Relapsed/Refractory Multiple Myeloma
Conditions
Keywords
Relapsed multiple myeloma, Refractory multiple myeloma, Multiple myeloma, Relapsed/refractory multiple myeloma
Brief summary
The Phase 1 primary objectives of this study were to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and recommended Phase 2 dose (RPTD) of ABT-199 (venetoclax) when administered in participants with relapsed or refractory multiple myeloma. This study also assessed the safety profile and PK of venetoclax in combination with dexamethasone in participants with t(11;14)-positive multiple myeloma. The Phase 2 primary objective was to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in participants with t(11;14)-positive multiple myeloma.
Interventions
DRUGVenetoclax
Each dose of venetoclax was to be taken with approximately 240 mL of water. On days that pre-dose pharmacokinetic (PK) sampling was required, dosing was to occur in the morning at the clinic at approximately 0900 (± 1 hour) to facilitate PK sampling. Dose Escalation cohort participants were to take venetoclax within 30 minutes after the completion of a standard low-fat breakfast with approximately 240 mL of water on Cycle 2 Day 1. On all other dosing days, participants were instructed to take venetoclax orally QD within 30 minutes after the completion of a low-fat breakfast. Tablets were to be swallowed whole and must not have been broken, chewed, or crushed.
DRUGDexamethasone
Tablets were administered by mouth per the dexamethasone prescribing information.
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
* ECOG (Eastern Cooperative Oncology Group) performance score of 1 or 0. Participants in the Phase 2 portion: ECOG performance score of 2, 1, or 0. * Diagnosis of multiple myeloma (MM) previously treated with at least one prior line of therapy. * Induction therapy followed by stem cell transplant and maintenance therapy will be considered a single line of therapy. * For Safety Expansion, participants must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide). * For Venetoclax-Dexamethasone Combination, participants must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide) AND have t(11;14)-positive multiple myeloma per the central lab testing. * For Phase 2, participants must have MM positive for the t(11;14) translocation, as determined by an analytically validated fluorescence in situ hybridization (FISH) assay per the central laboratory testing (enrollment with local t(11;14)-positive FISH results only will be considered at the discretion of the Therapeutic Area MD). Participants must have evidence of disease progression on or within 60 days of last dose of most recent previous treatment based on International Myeloma Working Group (IMWG) criteria AND must have previously received at least 2 lines of therapy, including an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib or ixazomib), daratumumab, and glucocorticoids. * For US participants: Daratumumab combination regimen must be one of the prior lines of therapy (for this study, daratumumab plus corticosteroids will not be considered a combination regimen). * For Non-US participants: Either daratumumab monotherapy or combination therapy is acceptable. Daratumumab monotherapy will be limited to approximately 20 percent of the total number of Phase 2 participants. * Measurable disease at Screening: * Serum monoclonal protein of at least 1.0 g/dL (10g/L) by protein electrophoresis. * At least 200 mg of monoclonal protein in the urine on 24-hr electrophoresis. * Serum immunoglobulin free light chain of at least 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio. * Participants with a history of autologous or allogenic stem cell transplantation must have adequate peripheral blood counts independent of any growth factor support, and have recovered from any transplant related toxicity(s) and be: * At least 100 days post-autologous transplant prior to first dose of study drug or * At least 6 months post-allogenic transplant prior to first dose of study drug and not have active graft-versus-host disease (GVHD), i.e., requiring treatment. * Meet the following laboratory parameters, per the reference range, at least once during the screening period: * Absolute Neutrophil Count (ANC) of at least 1000/μL (Participants may use growth factor support to achieve ANC eligibility criteria). * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) not higher than 3 x Upper Limit of Normal Range (ULN). * Calculated creatinine clearance of at least 30 mL/min using a modified Cockcroft-Gault calculation. * Platelet count of at least 30,000 mm³ (independent of transfusion for 2 weeks). * Hemoglobin of at least 8.0 g/dL (participants may receive blood transfusion to achieve hemoglobin eligibility criteria). * Total bilirubin not higher than 1.5 x ULN (Participants with Gilbert's Syndrome may have bilirubin higher than 1.5 x ULN).
