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Trial record 49 of 317 for:    IBRUTINIB

Combination of Ibrutinib and Bortezomib to Treat Patients With Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02356458
Recruitment Status : Recruiting
First Posted : February 5, 2015
Last Update Posted : April 9, 2019
Sponsor:
Collaborator:
European Mantle Cell Lymphoma Network
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Tracking Information
First Submitted Date  ICMJE February 2, 2015
First Posted Date  ICMJE February 5, 2015
Last Update Posted Date April 9, 2019
Actual Study Start Date  ICMJE August 31, 2015
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 3, 2017)
  • Phase I: Dose limiting toxicity (DLT) observed during the first cycle of trial treatment [ Time Frame: At day 8, 14, 21 during cycle 1 (1 cycle = 21 days) ]
    DLTs are defined based on adverse events observed in cycle 1 that are possibly, probably or definitively related to ibrutinib and/or bortezomib.
  • Phase II: Overall response (OR) (combination therapy) [ Time Frame: 4 1/2 months after registration. ]
    OR is defined as the proportion of patients whose best overall response, is either complete response (CR), complete response unconfirmed (CRu) or partial response (PR) according to the International Working group criteria for NHL. The primary endpoint of phase II is OR observed during the combination therapy.
Original Primary Outcome Measures  ICMJE
 (submitted: February 2, 2015)
  • Phase I: Dose limiting toxicity (DLT) observed during the first cycle of trial treatment [ Time Frame: At day 8, 14, 21 during cycle 1 (1 cycle = 21 days) ]
    DLTs are defined based on adverse events observed in cycle 1 that are possibly, probably or definitively related to ibrutinib and/or bortezomib.
  • Phase 2: Overall response (OR) (combination therapy) [ Time Frame: 4 1/2 months after inclusion of each patient ]
    OR is defined as the proportion of patients whose best overall response, is either complete response (CR) or partial response (PR).
Change History Complete list of historical versions of study NCT02356458 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: February 2, 2015)
  • Phase I and II: Adverse events (AE) until 30 days after end of trial therapy [ Time Frame: Until 30 days after up to 2 years of trial therapy ]
    All AEs will be assessed according to NCI CTCAE v4.0
  • Phase I: OR (combination therapy) [ Time Frame: 4 1/2 months after inclusion of each patient ]
    OR observed during the combination therapy.
  • Phase I: OR based on best response observed during treatment (combination and maintenance therapy) [ Time Frame: Estimated at 1 1/2 years after patient registration. ]
    OR observed during the combination therapy and OR observed during trial treatment.
  • Phase II: OR based on best response observed during treatment (combination and maintenance therapy [ Time Frame: Estimated at 1 1/2 years after patient registration. ]
    OR observed during the combination therapy and OR observed during trial treatment.
  • Phase II: Progression-free survival (PFS) [ Time Frame: Time from patient registration to progression free survival (estimated 2 years) ]
    Time from registration until progression of disease or death as a result of any cause.
  • Phase II: Time to treatment failure (TTF) [ Time Frame: Time from patient registration to treatment failure (estimated 2 years) ]
    Time from registration until treatment failure (due to unacceptable toxicity, progression, patient refusal, death, start of subsequent anti-MCL therapy or any other event that determines the termination of the trial treatment will be considered as treatment failure).
  • Phase II: Duration of objective response [ Time Frame: Time from patient registration to progression/relapse (estimated 2 years). ]
    Time from first observation of CR or PR until documentation of progression, or relapse thereafter. Only patients with CR or a PR will be included in this analysis.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Combination of Ibrutinib and Bortezomib to Treat Patients With Mantle Cell Lymphoma
Official Title  ICMJE Combination of Ibrutinib and Bortezomib Followed by Ibrutinib Maintenance to Treat Patients With Relapsed and Refractory Mantle Cell Lymphoma; a Multicenter Phase I/II Trial.
Brief Summary Mantle cell lymphoma (MCL) remains an incurable disease with frequent relapses and no standard therapeutic options in case of relapse. Prolongation of remissions or induction of longer remissions is therefore crucial. Recently, a synergistic increase in the proteasomal inhibition of ibrutinib in both bortezomib-sensitive and refractory MCL cells was shown. These findings, along with the reported single agent activities of both drugs and the non-overlapping toxicities, are the rationale to combine ibrutinib and bortezomib in MCL in this trial
Detailed Description

Disease background, therapy background and aim

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma. It represents ~5% of all lymphomas and typically is present in advanced stages, a median age of 60-65 years and a dismal prognosis with a median survival of ~3 years. Currently, it remains incurable, as the patients will relapse after first line treatment and require subsequent therapy. The disease-free survival is progressively shorter with each subsequent relapse.

