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Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Primary Purpose

Diffuse Large Cell B-lymphoma

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
ibrutinib
Sponsored by
Pharmacyclics LLC.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large Cell B-lymphoma focused on measuring PCI-32765, Lymphoma, B-Cell, Bruton's Tyrosine Kinase, Non Hodgkin's Lymphoma, Germinal Center B-Cell, Activated B-Cell

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Men and women ≥ 18 years of age.
  2. ECOG performance status ≤ 2.
  3. Pathologically confirmed de novo DLBCL
  4. Subjects must have available tissue for central pathology review to be eligible. Treatment Group 2: Subjects will be eligible if they have the non-GCB phenotype, as confirmed by Central IHC testing by the Hans method.
  5. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a CR, or 2) PR, SD, or progressive disease (PD) at completion of the treatment regimen preceding entry to the study (residual disease): Subjects must have previously received an appropriate first-line treatment regimen. Subjects who have not received HDT/ASCT must be ineligible for HDT/ASCT
  6. Treatment Group 1: Subjects must have ≥ 1 measurable (> 2 cm in longest dimension) disease sites on CT scan. Treatment Group 2: Subjects must have ≥ 1 measurable (> 1.5 cm in longest dimension) disease sites on CT scan.

Exclusion Criteria:

  1. Transformed DLBCL or DLBCL with coexistent histologies (eg, FL or MALT).
  2. Primary mediastinal (thymic) large B-cell lymphoma.
  3. Known central nervous system lymphoma. In addition, for subjects in Treatment Group 2, known leptomeningeal involvement is exclusionary.
  4. Certain exclusions on prior therapy
  5. Major surgery within 2 weeks of first dose of study drug.

  6. Any of the following laboratory abnormalities:

    1. ANC < 0.75 x 10^9/L. Treatment Group 2: Eligible subjects must be independent of growth factor support for 7 days prior to the screening lab tests.
    2. Platelet count < 50 x 10^9/L independent of transfusion support. Treatment Group 2 only: Eligible subjects must be independent of transfusion support for 7 days prior to the screening lab tests.
    3. AST or ALT ≥ 3.0 x upper limit of normal (ULN)
    4. Creatinine > 2.0 x ULN
    5. Treatment Group 2 only: Hemoglobin < 8.0 g/dL
    6. Treatment Group 2 only: Total Bilirubin > 1.5 x ULN
  7. Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon)
  8. Treatment Group 2: Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
  9. Treatment Group 2: Known bleeding diathesis, eg, von Willebrand's disease, hemophilia.

Sites / Locations

  • UCLA Medical Center
  • Stanford University School of Medicine
  • National Cancer Institute
  • Mayo Clinic
  • University of Nebraska Medical Center
  • Hackensack University Medical Center
  • Long Island Jewish Medical Center
  • New York University
  • Weill Medical College of Cornell University
  • Memorial Sloan-Kettering Cancer Center
  • University of Rochester School of Medicine and Dentistry
  • The Ohio Sate university
  • The University of Texas MD Anderson Cancer Center
  • Univerity of Washington
  • University of Wisconsin

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

PCI-32765: 560 mg

PCI-32765: 840 mg

Arm Description

Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis.

Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis.

Outcomes

Primary Outcome Measures

Percentage of Patients With an Overall Response to Study Drug
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator.

Secondary Outcome Measures

Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Participants will be followed until progression of the disease or start of another anticancer treatment. The clinical database captured all AEs from baseline through end of treatment. Treatment Emergent AEs were collected pre-dose, at the beginning of each cycle and 30 days post last dose of study drug, unless related to study drug.
Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765
Treatment Group 1 PK collection schedule: Cycle 1 Day 1: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 8: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Treatment Group 2 PK collection schedule: Cycle 1 Day 8: Pre-dose, 1, 2, 4 and 7 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Cycle 3 Day 1: Pre-dose, 1, 2, and 4 hours post-dose

Full Information

First Posted
February 2, 2011
Last Updated
March 2, 2017
Sponsor
Pharmacyclics LLC.
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1. Study Identification