Exclusion criteria
* Exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to: * Acute infection within 14 days prior to first dose of study drug requiring antibiotic, antifungal, or antiviral therapy. * Diagnosis of fever and neutropenia within 1 week prior to first dose of study drug. * Cardiovascular disability status of New York Heart Association Class ≥ 3. * Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular or hepatic disease, within the last 6 months that, in the opinion of the investigator, would adversely affect his/her participation in the study. * History of other active malignancies other than multiple myeloma within the past 3 years prior to study entry, with the following exceptions: * Adequately treated in situ carcinoma of the cervix uteri; * Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; * Localized prostate cancer Gleason grade 6 or lower AND with stable prostate specific antigen (PSA) levels off treatment * Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. * Known Human Immunodeficiency Viral (HIV) infection. * Active hepatitis B or C infection.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From first dose of study drug until 30 days following last dose of study drug (up to 2482 days) | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug. |
| Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose | Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval. |
| Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose | Tmax is the the time at which the maximum plasma concentration (Cmax) is observed. |
| Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose (dose escalation cohort); (1200 mg dose): Cycle 2, Day 1 at predose (safety expansion cohort, 1200 mg dose) | AUC is a measure of how long and how much drug is present in the body after dosing. |
| Phase 2: Overall Response Rate | Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months | Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria. |
| Phase 2: Very Good Partial Response Rate or Better | Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months | The percentage of participants with documented best overall response of Very Good Partial Response (VGPR) or better (VGPR, Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria was computed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit | The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in patients with cancer pain. The four pain severity items assess pain at its worst in last 24 hours, least in last 24 hours, average, and now (current pain). For these items, participants are asked to rate their pain on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you can imagine). The Worst Pain scores range from 0 to 10, with higher scores indicating severe pain. Negative changes from baseline indicate improvement. |
| Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit | The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Physical Functioning scale, participants rate five items on a four-point scale, with 1 as not at all and 4 as very much. The Physical Functioning Scale scores range from 0 to 100 and were calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high scale score represents high/healthy level of functioning. Positive changes from baseline indicate improvement. |
| Phase 1: Overall Response Rate | Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 8.1 months | Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2011 International Myeloma Working Group (IMWG) criteria. |
| Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit | PROMIS Cancer Fatigue SF is a seven item questionnaire that assesses the impact and experience of fatigue over the past 7 days. All questions employ the following five response options: 1 = Not at all, 2 = A little bit, 3 = Somewhat, 4 = Quite a bit, and 5 = Very much. The total raw score is the sum of the responses to each question and is converted to a T-score. The T-score re-scales the total raw score to a standardized score with a mean of 50 and a standard deviation of 10. The \[PROMIS\] Cancer Fatigue Short Form \[SF\] 7a T-Scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Negative changes from baseline indicate improvement. |
| Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit | The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Global Health Status/Quality of Life scale, participants rate two items on a seven point scale, with 1 as very poor and 7 as excellent. The Global Health Status/Quality of Life scale ranges from 0 to 100 and was calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high score for the global health status/QoL represents a high QoL. Positive changes from baseline indicate improvement. |
| Time to Response (TTR) | Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; Estimated median time on follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2 | TTR is defined as the number of days from the date of first dose of study drug until the date of their first favorable response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2011 International Myeloma Working Group (IMWG) criteria (Phase 1) or 2016 IMWG criteria (Phase 2). If a participant did not experience a favorable response, they were to be censored at the date of last adequate assessment. TTR was analyzed by Kaplan- Meier (K-M)\\ methodology. |
| Time to Progression (TTP) | Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2 | TTP is defined as the number of days from the date of first dose of study drug to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first. TTP was analyzed by Kaplan- Meier (K-M) methodology. |
| Duration of Response | Assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2 | DOR is defined as the number of days from the date of first response of Partial Response (PR) or better to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first. DOR was analyzed by Kaplan- Meier (K-M) methodology. |
| Phase 2: Progression-Free Survival (PFS) | Estimated median duration of follow-up was 31.7 months | PFS is defined as the number of days from the date of the first dose of study treatment to the date of first documented disease progression or death due to any cause, whichever occurs first. PFS was analyzed by Kaplan-Meier methodology. |
| Phase 2: Overall Survival (OS) | Estimated median duration of follow-up was 31.7 months | OS is defined as the number of days from the date of the first dose of study drug to the date of death due to any cause. If a participant was not known to have died, OS was censored at the last known alive date. The distribution of OS was estimated using Kaplan-Meier methodology. |
Countries
Belgium, France, Norway, United States
Participant flow
Pre-assignment details
Intent-to-Treat (ITT) population: all participants who received at least one dose of study drug
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Venetoclax 300 mg Participants in the dose-escalation cohort received 300 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. | 6 |
| Phase 1: Venetoclax 600 mg Participants in the dose-escalation cohort received 600 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. | 9 |
| Phase 1: Venetoclax 900 mg Participants in the dose-escalation cohort received 900 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. | 6 |
| Phase 1: Venetoclax 1200 mg Participants in the dose-escalation cohort received 1200 mg of venetoclax daily on Days 1 -21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. | 9 |
| Phase 1 Safety Expansion: Venetoclax 1200 mg Participants in the safety expansion cohort received 1200 mg of venetoclax daily on Days 1 - 21 of each cycle after a 2-week lead-in period, during which venetoclax doses were increased weekly. | 36 |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg Participants with t(11;14) translocation multiple myeloma received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years). | 20 |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg The Phase 2 cohort further explored the efficacy of venetoclax in combination with dexamethasone in relapsed or refractory participants with t(11;14) translocation multiple myeloma. Participants received daily venetoclax at a dose of 800 mg (no lead-in period) on Days 1- 21 of each cycle concomitant with weekly dexamethasone at a dose of 40 mg (20 mg for those aged ≥ 75 years). | 31 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse event- not related to progression | 1 | 1 | 0 | 0 | 2 | 0 | 0 |
| Overall Study | Adverse events- related to progression | 0 | 0 | 1 | 2 | 0 | 1 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 1 | 0 | 22 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Other, not specified | 0 | 0 | 1 | 1 | 4 | 1 | 2 |
| Overall Study | Progressive disease | 5 | 6 | 2 | 5 | 27 | 18 | 0 |
| Overall Study | Study terminated by sponsor | 0 | 0 | 1 | 0 | 1 | 0 | 7 |
| Overall Study | Toxicity | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew consent | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1: Venetoclax 300 mg | Phase 1: Venetoclax 600 mg | Phase 1: Venetoclax 900 mg | Phase 1: Venetoclax 1200 mg | Phase 1 Safety Expansion: Venetoclax 1200 mg | Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 7.32 | 63.1 years STANDARD_DEVIATION 9.03 | 61.8 years STANDARD_DEVIATION 12.06 | 67.3 years STANDARD_DEVIATION 8.32 | 60.8 years STANDARD_DEVIATION 10.58 | 63.4 years STANDARD_DEVIATION 8.13 | 64.9 years STANDARD_DEVIATION 8.31 | 63.1 years STANDARD_DEVIATION 9.25 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 5 Participants | 11 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Multi Race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 9 Participants | 4 Participants | 6 Participants | 34 Participants | 17 Participants | 24 Participants | 100 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 5 Participants | 5 Participants | 23 Participants | 3 Participants | 13 Participants | 52 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 1 Participants | 4 Participants | 13 Participants | 17 Participants | 18 Participants | 65 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 1 / 9 | 1 / 6 | 0 / 9 | 6 / 36 | 1 / 20 | 22 / 31 |
| other Total, other adverse events | 6 / 6 | 9 / 9 | 6 / 6 | 9 / 9 | 35 / 36 | 19 / 20 | 27 / 31 |
| serious Total, serious adverse events | 1 / 6 | 4 / 9 | 3 / 6 | 3 / 9 | 15 / 36 | 6 / 20 | 16 / 31 |
Outcome results
Primary
Number of Participants With Adverse Events
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. The investigator assesses the relationship of each event to the use of study drug. A serious adverse event (SAE) is an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs) are defined as any event that began or worsened in severity on or after the first dose of study drug.
