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

Study Overview
=================
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).

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

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

Intervention / Treatment
-----------------
* Drug: Ibrutinib
* Drug: DA-EPOCH-R
* Drug: Lenalidomide


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Dose Level 1<br>Ibrutinib 560 mg PO + DA-EPOCH-R | Drug: Ibrutinib<br>* Ibrutinib<br>Drug: DA-EPOCH-R<br>* Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim<br>|
| Experimental: Part 1: Dose Level 2<br>Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R | Drug: Ibrutinib<br>* Ibrutinib<br>Drug: DA-EPOCH-R<br>* Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim<br>Drug: Lenalidomide<br>* Lenalidomide<br>|
| Experimental: Part 1: Dose Level 3<br>Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R | Drug: Ibrutinib<br>* Ibrutinib<br>Drug: DA-EPOCH-R<br>* Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim<br>Drug: Lenalidomide<br>* Lenalidomide<br>|
| Experimental: Part 1: Dose Level 4<br>Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R | Drug: Ibrutinib<br>* Ibrutinib<br>Drug: DA-EPOCH-R<br>* Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim<br>Drug: Lenalidomide<br>* Lenalidomide<br>|
| Experimental: Part 2: RP2D<br>Recommended Phase 2 Dose(RP2D): Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R | Drug: Ibrutinib<br>* Ibrutinib<br>Drug: DA-EPOCH-R<br>* Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim<br>Drug: Lenalidomide<br>* Lenalidomide<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 1 year after last subjects received the first dose | 
| 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. | 1 year after last subjects received the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year after last subjects received the first dose | 
| 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. | 1 year after last subjects received the first dose | 
| 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. | 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. | 
| 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. | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
DLBCL, ABC, GCB, Primary Mediastinal B-cell lymphoma, Pharmacyclics, Lenalidomide, lymphoma, Rituximab, EPOCH, Recommended Phase 2 Dose(RP2D)