Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma
Conditions
Keywords
CLL, SLL
Brief summary
An Open-label Extension Study in Patients 65 Years or Older with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Who Participated in Study PCYC-1115-CA (Ibrutinib versus Chlorambucil)
Interventions
DRUGIbrutinib
Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily
DRUGNext-line ibrutinib
Ibrutinib 420 mg (3 x 140-mg capsules) is administered orally once daily
Sponsors
Janssen Research & Development, LLC
Pharmacyclics LLC.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label study
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Randomized in the parent study, PCYC-1115-CA 2. Informed consent for Study PCYC-1116-CA 3. Independent review committee (IRC)-confirmed disease progression (PD) in the parent study PCYC-1115-CA or closure of the parent study
Exclusion criteria
1. Disease progression involving the central nervous system (CNS) or transformation to another histology 2. Intervening chemotherapy, immunotherapy, or investigational agent specifically to treat CLL if administered before date of IRC confirmed progressive disease 3. In the 4 weeks before dosing: radiation therapy, major surgery, or receipt of an investigational drug 4. Requirement for treatment with a strong CYP3A inhibitor 5. Uncontrolled systemic infection or requirement for IV antibiotics 6. Noncompliance on the parent study(PCYC-1115-CA)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Investigator Assessment | Median overall follow-up of 82.7 months | PFS is defined as the time from the date of randomization to the date of disease progression determined by the investigator or date of death from any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to disease progression (PD) or death. Estimated by Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Median overall follow-up of 82.7 months | OS is defined as the time from randomization to death due to any cause. Kaplan-Meier landmark estimate of the OS rate at 60 months (that is, the estimated percentage of participants with OS at Month 60) is presented. |
| Time to Next Treatment (TTNT) | Median overall follow-up of 82.7 months | Time from randomization to initiation of any subsequent treatment for chronic lymphocytic leukemia (CLL). |
| Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2) | Median overall follow-up of 82.7 months | PFS2 is defined as the time from the date of randomization to the earliest occurrence of the following three types of events: * PD per investigator response assessment after initiation of the first subsequent anti-cancer therapy * Initiation of second subsequent anti-cancer therapy * Death due to any cause, regardless of administration of subsequent anticancer therapy. Kaplan-Meier landmark estimate of the PFS2 rate at 60 months (that is, the estimated percentage of participants with PFS2 at Month 60) is presented. |
| Rate of Minimal Residual Disease (MRD) Negativity | Median overall follow-up of 82.7 months | Percentage of participants who achieved MRD-negative response defined as \< 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate and/or peripheral blood sample per central laboratory at or prior to initiation of subsequent antineoplastic therapy. |
| Duration of Response (DOR) | Median overall follow-up of 82.7 months | DOR will be calculated for the participants achieving a protocol-defined response (Halleck 2008; CR, CRi, nPR, PR) per investigator assessment and is defined as time from the date of initial response including PR with lymphocytosis to the date of disease progression or the date of death from any cause, whichever occurs first. |
| Overall Response Rate (ORR) | Median overall follow-up of 82.7 months | ORR is defined as the percentage of participants who achieve complete response (CR), complete response with an incomplete marrow recovery (CRi), nodular partial response (nPR), or partial response (PR), as determined by the investigator at or prior to initiation of subsequent antineoplastic therapy according to the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy. |
Countries
Australia, Belgium, Canada, China, Czechia, Ireland, Israel, Italy, New Zealand, Poland, Russia, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
This extension study provided ongoing treatment and follow-up for participants previously enrolled in the parent study (PCYC-1115-CA; Study 1115; NCT01722487). Participants entered this study upon Independent Review Committee (IRC)-confirmed progressive disease (PD) or the closure of Study 1115, whichever was earlier.
Pre-assignment details
All participants randomized to chlorambucil in Study 1115 completed or discontinued their first-line treatment prior to rollover. Participants randomized to ibrutinib in Study 1115 with no PD could continue their first-line treatment in this study. Next-line treatment with ibrutinib after PD was a subsequent-therapy option for participants enrolled in the chlorambucil arm only.
Participants by arm
| Arm | Count |
|---|---|
| Ibrutinib Participants who received ibrutinib 420 mg daily in Study 1115 received ibrutinib orally once daily. Participants continuing in first-line ibrutinib therapy entered Study 1116 at the ibrutinib dose tolerated in Study 1115. | 136 |
| Chlorambucil Participants who received chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) Days 1 and 15 of 28-day cycle up to 12 cycles in Study 1115. In Study 1116, participants had the option to crossover to next-line ibrutinib 420 mg/day after PD. | 133 |
| Total | 269 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 42 | 42 |
| Overall Study | Did Not Rollover From Parent Study | 5 | 8 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Withdrawal by Subject | 27 | 19 |
Baseline characteristics
| Characteristic | Ibrutinib | Chlorambucil | Total |
|---|---|---|---|
| Age, Continuous | 73.1 years STANDARD_DEVIATION 5.67 | 73.4 years STANDARD_DEVIATION 5.95 | 73.3 years STANDARD_DEVIATION 5.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 132 Participants | 129 Participants | 261 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Asian | 9 Participants | 4 Participants | 13 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 3 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Subject declined to answer/unknown | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 120 Participants | 125 Participants | 245 Participants |
| Sex: Female, Male Female | 48 Participants | 52 Participants | 100 Participants |
| Sex: Female, Male Male | 88 Participants | 81 Participants | 169 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 42 / 135 | 44 / 132 | 24 / 78 |
| other Total, other adverse events | 134 / 135 | 120 / 132 | 75 / 78 |
| serious Total, serious adverse events | 111 / 135 | 33 / 132 | 49 / 78 |
Outcome results
Primary
Progression Free Survival (PFS) Based on Investigator Assessment
PFS is defined as the time from the date of randomization to the date of disease progression determined by the investigator or date of death from any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to disease progression (PD) or death. Estimated by Kaplan-Meier method.