Time frame: From first dose of study drug until 30 days following last dose of study drug (up to 2482 days)
Population: Safety population: all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Number of Participants With Adverse Events | TESAE | 1 Participants |
| Phase 1: Venetoclax 300 mg | Number of Participants With Adverse Events | Any TEAE | 6 Participants |
| Phase 1: Venetoclax 600 mg | Number of Participants With Adverse Events | TESAE | 4 Participants |
| Phase 1: Venetoclax 600 mg | Number of Participants With Adverse Events | Any TEAE | 9 Participants |
| Phase 1: Venetoclax 900 mg | Number of Participants With Adverse Events | TESAE | 3 Participants |
| Phase 1: Venetoclax 900 mg | Number of Participants With Adverse Events | Any TEAE | 6 Participants |
| Phase 1: Venetoclax 1200 mg | Number of Participants With Adverse Events | Any TEAE | 9 Participants |
| Phase 1: Venetoclax 1200 mg | Number of Participants With Adverse Events | TESAE | 3 Participants |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Number of Participants With Adverse Events | Any TEAE | 36 Participants |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Number of Participants With Adverse Events | TESAE | 15 Participants |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Number of Participants With Adverse Events | Any TEAE | 19 Participants |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Number of Participants With Adverse Events | TESAE | 6 Participants |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Number of Participants With Adverse Events | TESAE | 16 Participants |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Number of Participants With Adverse Events | Any TEAE | 30 Participants |
Primary
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
AUC is a measure of how long and how much drug is present in the body after dosing.
Time frame: Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose (dose escalation cohort); (1200 mg dose): Cycle 2, Day 1 at predose (safety expansion cohort, 1200 mg dose)
Population: Phase 1 dose escalation and safety expansion participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | 13.0 µg•h/mL | Standard Deviation 8.31 |
| Phase 1: Venetoclax 600 mg | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | 38.2 µg•h/mL | Standard Deviation 25.1 |
| Phase 1: Venetoclax 900 mg | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | 26.3 µg•h/mL | Standard Deviation 20.1 |
| Phase 1: Venetoclax 1200 mg | Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax | 71.5 µg•h/mL | Standard Deviation 35.8 |
Primary
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval.
Time frame: Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
Population: Phase 1 dose escalation and safety expansion participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | 0.897 µg/mL | Standard Deviation 0.593 |
| Phase 1: Venetoclax 600 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | 2.56 µg/mL | Standard Deviation 1.77 |
| Phase 1: Venetoclax 900 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | 1.85 µg/mL | Standard Deviation 1.3 |
| Phase 1: Venetoclax 1200 mg | Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax | 4.16 µg/mL | Standard Deviation 1.52 |
Primary
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
Tmax is the the time at which the maximum plasma concentration (Cmax) is observed.
Time frame: Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
Population: Phase 1 dose escalation and safety expansion participants with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | 5.0 hours |
| Phase 1: Venetoclax 600 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | 8.0 hours |
| Phase 1: Venetoclax 900 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | 6.0 hours |
| Phase 1: Venetoclax 1200 mg | Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax | 6.1 hours |
Primary
Phase 2: Overall Response Rate
Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria.
Time frame: Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months
Population: All enrolled Phase 2 participants who received venetoclax and had active disease at baseline; primary efficacy endpoints were pre-specified for Phase 2 only, and are reported for all participants with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Overall Response Rate | 48.4 percentage of participants |
Primary
Phase 2: Very Good Partial Response Rate or Better
The percentage of participants with documented best overall response of Very Good Partial Response (VGPR) or better (VGPR, Complete response \[CR\], or Stringent complete response \[sCR\]) per 2016 standard International Myeloma Working Group (IMWG) criteria was computed.
