Acute Myelogenous Leukemia, Acute Myeloid Leukemia, AML
Conditions
Keywords
GDC-0199, Acute Myelogenous Leukemia, AML, ABT-199, Acute Myeloid Leukemia, Myeloid Leukemia
Brief summary
This was a Phase 2, open-label, multicenter study evaluating the preliminary efficacy and safety of venetoclax (ABT-199) administered orally in participants with acute myelogenous leukemia (AML).
Detailed description
The primary objective was to evaluate the preliminary efficacy of venetoclax administered orally in participants with relapsed and/or refractory (R/R) acute myelogenous leukemia (AML) or frontline therapy in patients with AML who were unfit for intensive therapy. The secondary objective was to evaluate the preliminary safety of venetoclax administered orally in patients with AML. The first portion of the study was to consist of 19 participants with the objective of evaluating anti-tumor effects and confirming the safety of the regimen. The second portion (expansion) was to consist of 35 additional subjects to evaluate anti-tumor effects and safety and was to commence if an adequate efficacy signal (i.e., ≥ 5/19 achieved complete remission \[CR\], CR with incomplete bone marrow recovery \[CRi\] or partial remission \[PR\]) had been observed in the first portion of the study. The criterion for success would have been met if ≥ 16 of 54 participants achieved remission. The efficacy signal from first portion of the study was deemed insufficient for enrollment into the second portion of the study, as 4 of the 19 subjects achieved CR/CRi. During the trial, a number of participants were in screening at the point of the interim analysis. Given the early signs of clinical activity of venetoclax, disease severity, and prognosis of these participants without available options for therapy, they were allowed to initiate treatment ahead of completion of the interim analysis. Therefore, 32 participants were enrolled. No additional participants were screened or treated after the interim analysis was completed.
Interventions
DRUGABT-199
Tablet
Sponsors
Genentech, Inc.
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
1. Histological or cytological confirmation of relapsed or refractory acute myelogenous leukemia (AML) (by World Health Organization \[WHO\] classification) or untreated AML in participants who are unfit for intensive therapy. 2. Participant has an Eastern Cooperative Oncology Group (ECOG) Performance score of 0 to 2. 3. Participant must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 50 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula using ideal body mass (IBM) instead of mass. 4. Participant must have adequate liver function as demonstrated by: * aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN)\* * alanine aminotransferase (ALT) ≤ 3.0 × ULN\* * bilirubin ≤ 1.5 × ULN\* \*unless considered due to leukemic organ involvement. (Participants with Gilbert's Syndrome may have had a bilirubin \> 1.5 × ULN per discussion between the investigator and AbbVie medical monitor)
Exclusion criteria
1. Participant has received acute anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal or any investigational therapy within 14 days or 5 half-lives (whichever is shorter) prior to first dose of ABT-199. 2. Participant has received a monoclonal antibody for anti-neoplastic intent within 8 weeks prior to the first dose of study drug. 3. Participant has received potent Cytochrome P450, family 3, subfamily A (CYP3A) inducers (such as rifampin, carbamazepine, phenytoin and St. John's wort) and warfarin or requires the use of warfarin (due to potential drug-drug interactions that may potentially increase the exposure of warfarin and complications of this effect) within 7 days prior to the first dose of study drug. 4. Participant has received CYP3A inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 5 days prior to the first dose of study drug. 5. Participant has a white blood cell count \> 25 x 10\^9/L. 6. Participant has acute promyelocytic leukemia (French-American-British Class M3 AML). 7. Participants with known active central nervous system (CNS) disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Remission Rate | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The objective remission rate (ORR) was defined as the percentage of participants who achieved complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), or partial remission (PR) per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. Partial remission (PR) was defined as normalization in peripheral blood neutrophil and platelet counts with at least a 50% decrease in blasts persisting in bone marrow versus baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Remission | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | Duration of remission was defined as the number of days from the date of first remission (CR, CRi, or PR) per the International Working Group criteria for AML to the earliest recurrence or progressive disease (PD). In this study, the duration of remission analysis was not performed because of the low remission rate, per the Statistical Analysis Plan. |
| Time to Progression | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | Time to progression was defined as the number of months from the date of enrollment to the date of earliest disease progression. If a participant did not experience disease progression, then the data for that participant was censored at the date of the last disease assessment. |
| Progression-free Survival | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | Progression-free survival was defined as the number of months from the date of enrollment to the date of earliest progression or death. If a participant did not experience disease progression or death, then the data was censored at the date of the last disease assessment. |
| Overall Survival | Measured up to 2 years after the last subject had enrolled in the study. | Overall survival was defined as the number of months from the date of enrollment to the date of death for all dosed participants. For participants who did not die, their data were censored at the date of last study visit or the last known date to be alive, whichever was later. |
| Complete Remission Rate | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The complete remission (CR) rate was defined as the percentage of participants who achieved CR per the International Working Group criteria for AML. Complete remission was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. |
| Rate of Minimal Residual Disease (MRD) Negativity | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The rate of minimal residual disease (MRD) response was defined as the percentage of participants who had MRD negative status. Only participants with a reported MRD assessment (negative or positive) from the local laboratory at the investigator site were used in the calculation of MRD response rate. |
| Complete Remission With Incomplete Marrow Recovery (CRi) Rate | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The complete remission with incomplete bone marrow recovery (CRi) rate was defined as the percentage of participants who achieved CRi per the International Working Group criteria for AML. Complete remission with incomplete bone marrow recovery was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. |
