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B-cell LymphomaPhase 1BIBLOSNCT02055924

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

A Phase 1 study testing Ibrutinib and immunochemotherapies in people with B-cell Lymphoma, run by The Lymphoma Academic Research Organisation at 15 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 to 70 years
Conditions the study is for
B-cell Lymphoma
What is being tested?
Ibrutinib and immunochemotherapies
Could I receive a placebo?
No, everyone receives an active treatment
How many people
85 participants
Where
15 sitesin 2 countries
Study dates
26 May 2014to 9 Oct 2018
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 70 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2
  • Any of the following hematology values within 14 days prior to inclusion and prior to the first dose of study drug :
  • 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

Who cannot join

  • 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
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  • 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
  • Any of the following biochemical values within 14 days prior to inclusion and prior to the first dose of study drug :
  • 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)
  • Serum total bilirubin > 2.0 mg/dL (34 µmol/L), except in patients with hemolytic anemia or with Gilbert syndrome,
  • 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)
  • Patients with pre-existing ≥ Grade 2 neuropathy
  • 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
  • Use of any standard or experimental anti-cancer drug therapy within 28 days prior to the first dose of study drug
  • Women who are pregnant or breastfeeding
  • Medical history of hepatic chronic disease whatever the anteriority
  • Sinusoidal obstruction syndrome (Veno-Occlusive Disease (VOD)) whatever the anteriority

Trial locations and contacts

15 sites in 2 countries.

15 sites in 2 countries

France12 sites

  • Centre François Baclesse

    Caen, 14076

  • Hôpital Henri Mondor

    Créteil, 94010

  • CHU de Dijon - Hôpital le Bocage

    Dijon, 21034

  • CHRU de Lille - Hôpital Claude Huriez

    Lille, 59037

  • Centre Léon Bérard

    Lyon, 69373

  • CHU Montpellier

    Montpellier, 34295

  • CHU de Nantes

    Nantes, 44093

  • Hôpital Saint Louis

    Paris, 75475

  • Centre François Magendie - Hôpital du Haut Lévêque

    Pessac, 33604

  • Centre Hospitalier Lyon Sud

    Pierre-Bénite, 69495

  • CHU Pontchaillou

    Rennes, 35003

  • Centre Henri Becquerel

    Rouen, 76038

Other trials in France

Belgium3 sites

  • Universite Catholique de Louvain Saint Luc

    Brussels

  • CHU de Liège

    Liège, 04000

  • CHU UCL Namur asbl

    Yvoir, 5530

Other trials in Belgium

About this study

Official title: A Phase Ib Study of Ibrutinib Combined With R-DHAP or R-DHAOx in Patients With B-cell Lymphomas

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.

Read more

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.

Read the 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).

Conditions
B-cell Lymphoma
Being tested
Ibrutinib and immunochemotherapies
Keywords
Bruton's tyrosine kinase (BTK) Inhibition in B-cell Lymphomas
Medical subject headings
Lymphoma, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ibrutinib and immunochemotherapiesDrug

    Also called Ibrutinib + R-DHAP, Ibrutinib + R-DHAOx

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

Study groups in NCT02055924
Study groupRoleWhat they receive
Ibrutinib and immunochemotherapiesExperimentalCombination of immunochemotherapies (R-DHAP or R-DHAOx) and ibrutinib
Receives: Drug: Ibrutinib and immunochemotherapies

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: 21 days

Secondary outcomes (7)

  1. Secondary safety endpoints

    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.

    Measured: 84 days

  2. Response Rate

    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

    Measured: 30 days after the last dose of study drug is administered

  3. Duration of response (DoR)

    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

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

  4. Progression-Free Survival (PFS)

    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.

    Measured: 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

  5. Time to Next Anti-Lymphoma Treatment (TTNLT)

    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.

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

  6. Overall Survival (OS)

    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.

    Measured: from the date of inclusion to the date of death from any cause, assessed up to 52 months

  7. Pharmacokinetics profile of ibrutinib in Groups A bis and B bis

    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.

    Measured: During dose escalation part, on first day of ibrutinib administration (Day 5) and on Day 15 of cycle 1 and cycle 2

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2014 (estimated)
  2. Study start26 May 2014
  3. Primary completion1 Dec 2017
  4. Study completion9 Oct 2018

Why it stopped: ANSM decision due to veino occlusive disease (security alert)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
85 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02055924
Sponsor's protocol ID
BIBLOS
Acronym
BIBLOS
Status last verified
Oct 2018
First submitted
31 Jan 2014
Last updated
11 Oct 2018
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ibrutinib and immunochemotherapies in people with B-cell Lymphoma, run by The Lymphoma Academic Research Organisation at 15 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 11 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in France, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: ANSM decision due to veino occlusive disease (security alert)). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The primary endpoint is the incidence rate of DLTs at each dose level on cycle 1 (time frame: 21 days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02055924.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2018.

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