Time frame: Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 31.7 months
Population: All enrolled Phase 2 participants who received venetoclax and had active disease at baseline; primary efficacy endpoints were pre-specified for Phase 2 only, and are reported for all participants with available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Very Good Partial Response Rate or Better | 35.5 percentage of participants |
Secondary
Duration of Response
DOR is defined as the number of days from the date of first response of Partial Response (PR) or better to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first. DOR was analyzed by Kaplan- Meier (K-M) methodology.
Time frame: Assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
Population: All enrolled participants who received venetoclax, had active disease at baseline, and achieved a response of PR or better
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 600 mg | Duration of Response | 9.7 months |
| Phase 1: Venetoclax 900 mg | Duration of Response | NA months |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Duration of Response | 17.3 months |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Duration of Response | 13.1 months |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Duration of Response | 17.5 months |
Secondary
Phase 1: Overall Response Rate
Overall response rate is defined as the percentage of participants with documented best overall response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2011 International Myeloma Working Group (IMWG) criteria.
Time frame: Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; estimated median time on follow-up was 8.1 months
Population: All enrolled Phase 1 participants who had active disease at baseline and received venetoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 1: Overall Response Rate | 0 percentage of participants |
| Phase 1: Venetoclax 600 mg | Phase 1: Overall Response Rate | 11.1 percentage of participants |
| Phase 1: Venetoclax 900 mg | Phase 1: Overall Response Rate | 16.7 percentage of participants |
| Phase 1: Venetoclax 1200 mg | Phase 1: Overall Response Rate | 0 percentage of participants |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Phase 1: Overall Response Rate | 36.1 percentage of participants |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Phase 1: Overall Response Rate | 65.0 percentage of participants |
Secondary
Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain
The BPI-SF is a pain-specific measure developed to assess patient-reported severity (or intensity) of pain (4 items) and the impact of pain on daily functioning (7 items) in patients with cancer pain. The four pain severity items assess pain at its worst in last 24 hours, least in last 24 hours, average, and now (current pain). For these items, participants are asked to rate their pain on an 11-point numeric rating scale with anchors of 0 (no pain) and 10 (pain as bad as you can imagine). The Worst Pain scores range from 0 to 10, with higher scores indicating severe pain. Negative changes from baseline indicate improvement.
Time frame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
Population: Intent-to-Treat (ITT) population: all participants who received at least one dose of study drug; participants who have both baseline and post-baseline values are included in the analysis at each visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 3, Day 1 | 0.2 units on a scale | Standard Deviation 2.47 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 5, Day 1 | -0.9 units on a scale | Standard Deviation 1.43 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 7, Day 1 | -0.9 units on a scale | Standard Deviation 1.2 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 9, Day 1 | -0.9 units on a scale | Standard Deviation 1.46 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 11, Day 1 | -1.1 units on a scale | Standard Deviation 1.62 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 13, Day 1 | 0.5 units on a scale | Standard Deviation 3.84 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 15, Day 1 | -0.6 units on a scale | Standard Deviation 1.27 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 17, Day 1 | -1.6 units on a scale | Standard Deviation 1.29 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 19, Day 1 | -1.8 units on a scale | Standard Deviation 2 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 21, Day 1 | -1.6 units on a scale | Standard Deviation 2.3 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 23, Day 1 | -1.6 units on a scale | Standard Deviation 2.3 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Cycle 25, Day 1 | -3.8 units on a scale | — |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain | Final visit | -0.3 units on a scale | Standard Deviation 1.86 |
Secondary
Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Global Health Status/Quality of Life scale, participants rate two items on a seven point scale, with 1 as very poor and 7 as excellent. The Global Health Status/Quality of Life scale ranges from 0 to 100 and was calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high score for the global health status/QoL represents a high QoL. Positive changes from baseline indicate improvement.
