Chronic Lymphocytic Leukemia
Conditions
Keywords
Chronic Lymphocytic Leukemia (CLL), Navitoclax, ABT-263, Cancer
Brief summary
The Phase 1 portion of the study will evaluate the pharmacokinetic profile and safety of ABT-263 under two different dosing schedules with the objective of defining the dose limiting toxicity and maximum tolerated dose. The Phase 2a portion of the study will evaluate ABT-263 at the defined recommended Phase 2 dose to obtain additional safety information and a preliminary assessment of efficacy. The Extension Study portion will allow active subjects to continue to receive ABT-263 for up to 11 years after the last subject transitions with less frequent study evaluations.
Interventions
DRUGABT-263
Tablet; Oral
Sponsors
Genentech, Inc.
AbbVie
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Relapsed or refractory CLL and require treatment in opinion of investigator. * Eastern Cooperative Oncology Group (ECOG) \<= 1. * Adequate bone marrow independent of growth factor support, renal and hepatic function per defined laboratory criteria.
Exclusion criteria
* History or is clinically suspicious for cancer-related Central Nervous System disease. * Receipt of allogenic or autologous stem cell transplant. * Recent history (within 1 year of first dose) of underlying, predisposing condition of bleeding or currently exhibits signs of bleeding. * Active peptic ulcer disease or other potentially hemorrhagic esophagitis/gastritis. * Active immune thrombocytopenic purpura or history of being refractory to platelet transfusions (within 1 year of first dose).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | From first dose of study drug to 30 days post-last dose. Participants enrolled in the 14/21-day cycle received a mean of 21.7 treatment cycles; participants enrolled in the 21/21-day cycle received a mean of 19.4 treatment cycles. | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths. |
| Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | Cycle 1 (Up to 21 days) plus 7 days | DLTs were graded according to NCI CTCAE version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week. |
| Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase | Cycle 1 (Up to 21 days) plus 7 days | The MTD was defined as the dose at which 30% of participants experienced a DLT during the first cycle. DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week. |
| Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase | Cycle 1 (Up to 21 days) plus 7 days | The RPTD was determined based on observed DLTs and/or determination of the MTD in phase 1. (See Outcome Measures 2 and 3 above for definition of DLT and MTD.) |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8 | The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14. |
| Phase 1: Cmax/Dose | Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: AUC8/Dose | Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: AUC24/Dose | Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8 | The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14. |
| Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose | — |
| Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose | For t1/2, the harmonic mean and psuedo-standard deviation are used. |
| Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | From first dose of study drug to 30 days post-last dose. Participants enrolled in Phase 2 received a mean of 15.6 treatment cycles. | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths. |
| Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 1 Day 1: 4-8 h postdose; Cycle 1 Day 15: predose; Cycle 3 Day 1: predose, 4-8 h postdose; Cycle 5 Day 1: predose, 4-8 h postdose; Cycle 7 Day 1: predose, 4-8 h postdose; Cycle 9 Day 1: predose, 4-8 h postdose | — |
Countries
Australia, Germany, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg Navitoclax 10 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | 3 |
| Navitoclax 14/21 Day Cycle: 110 mg Navitoclax 110 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | 6 |
| Navitoclax 14/21 Day Cycle: 200 mg Navitoclax 200 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | 3 |
| Navitoclax 14/21 Day Cycle: 250 mg Navitoclax 250 mg administered for 14 consecutive days followed by 7 days off drug to complete a 21-day cycle. | 3 |
| Navitoclax 21/21 Day Cycle: 125 mg Navitoclax 125 mg administered for 21 consecutive days to complete a 21-day cycle. | 3 |
| Navitoclax 21/21 Day Cycle: 200 mg Navitoclax 200 mg administered for 21 consecutive days to complete a 21-day cycle. | 4 |
| Navitoclax 21/21 Day Cycle: 250 mg Navitoclax 250 mg administered for 21 consecutive days to complete a 21-day cycle. | 3 |
