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Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma

Primary Purpose

Diffuse Large B Cell Lymphoma Relapsed, Diffuse Large B Cell Lymphoma Refractory

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ibrutinib
DA-EPOCH-R
Lenalidomide
Sponsored by
Pharmacyclics LLC.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diffuse Large B Cell Lymphoma Relapsed focused on measuring DLBCL, ABC, GCB, Primary Mediastinal B-cell lymphoma, Pharmacyclics, Lenalidomide, lymphoma, Rituximab, EPOCH, Recommended Phase 2 Dose(RP2D)

Eligibility Criteria

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

Major inclusion criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status of ≤2
  • Pathologically confirmed relapsed/refractory DLBCL
  • Subjects must have ≥1 measurable disease site on CT scan (≥ 1.5 cm in longest dimension).

  • Adequate hepatic and renal function:

    • AST or ALT ≤2.5 x ULN
    • Serum Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥60 mL/min/1.73
    • Bilirubin ≤1.5 x ULN

  • Adequate hematologic function:

    • ANC >1,000 cells/mm3
    • Platelets ≥75,000 cells/mm3
    • Hemoglobin ≥8.0 g/dL
    • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be ≤1.5 x the upper limit of the normal range (ULN)
  • Must be registered into the Revlimid REMS™program and be willing to comply with the requirements of Revlimid REMS™.

Major Exclusion Criteria:

  • Known central nervous system lymphoma
  • Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2 weeks
  • Radio- or toxin-immunoconjugates within 10 weeks
  • Prior allogenetic stem cell (or other organ) transplant within 6 months or any evidence of active graft-versus-host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug

Sites / Locations

  • SITE-1
  • SITE-2
  • SITE-10
  • SITE-3
  • SITE-5
  • SITE-6
  • SITE-4
  • SITE-8
  • SITE-9
  • SITE-7

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part 1: Dose Level 1

Part 1: Dose Level 2

Part 1: Dose Level 3

Part 1: Dose Level 4

Part 2: RP2D

Arm Description

Ibrutinib 560 mg PO + DA-EPOCH-R

Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R

Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R

Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R

Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R

Outcomes

Primary Outcome Measures

Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability
Part-1: To determine the maximum tolerated dose (MTD) of the combination of ibrutinib and lenalidomide with dose adjusted EPOCH-R
Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy-ORR
Part 2 - Overall Response rate will be defined as the proportion of subjects who achieve either a Complete Response or a Partial Response according to the international Working Group Response Criteria for NHL as assessed by investigator.

Secondary Outcome Measures

Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy
Part-1: Overall Response rate (ORR) will defined as the proportion of subjects who achieve either a CR or a PR according to the international Working Group Response Criteria for NHL as assessed by investigator.
Number of Subjects With Adverse Events as a Measure of Safety and Tolerability
Part 2: The frequency (number and percentage) of treatment-emergent adverse events will be reported.
Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy
Part 2: PFS will be measured as time from first study drug administration to disease progression or death from any cause. OS will be measured from the time of first study drug administration until the date of death using Kaplan-Meier methodology.
Duration of Response (DOR)
Part 2: DOR will be measured from the time by which the measurement criteria are met for CR or PR until the first date by which recurrent or progressive disease is objectively documented.

Full Information

First Posted
May 12, 2014
Last Updated
January 14, 2019
Sponsor
Pharmacyclics LLC.
Collaborators
Celgene Corporation
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1. Study Identification

