Diffuse Large Cell B-lymphoma
Conditions
Keywords
PCI-32765, Lymphoma, B-Cell, Bruton's Tyrosine Kinase, Non Hodgkin's Lymphoma, Germinal Center B-Cell, Activated B-Cell
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.
Interventions
DRUGibrutinib
ibrutinib is an inhibitor of BTK
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With an Overall Response to Study Drug | The median follow up time on the study for all treated participants is 1.7 months (range 0.1- 32.3 months) | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events as a Measure of Safety and Tolerability | Adverse events determined to be related to study drug are collected from first dose until study exit (approximately 3 years). | 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 | Performed during the first month of receiving study drug. | 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 |
Countries
United States
Participant flow
Pre-assignment details
A total of 78 subjects were enrolled: 70 were treated with PCI-32765 (ibrutinib) 560 mg daily, and 8 were treated with ibrutinib 840mg daily. All subjects received at least 1 dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| PCI-32765: 560 mg Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis. | 70 |
| PCI-32765: 840 mg Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis. | 8 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 12 | 0 |
| Overall Study | Physician Decision | 2 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Rollerover Extension Study | 4 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | PCI-32765: 840 mg | PCI-32765: 560 mg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 32 Participants | 36 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 38 Participants | 42 Participants |
| Age, Continuous | 64.4 Years STANDARD_DEVIATION 13.96 | 62.5 Years STANDARD_DEVIATION 13.4 | 62.7 Years STANDARD_DEVIATION 13.38 |
| Region of Enrollment United States | 8 participants | 70 participants | 78 participants |
| Sex: Female, Male Female | 2 Participants | 20 Participants | 22 Participants |
| Sex: Female, Male Male | 6 Participants | 50 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 70 / 70 | 8 / 8 |
| serious Total, serious adverse events | 40 / 70 | 3 / 8 |
Outcome results
Primary
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.
Time frame: The median follow up time on the study for all treated participants is 1.7 months (range 0.1- 32.3 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765: 560 mg | Percentage of Patients With an Overall Response to Study Drug | 24.3 percentage of participants |
| PCI-32765: 840 mg | Percentage of Patients With an Overall Response to Study Drug | 12.5 percentage of participants |
Secondary
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
Time frame: Performed during the first month of receiving study drug.
Population: PK samples were collected in all participants (n=70 and 8 in PCI-32765: 560 mg and 840 mg, respectively). Of these, 59 participants in PCI-32765: 560 mg and 7 in PCI-32765: 840 mg on Cycle 1 Day 8 were evaluable for PK.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PCI-32765: 560 mg | Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | PCI-32765 - Day 8 | 1285 ng*h/mL | Standard Deviation 971 |
| PCI-32765: 560 mg | Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | PCI-45227 (Metabolite)- Day 8 | 1485 ng*h/mL | Standard Deviation 948 |
| PCI-32765: 840 mg | Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | PCI-32765 - Day 8 | 1337 ng*h/mL | Standard Deviation 1556 |
| PCI-32765: 840 mg | Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 | PCI-45227 (Metabolite)- Day 8 | 1671 ng*h/mL | Standard Deviation 1147 |
Secondary
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.
Time frame: Adverse events determined to be related to study drug are collected from first dose until study exit (approximately 3 years).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765: 560 mg | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 70 participants |
| PCI-32765: 840 mg | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 8 participants |