| Navitoclax 21/21 Day Cycle: 300 mg Navitoclax 300 mg administered for 21 consecutive days to complete a 21-day cycle. | 4 |
| Phase 2: Navitoclax 100 mg Navitoclax 100 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). | 4 |
| Phase 2: Navitoclax 250 mg Navitoclax 250 mg in participants with CLL who had relapsed following any (but no more than 5) prior myelosuppressive/chemotherapy treatment regimen(s). | 27 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 0 | 1 | 1 | 1 | 2 | 1 | 1 | 6 |
| Overall Study | No reason given | 0 | 0 | 1 | 1 | 1 | 0 | 1 | 1 | 1 | 4 |
| Overall Study | Other, Not Specified | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 4 |
| Overall Study | Progressive disease clinical | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 7 |
| Overall Study | Progressive disease clinical National Cancer Institute | 1 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive disease other | 1 | 1 | 0 | 1 | 1 | 1 | 0 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 6 |
Baseline characteristics
| Characteristic | Navitoclax 14/21 Day Cycle: 10 mg | Total | Navitoclax 14/21 Day Cycle: 110 mg | Navitoclax 14/21 Day Cycle: 200 mg | Navitoclax 14/21 Day Cycle: 250 mg | Navitoclax 21/21 Day Cycle: 125 mg | Navitoclax 21/21 Day Cycle: 200 mg | Navitoclax 21/21 Day Cycle: 250 mg | Navitoclax 21/21 Day Cycle: 300 mg | Phase 2: Navitoclax 100 mg | Phase 2: Navitoclax 250 mg |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Customized < 65 years | 1 Participants | 19 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants | 10 Participants |
| Age, Customized >= 65 years | 2 Participants | 41 Participants | 6 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 17 Participants |
| Race/Ethnicity, Customized American Indian/Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Mixed | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized No Ethnicity | 3 Participants | 60 Participants | 6 Participants | 3 Participants | 3 Participants | 3 Participants | 4 Participants | 3 Participants | 4 Participants | 4 Participants | 27 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 0 Participants | 5 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 3 Participants | 52 Participants | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 3 Participants | 4 Participants | 24 Participants |
| Sex: Female, Male Female | 2 Participants | 18 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 42 Participants | 5 Participants | 3 Participants | 2 Participants | 1 Participants | 3 Participants | 3 Participants | 1 Participants | 4 Participants | 19 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 | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 6 | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 4 | 0 / 3 | 0 / 4 | 1 / 4 | 8 / 27 |
| other Total, other adverse events | 3 / 3 | 6 / 6 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 4 / 4 | 27 / 27 |
| serious Total, serious adverse events | 2 / 3 | 4 / 6 | 2 / 3 | 2 / 3 | 2 / 3 | 4 / 4 | 2 / 3 | 3 / 4 | 1 / 4 | 12 / 27 |
Outcome results
Primary
Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24)
The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 2.7 μg•hr/mL | Standard Deviation 1 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 5.5 μg•hr/mL | Standard Deviation 2.7 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 15.0 μg•hr/mL | Standard Deviation 3.2 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 30.9 μg•hr/mL | Standard Deviation 7.7 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 34.0 μg•hr/mL | Standard Deviation 13.8 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 68.7 μg•hr/mL | Standard Deviation 42.9 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 67.8 μg•hr/mL | Standard Deviation 27.7 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 50.6 μg•hr/mL | Standard Deviation 0.36 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 37.5 μg•hr/mL | Standard Deviation 16 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 43.5 μg•hr/mL | Standard Deviation 16.6 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 44.0 μg•hr/mL | Standard Deviation 18.7 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 56.2 μg•hr/mL | Standard Deviation 28.6 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 72.7 μg•hr/mL | Standard Deviation 14.4 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 49.5 μg•hr/mL | Standard Deviation 12.3 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 1 | 52.9 μg•hr/mL | Standard Deviation 20.1 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 24 (AUC24) | Cycle 1 Day 14 | 64.8 μg•hr/mL | Standard Deviation 49.4 |
Primary
Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8)
Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 1.0 μg•hr/mL | Standard Deviation 0.65 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 2.2 μg•hr/mL | Standard Deviation 0.95 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 11.1 μg•hr/mL | Standard Deviation 2.7 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 5.7 μg•hr/mL | Standard Deviation 2.7 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 24.2 μg•hr/mL | Standard Deviation 18.1 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 10.6 μg•hr/mL | Standard Deviation 4 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 17.8 μg•hr/mL | Standard Deviation 2.3 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 19.8 μg•hr/mL | Standard Deviation 14 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 15.7 μg•hr/mL | Standard Deviation 6.8 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 12.0 μg•hr/mL | Standard Deviation 4.2 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 12.3 μg•hr/mL | Standard Deviation 3 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 18.4 μg•hr/mL | Standard Deviation 8.7 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 12.0 μg•hr/mL | Standard Deviation 9.2 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 24.4 μg•hr/mL | Standard Deviation 5.7 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 14 | 21.6 μg•hr/mL | Standard Deviation 15.6 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Area Under the Plasma Concentration-Time Curve From Time 0 to Hour 8 (AUC8) | Cycle 1 Day 1 | 14.3 μg•hr/mL | Standard Deviation 5.7 |
Primary
Phase 1: AUC24/Dose
The AUC24 was derived and reported from Cycle 1 Day 1 values and Cycle 1 Day 14 values; the pre-dose value taken on Day 14 was utilized as 24-hour timepoint on Day 14 to generate AUC24 for Day 14.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Cycle 1 Days 14: pre-dose, 2, 4, 6, 8
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 268 ng•hr/mL/mg | Standard Deviation 100 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 546 ng•hr/mL/mg | Standard Deviation 267 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 136 ng•hr/mL/mg | Standard Deviation 28.8 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 281 ng•hr/mL/mg | Standard Deviation 69.9 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 170 ng•hr/mL/mg | Standard Deviation 69.2 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 344 ng•hr/mL/mg | Standard Deviation 215 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 271 ng•hr/mL/mg | Standard Deviation 111 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 202 ng•hr/mL/mg | Standard Deviation 1.5 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 300 ng•hr/mL/mg | Standard Deviation 128 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 348 ng•hr/mL/mg | Standard Deviation 133 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 220 ng•hr/mL/mg | Standard Deviation 93.6 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 281 ng•hr/mL/mg | Standard Deviation 143 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 291 ng•hr/mL/mg | Standard Deviation 57.5 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 198 ng•hr/mL/mg | Standard Deviation 49.3 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: AUC24/Dose | Cycle 1 Day 1 | 176 ng•hr/mL/mg | Standard Deviation 67 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: AUC24/Dose | Cycle 1 Day 14 | 216.0 ng•hr/mL/mg | Standard Deviation 165 |
Primary
Phase 1: AUC8/Dose
Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 215.0 ng•hr/mL/mg | Standard Deviation 95.1 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 99.9 ng•hr/mL/mg | Standard Deviation 65 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 52.0 ng•hr/mL/mg | Standard Deviation 24.7 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 101.0 ng•hr/mL/mg | Standard Deviation 24.7 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 53.1 ng•hr/mL/mg | Standard Deviation 20.1 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 121.0 ng•hr/mL/mg | Standard Deviation 90.4 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 71.3 ng•hr/mL/mg | Standard Deviation 9.1 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 79.2 ng•hr/mL/mg | Standard Deviation 56.1 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 125.0 ng•hr/mL/mg | Standard Deviation 54.1 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 95.8 ng•hr/mL/mg | Standard Deviation 33.5 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 61.3 ng•hr/mL/mg | Standard Deviation 14.9 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 92.1 ng•hr/mL/mg | Standard Deviation 43.3 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 47.9 ng•hr/mL/mg | Standard Deviation 36.8 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 97.7 ng•hr/mL/mg | Standard Deviation 22.6 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: AUC8/Dose | Cycle 1 Day 14 | 72.0 ng•hr/mL/mg | Standard Deviation 51.9 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: AUC8/Dose | Cycle 1 Day 1 | 47.6 ng•hr/mL/mg | Standard Deviation 18.8 |
