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Study of Ibrutinib (a Bruton's Tyrosine Kinase Inhibitor), Versus Temsirolimus in Patients With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

This study has been completed.
Sponsor:
Collaborator:
Pharmacyclics LLC.
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01646021
First received: July 18, 2012
Last updated: January 11, 2017
Last verified: January 2017
  Purpose
The purpose of this study is to evaluate the efficacy and safety of ibrutinib versus temsirolimus in patients with relapsed or refractory mantle cell lymphoma who received at least 1 prior chemotherapy regimen.

Condition Intervention Phase
Mantle Cell Lymphoma
Drug: Ibrutinib
Drug: Temsirolimus
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, Versus Temsirolimus in Subjects With Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: Date of randomization up to disease progression or relapse from CR or death, whichever occurs first (approximately upto 28.2 months) ]
    Progression free survival is defined as the duration in months from the date of randomization to the date of disease progression or relapse from CR or death whichever was reported first .


Secondary Outcome Measures:
  • Overall Response Rate (ORR) [ Time Frame: Approximately 28.2 months ]
    Overall response rate (ORR), defined as the percentage of participants who achieved either CR or PR as best overall response as assessed by Independent Review Committee (IRC) at or prior to initiation of subsequent antineoplastic therapy. Complete Response (CR) = Disappearance of all target lesions; Partial Response (PR)= greater than or equal to 30 percentage decrease in the sum of the longest diameter of target lesions and Overall Response (OR) = CR + PR.

  • Overall Survival (OS) [ Time Frame: Approximately 28.2 months ]
    Overall survival (OS), defined as the duration (months) from the date of randomization to the date of the participant's death from any cause.

  • One Year Survival Rate [ Time Frame: Month 12 ]
    One -year survival rate, defined as the proportion of participants who were alive 1 year after randomization.

  • Duration of Response [ Time Frame: approximately 2.8 years ]
    Duration of response (CR or PR), defined as the duration in days from the date of initial response to the date of first documented evidence of progressive disease (or relapse for participants who experience CR during the study) or death.

  • Time-to-Next Treatment [ Time Frame: approximately 2.8 years ]
    Time to next treatment was measured from the date of randomization to the start date of any anti-lymphoma treatment subsequent to study treatment.

  • Time to Response [ Time Frame: Approximately 2.8 years ]
    Time to response for participants with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response.

  • Time to Worsening in the Lymphoma Sub Scale of Functional Assessment of Cancer Therapy- Lymphoma (FACT-Lym) [ Time Frame: Approximately 2 years ]
    Time to worsening in the Lymphoma subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening. Worsening was defined by a 5-point decrease from baseline. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60.

  • The Mean Change From Baseline in Euro QoL Five-Dimension (EQ-5D-5L) Scores for Each Post Baseline Assessment [ Time Frame: Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment ]
    The EQ-5D is a participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state.

  • Area Under the Plasma Concentration of Ibrutinib During Steady State (AUC-ss) [ Time Frame: Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr postdose; Cycle 3 (day 1): Predose ]
    The AUC-ss is the area under the plasma concentration time curve observed during steady state.

  • Number of Participants With Bio Markers That Alter B-cell Receptor (BCR) Signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib [ Time Frame: Approximately upto 28.2 months ]
  • Extent of Exposure of Time [ Time Frame: Approximately upto 28.2 months ]
    Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment.

  • Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately upto 28.2 months ]
    Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.

  • Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately upto 28.2 months ]
    Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.

  • Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI) [ Time Frame: Approximately upto 28.2 months ]
    Medical resource utilization data associated with medical encounters related to disease was reported for all participants throughout the study.


