Chronic Lymphocytic Leukemia
Conditions
Keywords
Oncology, Chronic Lymphocytic Leukemia, Cancer of the blood and bone marrow
Brief summary
This was an open-label, non-randomized, multicenter, Phase 2 study evaluating the efficacy and safety of ABT-199 in 127 participants with relapsed or refractory chronic lymphocytic leukemia (CLL) after B-cell receptor signaling pathway inhibitors (BCR PI) treatment.
Interventions
DRUGVenetoclax
Each dose of venetoclax was to be taken with approximately 240 mL of water within 30 minutes after the completion of breakfast or the participant's first meal of the day.
Sponsors
Roche-Genentech
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Participant must have a diagnosis of chronic lymphocytic leukemia (CLL) that meets 2008 Modified International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria * Participant has relapsed/refractory disease with an indication for treatment * Participant has refractory disease or developed recurrence after therapy with a B-cell receptor pathway inhibitor (BCR PI) * Participant must have an Eastern Cooperative Oncology Group performance score of ≤ 2 * Participant must have adequate bone marrow function at Screening * Participant must have adequate coagulation profile, renal, and hepatic function, per laboratory reference range at Screening
Exclusion criteria
* Participant has undergone an allogeneic stem cell transplant within the past year * Participant has developed Richter's transformation confirmed by biopsy * Participant has active and uncontrolled autoimmune cytopenia * Participant has malabsorption syndrome or other condition that precludes enteral route of administration * Participant is human immunodeficiency virus (HIV) positive or has chronic hepatitis B or hepatitis C virus requiring treatment * Participant has known contraindication or allergy to both xanthine oxidase inhibitors and rasburicase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | Overall response rate is defined as the percentage of participants with an overall response (per the investigator assessment) 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL) National Cancer Institute-Working Group (NCI-WG) criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | DOR is defined as the number of days from the date of first response (complete response \[CR\], complete response with incomplete marrow recovery \[CRi\], nodular partial remission \[nPR\], or partial remission \[PR\]) to the earliest recurrence or progressive disease. DOR was analyzed by Kaplan-Meier (K-M) methodology. |
| Time to Progression (TTP) | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | TTP is defined as the number of days from the date of first dose to the date of earliest disease progression (PD). TTP was analyzed by Kaplan-Meier (K-M) methodology. |
| Progression-free Survival (PFS) | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | PFS is defined as the number of days from the date of first dose to the date of earliest disease progression (PD) or death. PFS was analyzed by Kaplan-Meier methodology. |
| Overall Survival (OS) | At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort | OS is defined as the number of days from the date of first dose to the date of death for all dosed participants. For participants who did not die, their data was censored at the date of last study visit or the last known date to be alive, whichever was later. OS was estimated using Kaplan-Meier methodology. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Time to Next Anti-Chronic Lymphocytic Leukemia Treatment (TNNT) | Collected every 3 months for a period of 5 years after the last participant had enrolled into the study | TNNT is defined as the number of days from the date of the first dose of venetoclax to the date of first dose of any non-protocol anti-leukemia therapy (NPT) or death from any cause. For participants who did not take NPT, their data was censored at the last known date to be free of NPT. TTNT was analyzed by Kaplan-Meier methodology. |
| Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status | Assessed at Week 24, Day 1; after the first Complete Response, Complete Remission with Incomplete Marrow Recovery, or Partial Response; at 12-week interval visits until two consecutive negative MRD levels were reported | The rate of MRD response is defined as the percentage of participants who had MRD negative status. |
Countries
United States
Participant flow
Pre-assignment details
Safety population: all participants who received at least one dose of venetoclax
Participants by arm
| Arm | Count |
|---|---|
| ABT-199 After Ibrutinib Therapy Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 593 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. | 43 |
| ABT-199 After Idelalisib Therapy Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1023 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. | 21 |
| ABT-199 After Ibrutinib Therapy: Expansion Cohort Participants with ibrutinib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 622 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. | 48 |
| ABT-199 After Idelalisib Therapy: Expansion Cohort Participants with idelalisib-resistant or refractory chronic lymphocytic leukemia (CLL) received venetoclax tablets once daily (QD) until disease progression or study drug discontinuation; median time on treatment was 1189 days. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants enrolled into the Expansion Cohort with bulky disease at study entry who were non-responders or those who showed signs of clinical progression after completing the ramp up to 400 mg either by clinical disease assessment or by CT/MRI scan between Week 6 to Week 12 may have been permitted to escalate venetoclax to a daily dose of 600 mg. | 15 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse event, not related to progression | 8 | 1 | 3 | 1 |
| Overall Study | Adverse event, related to progression | 1 | 0 | 2 | 0 |
| Overall Study | COVID-19 infection | 1 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 4 | 2 |
| Overall Study | Other, not specified | 14 | 11 | 23 | 9 |
| Overall Study | Progressive disease per protocol | 12 | 7 | 9 | 2 |
| Overall Study | Progressive disease, Richter's | 4 | 1 | 1 | 1 |
| Overall Study | Stem cell transplant | 1 | 0 | 1 | 0 |
| Overall Study | Study terminated by Sponsor | 0 | 1 | 0 | 0 |
| Overall Study | Subject non-compliance | 0 | 0 | 1 | 0 |