Primary
Phase 1: Cmax/Dose
Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 24.5 ng/mL/mg | Standard Deviation 13.9 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 42.3 ng/mL/mg | Standard Deviation 16.6 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 10.7 ng/mL/mg | Standard Deviation 3.4 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 17.0 ng/mL/mg | Standard Deviation 6.4 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 13.0 ng/mL/mg | Standard Deviation 7.7 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 22.2 ng/mL/mg | Standard Deviation 17.9 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 20.8 ng/mL/mg | Standard Deviation 10.8 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 12.8 ng/mL/mg | Standard Deviation 0.48 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 17.9 ng/mL/mg | Standard Deviation 7.9 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 21.4 ng/mL/mg | Standard Deviation 8.9 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 13.7 ng/mL/mg | Standard Deviation 4.1 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 17.3 ng/mL/mg | Standard Deviation 7.9 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 15.0 ng/mL/mg | Standard Deviation 4.8 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 10.4 ng/mL/mg | Standard Deviation 6.4 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Cmax/Dose | Cycle 1 Day 1 | 11.0 ng/mL/mg | Standard Deviation 4 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Cmax/Dose | Cycle 1 Day 14 | 10.4 ng/mL/mg | Standard Deviation 7.5 |
Primary
Phase 1: Maximum Observed Plasma Concentration (Cmax)
Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 0.25 μg/mL | Standard Deviation 0.14 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 0.42 μg/mL | Standard Deviation 0.17 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 1.19 μg/mL | Standard Deviation 0.37 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 1.87 μg/mL | Standard Deviation 0.71 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 2.60 μg/mL | Standard Deviation 1.54 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 4.44 μg/mL | Standard Deviation 3.59 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 5.19 μg/mL | Standard Deviation 2.7 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 3.21 μg/mL | Standard Deviation 0.12 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 2.24 μg/mL | Standard Deviation 0.98 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 2.68 μg/mL | Standard Deviation 1.11 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 2.73 μg/mL | Standard Deviation 0.82 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 3.46 μg/mL | Standard Deviation 1.57 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 3.74 μg/mL | Standard Deviation 1.19 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 2.59 μg/mL | Standard Deviation 1.6 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 1 | 3.30 μg/mL | Standard Deviation 1.2 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) | Cycle 1 Day 14 | 3.11 μg/mL | Standard Deviation 2.26 |
Primary
Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase
The MTD was defined as the dose at which 30% of participants experienced a DLT during the first cycle. DLTs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week.
Time frame: Cycle 1 (Up to 21 days) plus 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase | 200 mg |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Maximum Tolerated Dose (MTD) in the Dose Escalation Phase | 250 mg |
Primary
Phase 1: Number of Participants With DLTs in the Dose Escalation Phase
DLTs were graded according to NCI CTCAE version 3.0 (grade 1=mild; grade 2=moderate; grade 3=severe; grade 4=life threatening; grade 5=death). Any of the following events, considered possibly or probably related to the administration of navitoclax, were considered a DLT: Grade 4 thrombocytopenia (\< 25,000/mm\^3); platelet counts \< 25,000/mm\^3, Grade 2 or higher bleeding associated with thrombocytopenia; all other Grade 3, 4 or 5 adverse events were considered a DLT. Exceptions included: Grade 3, 4 febrile neutropenia less than 7 days; Grade 3, 4 leukopenia; Grade 3, 4 lymphopenia; Grade 3 nausea, vomiting and/or diarrhea unless unresponsive to treatment; Grade 2 toxicity that requires dose modification or delay of \> 1 week.
