This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

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

This study is currently recruiting participants.
See Contacts and Locations
Verified March 2017 by The Lymphoma Academic Research Organisation
Sponsor:
Collaborator:
Janssen Pharmaceutica N.V., Belgium
Information provided by (Responsible Party):
The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier:
NCT02055924
First received: January 31, 2014
Last updated: March 8, 2017
Last verified: March 2017
  Purpose

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.


Condition Intervention Phase
B-cell Lymphoma Drug: Ibrutinib and immunochemotherapies Phase 1

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by The Lymphoma Academic Research Organisation:

Primary Outcome Measures:
  • 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 Outcome Measures:
  • 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.


Estimated Enrollment: 84
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)
Arms Assigned Interventions
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
Other Names:
  • Ibrutinib + R-DHAP
  • Ibrutinib + R-DHAOx

Detailed Description:
The primary objective of this study is to determine the recommended dose 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).
  Eligibility

Ages Eligible for Study:   18 Years to 70 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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)
  2. 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
  3. Patients eligible for autologous stem cell transplantation (ASCT) for whom R-DHAP or R-DHAOx is an acceptable therapy regarding the investigator's opinion
  4. Measurable disease defined by at least one single node or tumor lesion > 1.5 cm
  5. 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)
  6. Aged between 18 years and 70 years (included)
  7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  8. Any of the following hematology values within 14 days prior to inclusion and prior to the first dose of study drug :

    1. Absolute neutrophil count (ANC) > 1,000 cells/mm3 (1.0 x 109/L) unless if bone marrow infiltration from lymphoma
    2. 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)
  9. 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
  10. Life expectancy of ≥ 90 days (3 months)
  11. 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
  12. Women of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) or urine pregnancy test at Screening

Exclusion Criteria:

  1. Previous treatment with a BTK inhibitor
  2. Patients who progressed or became refractory while on treatment with a phosphoinositide 3-kinase (PI3K) inhibitors
  3. Inability to tolerate 4 courses of high dose ara-C / platin compound, especially if due to underlying comorbidities
  4. History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
  5. Major surgery, within 4 weeks prior to the first dose of study drug
  6. Known bleeding diathesis
  7. Condition that requires therapeutic anticoagulation with Vitamin K antagonists
  8. Condition that requires treatment with a strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitor
  9. 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
  10. Known central nervous system or meningeal involvement by lymphoma
  11. Contraindication to any drug contained in these regimen
  12. Known history of human immunodeficiency virus (HIV)
  13. 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.
  14. Left ventricular ejection fraction (LVEF) < 45% as determined by echocardiography or multiple uptake gated acquisition (MUGA) scan
  15. 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
  16. Any of the following biochemical values within 14 days prior to inclusion and prior to the first dose of study drug :

    1. Serum glutamic-oxaloacetic transaminase/aspartate aminotransferase (SGOT/ASAT) or serum glutamic-pyruvic transaminase/alanine aminotransferase (SGPT/ALAT) > 3.0 x upper limit of normal (ULN)
    2. Serum total bilirubin > 2.0 mg/dL (34 µmol/L), except in patients with hemolytic anemia or with Gilbert syndrome,
    3. Calculated creatinine clearance of < 50 mL /min (for patients who will have DHAOx chemotherapy) or < 70 mL/min (for patients who will have DHAP chemotherapy)
  17. Patients with pre-existing ≥ Grade 2 neuropathy
  18. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the patient has been free of the disease for ≥ 3 years
  19. Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug
  20. Women who are pregnant or breastfeeding
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02055924

Contacts
Contact: Christelle Seigne 04 72 66 93 33

Locations
Belgium
CHU de Liège Recruiting
Liège, Belgium, 04000
Contact: Christophe Bonnet, Dr    0032 43 66 84 20      
Sub-Investigator: Christophe Bonnet, Dr         
France
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         
CHU Pontchaillou Recruiting
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         
Sponsors and Collaborators
The Lymphoma Academic Research Organisation
Janssen Pharmaceutica N.V., Belgium
Investigators
Study Chair: Gilles SALLES, PhD CHU Lyon - Sud - LYSA
Study Chair: Christophe BONNET, MD CHU Liège - LYSA
  More Information

Responsible Party: The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier: NCT02055924     History of Changes
Other Study ID Numbers: BIBLOS
Study First Received: January 31, 2014
Last Updated: March 8, 2017

Keywords provided by The Lymphoma Academic Research Organisation:
Bruton's tyrosine kinase (BTK) Inhibition in B-cell Lymphomas

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin

ClinicalTrials.gov processed this record on June 23, 2017