinase (PI3K) inhibitors
• Inability to tolerate 4 courses of high dose ara-C / platin compound, especially if due to underlying comorbidities
• History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
• Major surgery, within 4 weeks prior to the first dose of study drug
• Known bleeding diathesis
• Condition that requires therapeutic anticoagulation with Vitamin K antagonists
• Condition that requires treatment with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor
• Any life-threatening illness, serious medical condition, laboratory abnormality, organ system dysfunction or psychiatric illness which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk and that would prevent the patient from signing the informed consent form
• Known central nervous system or meningeal involvement by lymphoma
• Contraindication to any drug contained in these regimen
• Known history of human immunodeficiency virus (HIV)
• Known active Hepatitis C Virus (HCV; RNA polymerase chain reaction (PCR)-positive) or active Hepatitis B Virus infection (HBs Ag positive or DNA PCR-positive) or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics. Patients with PCR-negative for hepatitis B virus (HBV) are permitted in the study.
• Left ventricular ejection fraction (LVEF) \< 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification

Sponsors & Collaborators

• The Lymphoma Academic Research Organisation: lead
• Janssen Pharmaceutica N.V., Belgium: collaborator

Study Sites (15)

Universite Catholique de Louvain Saint Luc

Brussels, Belgium

Location

CHU de Liège

Liège, 04000, Belgium

Location

CHU UCL Namur asbl

Yvoir, 5530, Belgium

Location

Centre François Baclesse

Caen, 14076, France

Location

Hôpital Henri Mondor

Créteil, 94010, France

Location

CHU de Dijon - Hôpital le Bocage

Dijon, 21034, France

Location

CHRU de Lille - Hôpital Claude Huriez

Lille, 59037, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

CHU Montpellier

Montpellier, 34295, France

Location

CHU de Nantes

Nantes, 44093, France

Location

Hôpital Saint Louis

Paris, 75475, France

Location

Centre François Magendie - Hôpital du Haut Lévêque

Pessac, 33604, France

Location

Centre Hospitalier Lyon Sud

Pierre-Bénite, 69495, France

Location

CHU Pontchaillou

Rennes, 35003, France

Location

Centre Henri Becquerel

Rouen, 76038, France

Location

MeSH Terms

Conditions

Lymphoma, B-Cell

Interventions

ibrutinib

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Gilles SALLES, PhD

  CHU Lyon - Sud - LYSA

  STUDY CHAIR

• Christophe BONNET, MD

  CHU Liège - LYSA

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2014
• First Posted: February 5, 2014
• Study Start: May 26, 2014
• Primary Completion: December 1, 2017
• Study Completion: October 9, 2018
• Last Updated: October 11, 2018

Record last verified: 2018-10

Locations

BE (3); FR (12)