Currently, there is no standard therapy for relapsed MCL patients. MCL is predominantly a disease of the elderly who are not suitable for aggressive chemotherapy. Allogeneic transplants are preferred in young and fit patients, whereas (preferably single agent) chemotherapy is used to treat older patients, but usually with short duration of responses. Recently, the therapeutic armamentarium has been expanded with the availability of novel agents targeting crucial and deregulated pathways in MCL. These include the Bruton's Kinase (BTK) inhibitor ibrutinib with excellent single agent activities. New therapeutic options in the targeted patient population are clearly needed to prolong remissions especially for elderly patients where aggressive chemotherapy and allogeneic transplants are no suitable treatment options. Recently, a synergistic increase in the proteasomal inhibition of ibrutinib in both bortezomib-sensitive and refractory MCL cells was shown.

This trial is targeting patients with diagnosis of refractory or relapsed MCL disease after pretreatment with ≤2 lines of non-bortezomib-containing chemotherapy. The proposed treatment of ibrutinib in combination with bortezomib might lead to an improvement of the therapy in the targeted relapsed/refractory patient population. Given the absence of a dose-limiting toxicity also when applied long-term, ibrutinib is well suited in this patient population as a maintenance therapy. Therefore, the combination treatment of the trial is followed by a maintenance therapy part for patients that had no disease progression. New treatment options should control the disease as best and long as possible.

Treatment

Treatment consists of 6 cycles of 21 days each of ibrutinib in combination with bortezomib, followed by a maintenance therapy with ibrutinib monotherapy. In the maintenance therapy courses repeat every 28-days in the absence of disease progression or unacceptable toxicity.

Objectives Phase I The primary object of the trial is to establish the recommended phase II dose (RP2D) of ibrutinib in combination with bortezomib in patients with relapsed or refractory MCL.

The secondary objectives are

  • to determine the safety and tolerability of ibrutinib in combination with bortezomib and
  • to assess the preliminary antitumor activity of ibrutinib in combination with bortezomib Phase II The main object of the trial is to define the efficacy of the combination treatment of ibrutinib with bortezomib in patients with relapsed or refractory MCL.

The secondary objectives are

  • to determine the safety and tolerability of the RP2D and
  • to assess the efficacy of ibrutinib in combination with bortezomib in patients with relapsed MCL followed by an ibrutinib maintenance therapy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Mantle Cell Lymphoma
Intervention  ICMJE
  • Drug: Ibrutinib

    Combination therapy:

    Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Ibrutinib: p.o daily; Phase I: according to DL; Phase II: RP2D established in phase I

    Maintenance therapy:

    p.o daily: 560 mg

    Other Name: Imbruvica
  • Drug: bortezomib

    Combination therapy:

    Trial treatment of ibrutinib in combination with bortezomib Cycles 1-6 (1 cycle = 21 days) Injection of Bortezomib (s.c.), dose of 1.3 mg/m2 on day 1, 4, 8, 11

    Other Name: Velcade®
Study Arms  ICMJE Experimental: Ibrutinib & Bortezomib
Combination therapy (trial treatment of ibrutinib in combination with bortezomib) followed by ibrutinib maintenance therapy
Interventions:
  • Drug: Ibrutinib
  • Drug: bortezomib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2015)
73
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2022
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patient must give written informed consent before registration indicating that the patient understands the purpose of the procedures required for the trial and is willing to participate in the trial.
  • Histologically confirmed mantle cell lymphoma with either overexpression of cyclin D1 protein or evidence of t(11;14)(q13;q32) assessed by cytogenetics, by fluorescence, in situ hybridization (FISH) or by polymerase chain reaction (PCR).
  • Refractory or relapsed disease in need of systemic therapy after pretreatment with non-bortezomib-containing chemotherapy (including high-dose therapy)
  • At least one measurable lesion ≥11 mm in its greatest transverse diameter measured with CT scan (contrast enhanced) or MRI (in case of the disease cannot be adequately imaged using CT and if contrast is not appropriate for patients according to the treating physician)
  • WHO performance status 0-2
  • Age ≥ 18 years
  • Adequate hematological values:

    • Absolute neutrophil count (ANC) > 1.0 x 109/L independent of growth factor support
    • Platelets ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support in either situation,
    • Hb ≥ 80 g/L
  • Adequate hepatic function:

    • Total bilirubin ≤1.5xupper limit of normal (ULN) unless bilirubin is due to Gilbert`s syndrome ≤ 5.0 x ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3xULN
  • Adequate renal function: Body surface area (BSA) corrected creatinine clearance >40mL/min/1.73m2 (calculated according to the formula of Cockcroft-Gault)
  • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the trial (see below) consistent with local regulations regarding the use of birth control methods for patients participating in clinical trials (see section 9.12). Men must agree to not donate sperm during and after the trial. These restrictions apply for

    • Ibrutinib: 3 month after the last dose of trial drug for males and 1 month for females.
    • Bortezomib: during trial treatment (for males and females): no restrictions of birth control after last dose of trial drug. Donation of sperm: 6 month after the last dose of trial drug.
  • Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [β-hCG]) or urine pregnancy test at baseline. Women who are pregnant or breastfeeding are ineligible for this trial.

Exclusion Criteria:

  • Prior therapy with ibrutinib or bortezomib
  • Adverse event neuropathy of prior therapy grade ≥2 (according to CTCAE criteria) at registration
  • Previous malignancy within 5 years with the exception of adequately treated in situ cervical cancer or localized non-melanoma skin cancer.
  • Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningeosis)
  • Evidence of ongoing systemic infections of all kind
  • Exclusion of the following prior treatments prior to trial registration

    • major surgery within 4 weeks
    • concurrent treatment with other experimental drugs or treatment in a clinical trial within 30 days.
    • treatment with chemotherapy and radiotherapy within ≥ 3 weeks
    • vaccinated with live, attenuated vaccines within 4 weeks
  • History of stroke or intracranial hemorrhage within 6 months prior to trial registration.
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon)
  • Requires treatment with strong or moderate CYP3A inhibitors (see http://medicine.iupui.edu/)
  • Clinically significant cardiovascular disease such as congestive heart failure NYHA III or IV (as defined by the New York Heart Association Functional Classification), uncontrolled or symptomatic arrhythmias, significant QT-prolongation, unstable angina pectoris myocardial infarction within 6 months of prior to registration,
  • 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 treatment.
  • Prior allogeneic bone marrow or solid organ transplantation
  • Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion,

    • could impair the ability of the patient to participate in the trial
    • could compromise the patient's safety,
    • could interfere with the absorption or metabolism of ibrutinib capsules, or
    • could put the trial outcomes at undue risk
    • could prevent compliance with trial treatment.
  • Psychiatric disorder precluding understanding of trial information, giving informed consent, or interfering with compliance for oral drug intake.
  • Known hypersensitivity to trial drug(s) or hypersensitivity to any other component of the trial drugs.
  • Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the trial protocol and follow‐up.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Simon Schäfer +41 31 389 91 91 trials@sakk.ch
Listed Location Countries  ICMJE Germany,   Italy,   Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02356458
Other Study ID Numbers  ICMJE SAKK 36/13
2014-003893-17 ( EudraCT Number )
SNCTP000001235 ( Other Identifier: Swiss National Clinical Trial Portal )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Swiss Group for Clinical Cancer Research
Study Sponsor  ICMJE Swiss Group for Clinical Cancer Research
Collaborators  ICMJE European Mantle Cell Lymphoma Network
Investigators  ICMJE
Study Chair: Urban Novak, PD Dr. med. University Hospital Bern - Inselspital
PRS Account Swiss Group for Clinical Cancer Research
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP