B-cell Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
Lymphoma, B-Cell, Leukemia, Lymphoid, Leukemia, B-Cell, Bruton's Tyrosine Kinase
Brief summary
The purpose of this study is to establish the safety of orally administered PCI-32765 in combination with fludarabine/cyclophosphamide/rituximab (FCR) and bendamustine/rituximab (BR) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma(SLL).
Detailed description
This is a Phase 1b, open-label, parallel-group, nonrandomized, multicenter study of PCI 32765 420 mg once daily oral (PO) administration in combination with 2 different chemotherapy regimens in subjects with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
Interventions
DRUGPCI-32765
420 mg daily
Sponsors
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed CLL or SLL and satisfying at least 1 of the following criteria for requiring treatment: * Progressive splenomegaly and/or lymphadenopathy identified by physical examination or radiographic studies * Anemia (\<11 g/dL) or thrombocytopenia (\<100,000/μL) due to bone marrow involvement * Presence of unintentional weight loss \> 10% over the preceding 6 months * NCI CTCAE Grade 2 or 3 fatigue * Fevers \> 100.5° or night sweats for \> 2 weeks without evidence of infection * Progressive lymphocytosis with an increase of \> 50% over a 2 month period or an anticipated doubling time of \< 6 months 2. 1 to 3 prior treatment regimens for CLL/SLL 3. ECOG performance status of ≤ 1 4. ≥ 18 years of age 5. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty 6. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations)
Exclusion criteria
1. Any chemotherapy, therapeutic antineoplastic antibodies (not including radio- or toxin immunoconjugates), radiation therapy, or experimental antineoplastic therapy within 4 weeks of first dose of study drug 2. Radio- or toxin-conjugated antibody therapy within 10 weeks of first dose of study drug 3. Concomitant use of medicines known to cause QT prolongation or torsades de pointes 4. Transformed lymphoma or Richter's transformation Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of PCI-32765 PO, or put the study outcomes at undue risk 5. Any of the following laboratory abnormalities: oAbsolute neutrophil count (ANC) \< 1000 cells/mm3 (1.0 x 109/L) oPlatelet count \< 50,000/mm3 (50 x 109/L) oSerum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) oCreatinine \> 2.0 x ULN or creatinine clearance \< 40 mL/min
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Prolonged Hematologic Toxicity Started in Cycle 1 | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0 | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | — |
| Overall Incidence of Serious Adverse Events (SAEs) | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | — |
| Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib | From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months. | — |
| Sustained Hematologic Improvement in Subjects With Neutropenia, Anemia, or Thrombocytopenia at Baseline | From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months. | — |
| Progression Free Survival Rate at 12 Months | From first dose of any study medication to 12 months after first dose to progressive disease or death or the last clinical assessment before receiving new anticancer therapy or loss to follow-up, whichever occured the earliest. | Criteria for progression are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. progression defined as a 50% increase in lymph node size. |
| Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR]) | From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months. | Response criteria are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. response requires 50% reduction in lymph node size. Assessment of response to treatment will be done every 2 cycles for the first 6 months and then every 3 months thereafter until disease progression or prior to the administration of a new anticancer therapy and at follow-up visits. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PCI-32765 Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) PCI-32765: 420 mg daily | 3 |
| PCI-32765 Plus Bendamustine/Rituximab (BR) PCI-32765: 420 mg daily | 30 |
| Total | 33 |
Baseline characteristics
| Characteristic | PCI-32765 Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) | PCI-32765 Plus Bendamustine/Rituximab (BR) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 11 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 19 Participants | 22 Participants |
| Age, Continuous | 56.3 Years STANDARD_DEVIATION 1.53 | 61.3 Years STANDARD_DEVIATION 9.58 | 60.8 Years STANDARD_DEVIATION 9.24 |
| Region of Enrollment United States | 3 participants | 30 participants | 33 participants |
| Sex: Female, Male Female | 0 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 25 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 3 / 3 |
| serious Total, serious adverse events | 6 / 30 | 1 / 3 |
Outcome results
Primary
Incidence of Prolonged Hematologic Toxicity Started in Cycle 1
Time frame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
Population: The FCR arm was discontinued due to very limited use of this chemo regimen in this setting, statistical analysis were limited due to the small numbers of subjects in this treatment arm.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Incidence of Prolonged Hematologic Toxicity Started in Cycle 1 | 0 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Incidence of Prolonged Hematologic Toxicity Started in Cycle 1 | 0 Percentage of Participants |
Secondary
Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib
Time frame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib | 53.3 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Incidence of Adverse Events Requiring Dose Delay or Discontinuation of Ibrutinib | 33.3 Percentage of Participants |
Secondary
Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0
Time frame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0 | 66.7 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Overall Incidence of Grade ≥3 Adverse Events (AEs) Per NCI CTCAE V4.0 | 0 Percentage of Participants |
Secondary
Overall Incidence of Serious Adverse Events (SAEs)
Time frame: From First day of dose to 30 days after last dose of any study medication. Participants were followed with a median follow-up time of 15.8 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Overall Incidence of Serious Adverse Events (SAEs) | 20 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Overall Incidence of Serious Adverse Events (SAEs) | 33.3 Percentage of Participants |
Secondary
Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR])
Response criteria are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. response requires 50% reduction in lymph node size. Assessment of response to treatment will be done every 2 cycles for the first 6 months and then every 3 months thereafter until disease progression or prior to the administration of a new anticancer therapy and at follow-up visits.
Time frame: From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR]) | 93.3 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Overall Response Rate (Complete Response [CR] + Complete Response With Incomplete Marrow Recovery [CRi] + Nodular Partial Response [nPR] + Partial Response [PR]) | 100 Percentage of Participants |
Secondary
Progression Free Survival Rate at 12 Months
Criteria for progression are as outlined in the IWCLL 2008 criteria (Hallek 2008) and as assessed by investigator, e.g. progression defined as a 50% increase in lymph node size.
Time frame: From first dose of any study medication to 12 months after first dose to progressive disease or death or the last clinical assessment before receiving new anticancer therapy or loss to follow-up, whichever occured the earliest.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Progression Free Survival Rate at 12 Months | 85.9 Percentage of Participants |
| PCI-32765 Plus Fludarabine/ Cyclophosphamide/ Rituximab (FCR) | Progression Free Survival Rate at 12 Months | 100 Percentage of Participants |
Secondary
Sustained Hematologic Improvement in Subjects With Neutropenia, Anemia, or Thrombocytopenia at Baseline
Time frame: From first response assessment to last response assessment. Participants were followed with a median follow-up time of 15.8 months.
Population: No participants in the FCR group had neutropenia, anemia or thrombocytopenia at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PCI-32765 Plus Bendamustine/Rituximab (BR) | Sustained Hematologic Improvement in Subjects With Neutropenia, Anemia, or Thrombocytopenia at Baseline | 76.2 Percentage of Participants |