Diffuse Large B Cell Lymphoma Refractory, Diffuse Large B Cell Lymphoma Relapsed
Conditions
Keywords
DLBCL, ABC, GCB, Primary Mediastinal B-cell lymphoma, Pharmacyclics, Lenalidomide, lymphoma, Rituximab, EPOCH, Recommended Phase 2 Dose(RP2D)
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).
Interventions
DRUGIbrutinib
Ibrutinib
DRUGDA-EPOCH-R
Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim
DRUGLenalidomide
Lenalidomide
Sponsors
Celgene Corporation
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 1 year after last subjects received the first dose | 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 | 1 year after last subjects received the first dose | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 1 year after last subjects received the first dose | 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 | 1 year after last subjects received the first dose | 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 | 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. | 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) | 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. | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Dose Level 1 Ibrutinib 560 mg PO + DA-EPOCH-R
DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim | 3 |
| Part 1: Dose Level 2 Ibrutinib 560 mg (PO) +lenalidomide 15 mg (PO) + DA-EPOCH-R
DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim | 3 |
| Part 1: Dose Level 3 Ibrutinib 560 mg (PO) +lenalidomide 20 mg (PO) + DA-EPOCH-R
DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim | 3 |
| 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 | 6 |
| Part 2: RP2D Ibrutinib 560 mg (PO) +lenalidomide 25 mg (PO) + DA-EPOCH-R
DA-EPOCH-R: Etoposide, Prednisone, Doxorubicin, Cyclophosphamide, Vincristine, Rituximab, Pegfilgrastim | 20 |
| Total | 35 |
Baseline characteristics
| Characteristic | Part 1: Dose Level 1 | Part 1: Dose Level 2 | Part 1: Dose Level 3 | Part 1: Dose Level 4 | Part 2: RP2D | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 9 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 3 Participants | 1 Participants | 6 Participants | 11 Participants | 22 Participants |
| Age, Continuous | 69 years | 58 years | 67 years | 55 years | 59 years | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 17 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 3 Participants | 6 Participants | 15 Participants | 29 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 6 participants | 20 participants | 35 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 3 Participants | 5 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 6 | 3 / 26 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 26 / 26 |
| serious Total, serious adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 5 / 6 | 19 / 26 |
Outcome results
Primary
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.
Time frame: 1 year after last subjects received the first dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Level 1 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy-ORR | 16 Participants |
| Part 1: Dose Level 2 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy-ORR | 9 Participants |
Primary
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
Time frame: 1 year after last subjects received the first dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Level 1 | Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 0 Participants |
| Part 1: Dose Level 2 | Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 0 Participants |
| Part 1: Dose Level 3 | Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 0 Participants |
| Part 1: Dose Level 4 | Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 1 Participants |
| Part 1: All Treated | Number of Participants With Dose-Limiting Toxicities as a Measure of Safety and Tolerability | 1 Participants |
Secondary
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.
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Dose Level 1 | Duration of Response (DOR) | 3.94 Months |
| Part 1: Dose Level 2 | Duration of Response (DOR) | 4.09 Months |
Secondary
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.
Time frame: 1 year after last subjects received the first dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Level 1 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 1 Participants |
| Part 1: Dose Level 2 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 2 Participants |
| Part 1: Dose Level 3 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 0 Participants |
| Part 1: Dose Level 4 | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 3 Participants |
| Part 1: All Treated | Number of Participants With Complete Responses (CR) and Partial Responses (PR) as a Measure of Efficacy | 6 Participants |
Secondary
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.
Time frame: 1 year after last subjects received the first dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Dose Level 1 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 26 Participants |
| Part 1: Dose Level 2 | Number of Subjects With Adverse Events as a Measure of Safety and Tolerability | 14 Participants |
Secondary
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.
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Dose Level 1 | Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy | Progression Free Survival (PFS) | 4.86 Months |
| Part 1: Dose Level 1 | Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy | Overall Survival (OS) | 15.84 Months |
| Part 1: Dose Level 2 | Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy | Progression Free Survival (PFS) | 4.86 Months |
| Part 1: Dose Level 2 | Progression Free Survival (PFS) and Overall Survival (OS) as a Measure of Efficacy | Overall Survival (OS) | 15.84 Months |