| Overall Study | Withdrew consent | 2 | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | ABT-199 After Ibrutinib Therapy | ABT-199 After Idelalisib Therapy | ABT-199 After Ibrutinib Therapy: Expansion Cohort | ABT-199 After Idelalisib Therapy: Expansion Cohort | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65.7 years STANDARD_DEVIATION 8.74 | 68.0 years STANDARD_DEVIATION 7.26 | 64.2 years STANDARD_DEVIATION 10.72 | 68.7 years STANDARD_DEVIATION 8.35 | 65.9 years STANDARD_DEVIATION 9.34 |
| Race/Ethnicity, Customized American Indian/Alaska native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 8 Participants |
| Race/Ethnicity, Customized Multi race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 40 Participants | 19 Participants | 45 Participants | 13 Participants | 117 Participants |
| Sex: Female, Male Female | 10 Participants | 6 Participants | 17 Participants | 5 Participants | 38 Participants |
| Sex: Female, Male Male | 33 Participants | 15 Participants | 31 Participants | 10 Participants | 89 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 25 / 43 | 9 / 21 | 34 / 64 | 17 / 48 | 4 / 15 | 21 / 63 | 42 / 91 | 13 / 36 | 55 / 127 |
| other Total, other adverse events | 43 / 43 | 21 / 21 | 64 / 64 | 48 / 48 | 15 / 15 | 63 / 63 | 91 / 91 | 36 / 36 | 127 / 127 |
| serious Total, serious adverse events | 35 / 43 | 14 / 21 | 49 / 64 | 26 / 48 | 9 / 15 | 35 / 63 | 61 / 91 | 23 / 36 | 84 / 127 |
Outcome results
Primary
Overall Response Rate (ORR)
Overall response rate is defined as the percentage of participants with an overall response (per the investigator assessment) 2008 Modified International Workshop for Chronic Lymphocytic Leukemia (IWCLL) National Cancer Institute-Working Group (NCI-WG) criteria.
Time frame: At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort
Population: All participants in the Main and Expansion Cohorts who received at least one dose of venetoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Overall Response Rate (ORR) | 64.8 percentage of participants |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Overall Response Rate (ORR) | 69.4 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the number of days from the date of first response (complete response \[CR\], complete response with incomplete marrow recovery \[CRi\], nodular partial remission \[nPR\], or partial remission \[PR\]) to the earliest recurrence or progressive disease. DOR was analyzed by Kaplan-Meier (K-M) methodology.
Time frame: At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort
Population: All enrolled participants who received venetoclax, had active disease at baseline, and achieved a response of PR or better
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Duration of Response (DOR) | 35.1 months |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Duration of Response (DOR) | 55.4 months |
Secondary
Overall Survival (OS)
OS is defined as the number of days from the date of first dose to the date of death for all dosed participants. For participants who did not die, their data was censored at the date of last study visit or the last known date to be alive, whichever was later. OS was estimated using Kaplan-Meier methodology.
Time frame: At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort
Population: All participants in the Main and Expansion Cohorts who received at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Overall Survival (OS) | 69.6 months |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the number of days from the date of first dose to the date of earliest disease progression (PD) or death. PFS was analyzed by Kaplan-Meier methodology.
Time frame: At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort
Population: All enrolled participants who received venetoclax and had active disease at baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Progression-free Survival (PFS) | 24.7 months |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Progression-free Survival (PFS) | 43.4 months |
Secondary
Time to Progression (TTP)
TTP is defined as the number of days from the date of first dose to the date of earliest disease progression (PD). TTP was analyzed by Kaplan-Meier (K-M) methodology.
Time frame: At Wk 5, Day 1; Wk 8, Day 1; Wk 12, Day 1; Wk 16, Day 1; Wk 20, Day 1; Wk 24, Day 1; Wk 36, Day 1; every 12 wks after Wk 36; Final Visit; estimated median time on follow-up was 1694 d for ibrutinib failure cohort and 1942 d for idelalisib failure cohort
Population: All participants in the Main and Expansion Cohorts who received at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Time to Progression (TTP) | 36.1 months |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Time to Progression (TTP) | 43.4 months |
Other Pre-specified
Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status
The rate of MRD response is defined as the percentage of participants who had MRD negative status.
Time frame: Assessed at Week 24, Day 1; after the first Complete Response, Complete Remission with Incomplete Marrow Recovery, or Partial Response; at 12-week interval visits until two consecutive negative MRD levels were reported
Population: All participants in the Main and Expansion Cohorts who received at least one dose of venetoclax; indeterminate or missing samples were considered MRD positive for the calculation
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status | Peripheral blood | 30.8 percentage of participants |
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status | Bone marrow | 6.6 percentage of participants |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status | Peripheral blood | 25.0 percentage of participants |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Percentage of Participants With Minimal Residual Disease (MRD) Negativity Status | Bone marrow | 11.1 percentage of participants |
Other Pre-specified
Time to Next Anti-Chronic Lymphocytic Leukemia Treatment (TNNT)
TNNT is defined as the number of days from the date of the first dose of venetoclax to the date of first dose of any non-protocol anti-leukemia therapy (NPT) or death from any cause. For participants who did not take NPT, their data was censored at the last known date to be free of NPT. TTNT was analyzed by Kaplan-Meier methodology.
Time frame: Collected every 3 months for a period of 5 years after the last participant had enrolled into the study
Population: All participants in the Main and Expansion Cohorts who received at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 After Ibrutinib Therapy: Main and Expansion Cohorts | Time to Next Anti-Chronic Lymphocytic Leukemia Treatment (TNNT) | 24.0 months |
| ABT-199 After Idelalisib Therapy: Main and Expansion Cohorts | Time to Next Anti-Chronic Lymphocytic Leukemia Treatment (TNNT) | 37.8 months |