Unique Protocol Identification Number
NCT02142049
Brief Title
Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma
Official Title
A Multicenter Study of Ibrutinib and Lenalidomide in Combination With DA-EPOCH-R in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
May 2014 (undefined)
Primary Completion Date
August 2017 (Actual)
Study Completion Date
August 2017 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a Phase 1b/2, open-label, non-randomized multicenter study to assess the safety and efficacy of ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects with relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL).
Detailed Description
This is a Phase 1b, open-label, non-randomized multicenter study conducted in 2 parts. Part 1, will determine the MTD of the combination of ibrutinib, lenalidomide and DA-EPOCH-R in subjects with DLBCL. Ibrutinib will be administered at a fixed dose of 560 mg and lenalidomide will be dose-escalated. DA-EPOCH-R will be given at standard doses. For Part 2, the MTD determined in Part 1 will be the dose used for all subjects. If no MTD is identified, then subjects in Part 2 will be treated with the maximum administered doses (MAD, treatment doses from dose Level 4). The primary objective for Part 2 is to determine the ORR of ibrutinib and lenalidomide in combination with DA-EPOCH-R in subjects with ABC DLBCL as analyzed by gene expression profiling when treated at recommended phase 2 dose (RP2D).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diffuse Large B Cell Lymphoma Relapsed, Diffuse Large B Cell Lymphoma Refractory
Keywords
DLBCL, ABC, GCB, Primary Mediastinal B-cell lymphoma, Pharmacyclics, Lenalidomide, lymphoma, Rituximab, EPOCH, Recommended Phase 2 Dose(RP2D)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
35 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part 1: Dose Level 1
Arm Type
Experimental
Arm Description
Ibrutinib 560 mg PO + DA-EPOCH-R
Arm Title
Part 1: Dose Level 2
Arm Type
Experimental
Arm Description
Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R
Arm Title
Part 1: Dose Level 3
Arm Type
Experimental
Arm Description
Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R
Arm Title
Part 1: Dose Level 4
Arm Type
Experimental
Arm Description
Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R
Arm Title
Part 2: RP2D
Arm Type
Experimental
Arm Description
Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Intervention Description
Ibrutinib
Intervention Type
Drug
Intervention Name(s)
DA-EPOCH-R
Intervention Description
Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim
Intervention Type
Drug
Intervention Name(s)
Lenalidomide
Intervention Description
Lenalidomide
Primary Outcome Measure Information:
Title
Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability
Description
Part-1: To determine the maximum tolerated dose (MTD) of the combination of ibrutinib and lenalidomide with dose adjusted EPOCH-R
Time Frame
1 year after last subjects received the first dose
Title
Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy-ORR
Description
Part 2 - Overall Response rate will be defined as the proportion of subjects who achieve either a Complete Response or a Partial Response according to the international Working Group Response Criteria for NHL as assessed by investigator.
Time Frame
1 year after last subjects received the first dose
Secondary Outcome Measure Information:
Title
Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy
Description
Part-1: Overall Response rate (ORR) will defined as the proportion of subjects who achieve either a CR or a PR according to the international Working Group Response Criteria for NHL as assessed by investigator.
Time Frame
1 year after last subjects received the first dose
Title
Number of Subjects With Adverse Events as a Measure of Safety and Tolerability
Description
Part 2: The frequency (number and percentage) of treatment-emergent adverse events will be reported.
Time Frame
1 year after last subjects received the first dose
Title
Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy
Description
Part 2: PFS will be measured as time from first study drug administration to disease progression or death from any cause. OS will be measured from the time of first study drug administration until the date of death using Kaplan-Meier methodology.
Time Frame
From initial dose date until the date of first documented progression or death from any cause, whichever came first, assessed up to approximately 1 year after the last subject received the first dose, up to 36 months at the most.
Title
Duration of Response (DOR)
Description
Part 2: DOR will be measured from the time by which the measurement criteria are met for CR or PR until the first date by which recurrent or progressive disease is objectively documented.
Time Frame
From initial response date until the date of first documented progression or death from any cause, whichever came first, assessed up to approximately 1 year after the last subject received the first dose.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Major inclusion criteria: Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 Pathologically confirmed relapsed/refractory DLBCL Subjects must have ≥1 measurable disease site on CT scan (≥ 1.5 cm in longest dimension). Adequate hepatic and renal function: AST or ALT ≤2.5 x ULN Serum Creatinine ≤ 2.0 mg/dL and creatinine clearance ≥60 mL/min/1.73 Bilirubin ≤1.5 x ULN Adequate hematologic function: ANC >1,000 cells/mm3 Platelets ≥75,000 cells/mm3 Hemoglobin ≥8.0 g/dL Prothrombin time (PT) and activated partial thromboplastin time (aPTT) must be ≤1.5 x the upper limit of the normal range (ULN) Must be registered into the Revlimid REMS™program and be willing to comply with the requirements of Revlimid REMS™. Major Exclusion Criteria: Known central nervous system lymphoma Any chemotherapy, external beam radiation therapy, or anti-cancer antibodies within 2 weeks Radio- or toxin-immunoconjugates within 10 weeks Prior allogenetic stem cell (or other organ) transplant within 6 months or any evidence of active graft-versus-host disease or requirement for immunosuppressants within 28 days prior to first dose of study drug
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jutta Neuenburg, MD
Organizational Affiliation
Pharmacyclics LLC (An AbbVie Company)
Official's Role
Study Director
Facility Information:
Facility Name
SITE-1
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States
Facility Name
SITE-2
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
SITE-10
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
SITE-3
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
SITE-5
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
SITE-6
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
SITE-4
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
SITE-8
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87106
Country
United States
Facility Name
SITE-9
City
Stony Brook
State/Province
New York
ZIP/Postal Code
11794
Country
United States
Facility Name
SITE-7
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33856277
Citation
Wilson WH, Phillips T, Popplewell L, de Vos S, Chhabra S, Kimball AS, Beaupre D, Huang DW, Wright G, Kwei K, Ping J, Neuenburg JK, Staudt LM. Phase 1b/2 study of ibrutinib and lenalidomide with dose-adjusted EPOCH-R in patients with relapsed/refractory diffuse large B-cell lymphoma. Leuk Lymphoma. 2021 Sep;62(9):2094-2106. doi: 10.1080/10428194.2021.1907371. Epub 2021 Apr 15.
Results Reference
derived

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Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma

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