| Complete Remission Rate and Complete Remission With Incomplete Marrow Recovery (CRi) Rate | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The complete remission rate and the complete remission with incomplete marrow recovery rate (Cri) was defined as the percentage of participants who achieved complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi), per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. |
| Percentage of Participants Who Received Subsequent Stem Cell Transplant | When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier | The percentage of participants who received a subsequent allogenic (from a healthy donor) stem cell transplant was summarized. |
Participant flow
Pre-assignment details
All participants who received at least 1 dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| ABT-199 Continuous dosing of venetoclax (ABT-199) QD (once daily) beginning with dose-escalation on Week 1 Day 1. Participants received a dose of 20 mg of ABT-199 on Week 1 Day 1, 50 mg on Day 2, 100 mg on Day 3, 200 mg on Day 4, 400 mg on Day 5, 800 mg on Day 6 and QD thereafter. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse event not related to progression | 1 |
| Overall Study | Adv event related to progressive disease | 3 |
| Overall Study | Chose palliative care | 1 |
| Overall Study | Fatal progressive disease | 2 |
| Overall Study | Proceeded to transplant | 1 |
| Overall Study | Progressive disease per protocol | 23 |
| Overall Study | Removed from study due to no response | 1 |
Baseline characteristics
| Characteristic | ABT-199 |
|---|---|
| Age, Continuous | 65.9 years STANDARD_DEVIATION 14.8 |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 32 |
| serious Total, serious adverse events | 27 / 32 |
Outcome results
Primary
Objective Remission Rate
The objective remission rate (ORR) was defined as the percentage of participants who achieved complete remission (CR), complete remission with incomplete bone marrow recovery (CRi), or partial remission (PR) per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL. Partial remission (PR) was defined as normalization in peripheral blood neutrophil and platelet counts with at least a 50% decrease in blasts persisting in bone marrow versus baseline.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Objective Remission Rate | 18.8 percentage of participants |
Secondary
Complete Remission Rate
The complete remission (CR) rate was defined as the percentage of participants who achieved CR per the International Working Group criteria for AML. Complete remission was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Complete Remission Rate | 6.3 percentage of participants |
Secondary
Complete Remission Rate and Complete Remission With Incomplete Marrow Recovery (CRi) Rate
The complete remission rate and the complete remission with incomplete marrow recovery rate (Cri) was defined as the percentage of participants who achieved complete remission (CR) or complete remission with incomplete bone marrow recovery (CRi), per the International Working Group criteria for AML. Complete remission (CR) was defined as peripheral neutrophils at least 10˄3/μL, platelets ≥ 10˄5/μL and normocellular bone marrow with ≤ 5% blasts. Complete remission with incomplete bone marrow recovery (CRi) was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Complete Remission Rate and Complete Remission With Incomplete Marrow Recovery (CRi) Rate | 18.8 percentage of participants |
Secondary
Complete Remission With Incomplete Marrow Recovery (CRi) Rate
The complete remission with incomplete bone marrow recovery (CRi) rate was defined as the percentage of participants who achieved CRi per the International Working Group criteria for AML. Complete remission with incomplete bone marrow recovery was defined as bone marrow with less than 5% blasts, with peripheral neutrophils of at least 10˄3/μL or platelets ≥ 10˄5/μL.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Complete Remission With Incomplete Marrow Recovery (CRi) Rate | 12.5 percentage of participants |
Secondary
Duration of Remission
Duration of remission was defined as the number of days from the date of first remission (CR, CRi, or PR) per the International Working Group criteria for AML to the earliest recurrence or progressive disease (PD). In this study, the duration of remission analysis was not performed because of the low remission rate, per the Statistical Analysis Plan.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: The duration of remission analysis was not performed because of the low remission rate, per the Statistical Analysis Plan.
Secondary
Overall Survival
Overall survival was defined as the number of months from the date of enrollment to the date of death for all dosed participants. For participants who did not die, their data were censored at the date of last study visit or the last known date to be alive, whichever was later.
Time frame: Measured up to 2 years after the last subject had enrolled in the study.
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 | Overall Survival | 4.7 months |
Secondary
Percentage of Participants Who Received Subsequent Stem Cell Transplant
The percentage of participants who received a subsequent allogenic (from a healthy donor) stem cell transplant was summarized.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Percentage of Participants Who Received Subsequent Stem Cell Transplant | 3.1 percentage of participants |
Secondary
Progression-free Survival
Progression-free survival was defined as the number of months from the date of enrollment to the date of earliest progression or death. If a participant did not experience disease progression or death, then the data was censored at the date of the last disease assessment.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 | Progression-free Survival | 2.3 months |
Secondary
Rate of Minimal Residual Disease (MRD) Negativity
The rate of minimal residual disease (MRD) response was defined as the percentage of participants who had MRD negative status. Only participants with a reported MRD assessment (negative or positive) from the local laboratory at the investigator site were used in the calculation of MRD response rate.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: Participants with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ABT-199 | Rate of Minimal Residual Disease (MRD) Negativity | 43.5 percentage of participants |
Secondary
Time to Progression
Time to progression was defined as the number of months from the date of enrollment to the date of earliest disease progression. If a participant did not experience disease progression, then the data for that participant was censored at the date of the last disease assessment.
Time frame: When 19 participants had completed at least 12 weeks of treatment or after all enrolled participants had discontinued venetoclax, whichever was earlier
Population: All participants who received at least 1 dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ABT-199 | Time to Progression | 2.5 months |