Time frame: Cycle 1 (Up to 21 days) plus 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 0 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 1 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 0 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 0 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 1 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 1 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With DLTs in the Dose Escalation Phase | 1 Participants |
Primary
Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths.
Time frame: From first dose of study drug to 30 days post-last dose. Participants enrolled in the 14/21-day cycle received a mean of 21.7 treatment cycles; participants enrolled in the 21/21-day cycle received a mean of 19.4 treatment cycles.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 3 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 0 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 0 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 3 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 1 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 0 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 1 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 3 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 4 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 2 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 6 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 4 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 4 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 2 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 1 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 1 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 4 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 4 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 3 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 1 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 3 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 3 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 3 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 2 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 3 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 0 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 1 Participants |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 0 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 2 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 1 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 3 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 3 Participants |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 3 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 3 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 2 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 0 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 1 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 0 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 0 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 1 Participants |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 1 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 1 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 2 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 1 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 0 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 4 Participants |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 2 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 3 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 2 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 0 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 3 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 2 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 3 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 3 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 3 Participants |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 2 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax interruption | 4 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to dose delay | 2 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any SAE | 3 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any fatal AE | 0 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Deaths | 0 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade ≥ 3 | 4 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE | 4 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any dose limiting toxicity (DLT) | 2 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax discontinuation | 1 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE with NCI CTCAE Grade 3 or 4 | 4 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE at least possibly related to navitoclax | 4 Participants |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | Any AE leading to navitoclax dose reduction | 0 Participants |
Primary
Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase
The RPTD was determined based on observed DLTs and/or determination of the MTD in phase 1. (See Outcome Measures 2 and 3 above for definition of DLT and MTD.)
Time frame: Cycle 1 (Up to 21 days) plus 7 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase | 250 mg |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Recommended Phase 2 Dose (RPTD) Determined in the Dose Escalation Phase | 250 mg |
Primary
Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax
For t1/2, the harmonic mean and psuedo-standard deviation are used.
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 9.62 hours | Standard Deviation 4.18 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 8.99 hours | Standard Deviation 0.66 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 10.41 hours | Standard Deviation 5.21 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 11.72 hours | — |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 10.51 hours | Standard Deviation 4.01 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Terminal Phase Elimination Half-life (t1/2) of Navitoclax | 17.88 hours | — |
Primary
Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax
Time frame: Cycle 1 Day 1: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.072 1/H | Standard Deviation 0.029 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.077 1/H | Standard Deviation 0.006 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.067 1/H | Standard Deviation 0.03 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.059 1/H | — |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.066 1/H | Standard Deviation 0.025 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Terminal Phase Elimination Rate Constant (β) for Navitoclax | 0.039 1/H | — |
