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Lymphoma, Large B-Cell, Diffuse

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Ibrutinib

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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

Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

DA-EPOCH-R

Jutta Neuenburg, MD

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).

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).

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

A Multicenter Study of Ibrutinib and Lenalidomide in Combination With DA-EPOCH-R in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

Part-1: To determine the maximum tolerated dose (MTD) of the combination of ibrutinib and lenalidomide with dose adjusted EPOCH-R

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.

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.

Part 2: The frequency (number and percentage) of treatment-emergent adverse events will be reported.

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.

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.

Celgene Corporation

Pharmacyclics LLC.

Ibrutinib 560 mg PO + DA-EPOCH-R + lenalidomide 0 (PO)

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 1: Dose Level 1

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 1: Dose Level 2

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 1: Dose Level 3

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 1: Dose Level 4

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

All Subjects Treated at RP2D

Ibrutinib 560 mg PO + DA-EPOCH-R

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 2: RP2D

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Director of Clinical Operations

Ibrutinib 560 mg (PO) +lenalidomide 0,15, 20, and 25 mg (PO) + DA-EPOCH-R

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Part 1: All Treated

Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Note: There are only 17 samples available for DLBCL subtype test per GEP. Among of them 14 subjects were identified with ABC.

ABC Subjects Treated at RP2D

Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy-ORR

Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy

Number of Subjects With Adverse Events as a Measure of Safety and Tolerability

Progression Free Survival (PFS)

Overall Survival (OS)

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

DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim

Note: There are only 17 samples available for DLBCL subtype test per GEP. Among them 14 subjects were identified with ABC.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma	NCT02142049	Diffuse Large B... Diffuse Large B...	Ibrutinib DA-EPOCH-R Lenalidomide	18 Years -	Pharmacyclics LLC.
Ibrutinib and Lenalidomide With Dose Adjusted EPOCH-R in Subjects With Relapsed/Refractory Diffuse Large B-cell Lymphoma	NCT02142049	Diffuse Large B... Diffuse Large B...	Ibrutinib DA-EPOCH-R Lenalidomide	18 Years -	Pharmacyclics LLC.

Spots Global Cancer Trial Database for recommended phase 2 dose(rp2d)