Unique Protocol Identification Number
NCT01325701
Brief Title
Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma
Official Title
A Multicenter, Open-label, Phase 2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Refractory or de Novo Diffuse Large B-cell Lymphoma (DLBCL)
Study Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Completed
Study Start Date
May 2011 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Pharmacyclics LLC.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the efficacy of ibrutinib (PCI-32765) in relapsed/refractory de novo activated B-cell (ABC) and germinal-cell B-Cell (GCB) Diffuse Large B-cell Lymphoma (DLBCL).
Detailed Description
The primary objectives of this study were to evaluate the efficacy of ibrutinib administered at 560 mg once per day in relapsed or refractory de novo ABC and GCB DLBCL, and to evaluate the efficacy of ibrutinib administered at 840 mg once per day in relapsed or refractory de novo ABC DLBCL. The secondary objective was to evaluate the safety and tolerability of a fixed daily oral dosing regimen of ibrutinib in relapsed/refractory de novo DLBCL.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large Cell B-lymphoma
Keywords
PCI-32765, Lymphoma, B-Cell, Bruton's Tyrosine Kinase, Non Hodgkin's Lymphoma, Germinal Center B-Cell, Activated B-Cell

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
78 (Actual)

8. Arms, Groups, and Interventions

Arm Title
PCI-32765: 560 mg
Arm Type
Experimental
Arm Description
Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis.
Arm Title
PCI-32765: 840 mg
Arm Type
Experimental
Arm Description
Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis.
Intervention Type
Drug
Intervention Name(s)
ibrutinib
Other Intervention Name(s)
PCI-32765, Imbruvica
Intervention Description
ibrutinib is an inhibitor of BTK
Primary Outcome Measure Information:
Title
Percentage of Patients With an Overall Response to Study Drug
Description
The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator.
Time Frame
The median follow up time on the study for all treated participants is 1.7 months (range 0.1- 32.3 months)
Secondary Outcome Measure Information:
Title
Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Description
Participants will be followed until progression of the disease or start of another anticancer treatment. The clinical database captured all AEs from baseline through end of treatment. Treatment Emergent AEs were collected pre-dose, at the beginning of each cycle and 30 days post last dose of study drug, unless related to study drug.
Time Frame
Adverse events determined to be related to study drug are collected from first dose until study exit (approximately 3 years).
Title
Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765
Description
Treatment Group 1 PK collection schedule: Cycle 1 Day 1: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 8: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Treatment Group 2 PK collection schedule: Cycle 1 Day 8: Pre-dose, 1, 2, 4 and 7 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Cycle 3 Day 1: Pre-dose, 1, 2, and 4 hours post-dose
Time Frame
Performed during the first month of receiving study drug.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women ≥ 18 years of age. ECOG performance status ≤ 2. Pathologically confirmed de novo DLBCL Subjects must have available tissue for central pathology review to be eligible. Treatment Group 2: Subjects will be eligible if they have the non-GCB phenotype, as confirmed by Central IHC testing by the Hans method. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a CR, or 2) PR, SD, or progressive disease (PD) at completion of the treatment regimen preceding entry to the study (residual disease): Subjects must have previously received an appropriate first-line treatment regimen. Subjects who have not received HDT/ASCT must be ineligible for HDT/ASCT Treatment Group 1: Subjects must have ≥ 1 measurable (> 2 cm in longest dimension) disease sites on CT scan. Treatment Group 2: Subjects must have ≥ 1 measurable (> 1.5 cm in longest dimension) disease sites on CT scan. Exclusion Criteria: Transformed DLBCL or DLBCL with coexistent histologies (eg, FL or MALT). Primary mediastinal (thymic) large B-cell lymphoma. Known central nervous system lymphoma. In addition, for subjects in Treatment Group 2, known leptomeningeal involvement is exclusionary. Certain exclusions on prior therapy Major surgery within 2 weeks of first dose of study drug. Any of the following laboratory abnormalities: ANC < 0.75 x 10^9/L. Treatment Group 2: Eligible subjects must be independent of growth factor support for 7 days prior to the screening lab tests. Platelet count < 50 x 10^9/L independent of transfusion support. Treatment Group 2 only: Eligible subjects must be independent of transfusion support for 7 days prior to the screening lab tests. AST or ALT ≥ 3.0 x upper limit of normal (ULN) Creatinine > 2.0 x ULN Treatment Group 2 only: Hemoglobin < 8.0 g/dL Treatment Group 2 only: Total Bilirubin > 1.5 x ULN Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon) Treatment Group 2: Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor Treatment Group 2: Known bleeding diathesis, eg, von Willebrand's disease, hemophilia.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Darrin Beaupre, MD
Organizational Affiliation
Pharmacyclics LLC.
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Stanford University School of Medicine
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
National Cancer Institute
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892-1203
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Long Island Jewish Medical Center
City
New Hyde Park
State/Province
New York
ZIP/Postal Code
11042
Country
United States
Facility Name
New York University
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Weill Medical College of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
University of Rochester School of Medicine and Dentistry
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
The Ohio Sate university
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Univerity of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53705
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
26193343
Citation
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. doi: 10.1038/nm.3884. Epub 2015 Jul 20.
Results Reference
derived

Learn more about this trial

Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

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