Primary
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax
Time frame: Cycle 1 Days 1 and 14: pre-dose, 2, 4, 6, 8 hours post-dose
Population: Participants with an assessment at given time point. One participant in the Navitoclax 14/21 Day Cycle: 250 mg arm dose-reduced to 200 mg on Days 4 to14, and therefore was analyzed in the Navitoclax 14/21 Day Cycle: 200 mg arm for Cycle 1 Day 14.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 6.0 hours | Standard Deviation 2 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 4.3 hours | Standard Deviation 1.5 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 5.9 hours | Standard Deviation 1.6 |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 3.5 hours | Standard Deviation 2.8 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 6.7 hours | Standard Deviation 1.2 |
| Navitoclax 14/21 Day Cycle: 200 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 6.8 hours | Standard Deviation 1.5 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 7.3 hours | Standard Deviation 1.2 |
| Navitoclax 14/21 Day Cycle: 250 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 5.7 hours | Standard Deviation 0.4 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 7.3 hours | Standard Deviation 1.2 |
| Navitoclax 21/21 Day Cycle: 125 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 5.8 hours | Standard Deviation 1.8 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 6.5 hours | Standard Deviation 1 |
| Navitoclax 21/21 Day Cycle: 200 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 6.7 hours | Standard Deviation 1.2 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 6.9 hours | Standard Deviation 1.8 |
| Navitoclax 21/21 Day Cycle: 250 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 6.7 hours | Standard Deviation 2.3 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 1 | 7.5 hours | Standard Deviation 1 |
| Navitoclax 21/21 Day Cycle: 300 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Navitoclax | Cycle 1 Day 14 | 7.3 hours | Standard Deviation 1.2 |
Primary
Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing
Time frame: Cycle 1 Day 1: 4-8 h postdose; Cycle 1 Day 15: predose; Cycle 3 Day 1: predose, 4-8 h postdose; Cycle 5 Day 1: predose, 4-8 h postdose; Cycle 7 Day 1: predose, 4-8 h postdose; Cycle 9 Day 1: predose, 4-8 h postdose
Population: Participants with an assessment at given time point. It was pre-specified in the statistical analysis plans to analyze the dose-normalized assessments in phase 2 navitoclax arms combined.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 3 Day 1: predose | 9.84 (ng/mL)/mg | Standard Deviation 3.55 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 3 Day 1: 4-8 h postdose | 15.2 (ng/mL)/mg | Standard Deviation 8.04 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 5 Day 1: predose | 9.84 (ng/mL)/mg | Standard Deviation 4.38 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 5 Day 1: 4-8 h postdose | 15.7 (ng/mL)/mg | Standard Deviation 8.28 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 7 Day 1: predose | 10.4 (ng/mL)/mg | Standard Deviation 5.26 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 1 Day 1: 4-8 h postdose | 9.49 (ng/mL)/mg | Standard Deviation 4.8 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 1 Day 15: predose | 9.64 (ng/mL)/mg | Standard Deviation 5.85 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 7 Day 1: 4-8 h postdose | 15.9 (ng/mL)/mg | Standard Deviation 9.14 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 9 Day 1: predose | 11.4 (ng/mL)/mg | Standard Deviation 9.68 |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Dose-Normalized Plasma Concentrations After Navitoclax Once Daily Dosing | Cycle 9 Day 1: 4-8 h postdose | 13.5 (ng/mL)/mg | Standard Deviation 6.41 |
Primary
Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An SAE is one that: results in death, hospitalization, prolongation of hospitalization, or persistent or significant disability/incapacity; is life-threatening, a congenital anomaly, or other important medical event. Events were graded as 1=mild, 2=moderate, 3=severe, 4=life-threatening, or 5=death. The investigator assessed the relationship of each event to the use of study drug as either probably related, possibly related, probably not related or not related. A treatment-emergent adverse event is defined as any adverse event with onset or worsening reported by a subject from the time that the first dose of study drug is administered until 30 days have elapsed following discontinuation of study drug administration. Deaths category included non treatment emergent deaths.
Time frame: From first dose of study drug to 30 days post-last dose. Participants enrolled in Phase 2 received a mean of 15.6 treatment cycles.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax interruption | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE | 4 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE at least possibly related to navitoclax | 4 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE with NCI CTCAE Grade ≥ 3 | 3 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE with NCI CTCAE Grade 3 or 4 | 3 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any SAE | 1 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax discontinuation | 1 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax dose reduction | 1 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax dose delay | 2 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any fatal AE | 0 Participants |
| Navitoclax 14/21 Day Cycle: 10 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Deaths | 1 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax dose delay | 5 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax discontinuation | 9 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE | 27 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Deaths | 8 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE at least possibly related to navitoclax | 26 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax dose reduction | 10 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE with NCI CTCAE Grade ≥ 3 | 23 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE leading to navitoclax interruption | 16 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any AE with NCI CTCAE Grade 3 or 4 | 23 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any fatal AE | 1 Participants |
| Navitoclax 14/21 Day Cycle: 110 mg | Phase 2: Number of Participants With TEAEs, SAEs, and Discontinuations Due to AEs | Any SAE | 12 Participants |