Enrollment: 280
Study Start Date: December 2012
Study Completion Date: December 2016
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ibrutinib Drug: Ibrutinib
560 mg once daily continuous (without interruption) by mouth for 21-day cycles
Experimental: Temsirolimus Drug: Temsirolimus
175 mg once daily intravenous infusion on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each 21-day cycle

Detailed Description:
This is a randomized (individuals assigned to study treatment by chance), open-label (identity of assigned study drug will be known), study to evaluate the efficacy and safety of ibrutinib when compared with temsirolimus in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen. Approximately 280 eligible patients will be randomly assigned in a 1:1 ratio and stratified (grouped) by the number of prior lines of therapy (1 or 2 versus >=3) and simplified MCL International Prognostic Index criteria to receive either ibrutinib by mouth (Treatment Arm A) or temsirolimus intravenous infusion (Treatment Arm B). The study will consist of screening, treatment, and posttreatment phases. Data will be collected on disease response to the treatment, progression-free survival, overall survival, subsequent anti-MCL therapies, patient reported outcomes, and medical resource utilization. Tumor samples, blood collected at multiple time points, and a bone marrow aspirate will be evaluated to identify markers predictive of response or resistance to ibrutinib. Serial pharmacokinetic (study of what the body does to a drug) samples will be collected as detailed in the protocol. Safety will be monitored throughout the study. Disease evaluations will be performed every 9 weeks for up to 15 months from the start of study drug, and every 24 weeks thereafter, until disease progression, death, or the clinical cutoff, whichever comes first. Patients who receive treatment with temsirolimus and have disease progression (confirmed by an Independent Review Committee) may be eligible to crossover and receive treatment with ibrutinib 560 mg orally, daily, on a 21-day cycle until disease progression, unacceptable toxicity, or study end. Data will be analyzed up to 3 years after the last patient is enrolled for the final follow-up.
  Eligibility

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

Inclusion Criteria:

  • Confirmed diagnosis of mantle cell lymphoma (MCL)
  • Received at least 1 prior rituximab-containing chemotherapy regimen (separate lines of therapy are defined as single or combination therapies that are either separated by disease progression or by a > 6 month treatment-free interval)
  • Documented relapse or disease progression following the last anti-MCL treatment
  • At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma
  • Eastern Cooperative Oncology Group performance status grade 0 or 1
  • Protocol-defined hematology and biochemistry laboratory values

Exclusion Criteria:

  • Prior nitrosoureas within 6 weeks, chemotherapy within 3 weeks, therapeutic anticancer antibodies within 4 weeks, radio- or toxin-immunoconjugates within 10 weeks, radiation therapy or other investigational agents within 3 weeks, or major surgery within 4 weeks of randomization
  • Prior treatment with temsirolimus, other mTOR inhibitors, ibrutinib, or other Bruton's tyrosine kinase (BTK) inhibitors
  • Known central nervous system lymphoma
  • Received an allogeneic or autologous hematopoietic stem cell transplant <=6 months from the date of randomization and on immunosuppressive therapy or have evidence of active graft versus host disease
  • Diagnosed or treated for malignancy other than MCL, except: malignancy treated with curative intent and with no known active disease present for >=3 years before randomization, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated cervical carcinoma in situ without evidence of disease
  • History of stroke or intracranial hemorrhage within 6 months prior to randomization
  • Requires anticoagulation with warfarin or equivalent vitamin K antagonist
  • Requires treatment with strong CYP3A inhibitor
  • Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
  • Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV) infection or any uncontrolled active systemic infection requiring intravenous antibiotics
  • Woman who is pregnant or breast-feeding
  • Any life-threatening illness, medical condition, or organ system dysfunction 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
  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: NCT01646021

  Show 98 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Pharmacyclics LLC.
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT01646021     History of Changes
Other Study ID Numbers: CR100848
PCI-32765MCL3001 ( Other Identifier: Janssen Research & Development, LLC )
2012-000601-74 ( EudraCT Number )
U1111-1135-6930 ( Other Identifier: Universal Trial Number )
Study First Received: July 18, 2012
Results First Received: June 2, 2016
Last Updated: January 11, 2017

Keywords provided by Janssen Research & Development, LLC:
Mantle cell lymphoma
Relapsed mantle cell lymphoma
Refractory mantle cell lymphoma
Ibrutinib
Bruton's tyrosine kinase inhibitor
Temsirolimus

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents

ClinicalTrials.gov processed this record on April 24, 2017