Time frame: Median overall follow-up of 82.7 months
Population: Intent-to-Treat (ITT) Population: All randomized participants in Study 1115.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Progression Free Survival (PFS) Based on Investigator Assessment | 106.9 months |
| Chlorambucil | Progression Free Survival (PFS) Based on Investigator Assessment | 15.0 months |
p-value: <0.000195% CI: [0.11, 0.22]Log Rank
Secondary
Duration of Response (DOR)
DOR will be calculated for the participants achieving a protocol-defined response (Halleck 2008; CR, CRi, nPR, PR) per investigator assessment and is defined as time from the date of initial response including PR with lymphocytosis to the date of disease progression or the date of death from any cause, whichever occurs first.
Time frame: Median overall follow-up of 82.7 months
Population: ITT Participants Achieving Response (Partial Response or Better) per protocol definitions (Halleck 2008).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Duration of Response (DOR) | NA months |
| Chlorambucil | Duration of Response (DOR) | 29.7 months |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of participants who achieve complete response (CR), complete response with an incomplete marrow recovery (CRi), nodular partial response (nPR), or partial response (PR), as determined by the investigator at or prior to initiation of subsequent antineoplastic therapy according to the International Workshop on CLL (iwCLL) 2008 criteria with the 2012 iwCLL modification stating that treatment-related lymphocytosis in the setting of improvement in other parameters was not considered as PD and the 2013 iwCLL clarification of criteria for a partial response to therapy.
Time frame: Median overall follow-up of 82.7 months
Population: ITT Population: All randomized participants in Study 1115.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Overall Response Rate (ORR) | 91.2 percentage of participants |
| Chlorambucil | Overall Response Rate (ORR) | 36.8 percentage of participants |
p-value: <0.000195% CI: [1.99, 3.131]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
OS is defined as the time from randomization to death due to any cause. Kaplan-Meier landmark estimate of the OS rate at 60 months (that is, the estimated percentage of participants with OS at Month 60) is presented.
Time frame: Median overall follow-up of 82.7 months
Population: ITT Population: All randomized participants in Study 1115.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Overall Survival (OS) | 82.8 percentage of participants |
| Chlorambucil | Overall Survival (OS) | 68.4 percentage of participants |
Secondary
Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2)
PFS2 is defined as the time from the date of randomization to the earliest occurrence of the following three types of events: * PD per investigator response assessment after initiation of the first subsequent anti-cancer therapy * Initiation of second subsequent anti-cancer therapy * Death due to any cause, regardless of administration of subsequent anticancer therapy. Kaplan-Meier landmark estimate of the PFS2 rate at 60 months (that is, the estimated percentage of participants with PFS2 at Month 60) is presented.
Time frame: Median overall follow-up of 82.7 months
Population: ITT Population: All randomized participants in Study 1115.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2) | 79.3 percentage of participants |
| Chlorambucil | Progression Free Survival After Initiation of Subsequent Anticancer Therapy (PFS2) | 58.4 percentage of participants |
Secondary
Rate of Minimal Residual Disease (MRD) Negativity
Percentage of participants who achieved MRD-negative response defined as \< 1 CLL cell per 10,000 leukocytes as assessed by flow cytometry of a bone marrow aspirate and/or peripheral blood sample per central laboratory at or prior to initiation of subsequent antineoplastic therapy.
Time frame: Median overall follow-up of 82.7 months
Population: ITT Population: All randomized participants in Study 1115.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibrutinib | Rate of Minimal Residual Disease (MRD) Negativity | 5.1 percentage of participants |
| Chlorambucil | Rate of Minimal Residual Disease (MRD) Negativity | 0 percentage of participants |
Secondary
Time to Next Treatment (TTNT)
Time from randomization to initiation of any subsequent treatment for chronic lymphocytic leukemia (CLL).
Time frame: Median overall follow-up of 82.7 months
Population: ITT Population: All randomized participants in Study 1115.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ibrutinib | Time to Next Treatment (TTNT) | NA months |
| Chlorambucil | Time to Next Treatment (TTNT) | 25.1 months |
p-value: <0.000195% CI: [0.054, 0.141]Log Rank