Time frame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
Population: Intent-to-Treat (ITT) population: all participants who received at least one dose of study drug; participants who have both baseline and post-baseline values are included in the analysis at each visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 3, Day 1 | -5.2 units on a scale | Standard Deviation 25.44 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 5, Day 1 | 6.7 units on a scale | Standard Deviation 5.27 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 7, Day 1 | 3.1 units on a scale | Standard Deviation 7.63 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 9, Day 1 | 8.3 units on a scale | Standard Deviation 11.79 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 11, Day 1 | 0.0 units on a scale | Standard Deviation 11.79 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 13, Day 1 | -6.0 units on a scale | Standard Deviation 6.3 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 15, Day 1 | 4.8 units on a scale | Standard Deviation 8.13 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 17, Day 1 | -1.4 units on a scale | Standard Deviation 12.27 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 19, Day 1 | -19.4 units on a scale | Standard Deviation 4.81 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 21, Day 1 | -33.3 units on a scale | Standard Deviation 23.57 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 23, Day 1 | -8.3 units on a scale | Standard Deviation 0 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 25, Day 1 | -8.3 units on a scale | — |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Global Health Status/Quality of Life Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Final visit | -11.5 units on a scale | Standard Deviation 23.55 |
Secondary
Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score
PROMIS Cancer Fatigue SF is a seven item questionnaire that assesses the impact and experience of fatigue over the past 7 days. All questions employ the following five response options: 1 = Not at all, 2 = A little bit, 3 = Somewhat, 4 = Quite a bit, and 5 = Very much. The total raw score is the sum of the responses to each question and is converted to a T-score. The T-score re-scales the total raw score to a standardized score with a mean of 50 and a standard deviation of 10. The \[PROMIS\] Cancer Fatigue Short Form \[SF\] 7a T-Scores range from 29.4 to 83.2, with higher scores indicating more fatigue. Negative changes from baseline indicate improvement.
Time frame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
Population: Intent-to-Treat (ITT) population: all participants who received at least one dose of study drug; participants who have both baseline and post-baseline values are included in the analysis at each visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 7, Day 1 | -1.8 T-score | Standard Deviation 4.21 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 9, Day 1 | -1.6 T-score | Standard Deviation 4.85 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 3, Day 1 | 0.6 T-score | Standard Deviation 5.88 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 5, Day 1 | -2.9 T-score | Standard Deviation 5.3 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 11, Day 1 | 0.1 T-score | Standard Deviation 7.24 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 13, Day 1 | 1.0 T-score | Standard Deviation 4.54 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 15, Day 1 | -3.4 T-score | Standard Deviation 5.69 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 17, Day 1 | 0.6 T-score | Standard Deviation 7.36 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 19, Day 1 | 6.6 T-score | Standard Deviation 2.25 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 21, Day 1 | 11.6 T-score | Standard Deviation 6.51 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 23, Day 1 | 6.0 T-score | Standard Deviation 0.57 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Cycle 25, Day 1 | 5.6 T-score | — |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score | Final visit | 1.4 T-score | Standard Deviation 6.51 |
Secondary
Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)
The QLQ-C30 is a 30-item subject self-report questionnaire composed of both multi-item and single scales, including five functional scales (physical, role, emotional, social, and cognitive), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/quality of life scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). For the Physical Functioning scale, participants rate five items on a four-point scale, with 1 as not at all and 4 as very much. The Physical Functioning Scale scores range from 0 to 100 and were calculated per the EORTC QLQ-C30 Scoring Manual (3rd edition), version 3.0. A high scale score represents high/healthy level of functioning. Positive changes from baseline indicate improvement.
Time frame: Baseline; Cycle 3, Day 1; Cycle 5, Day 1; Cycle 7, Day 1; Cycle 9, Day 1; Cycle 11, Day 1; Cycle 13, Day 1; Cycle 15, Day 1; Cycle 17, Day 1; Cycle 19, Day 1; Cycle 21, Day 1; Cycle 23, Day 1; Cycle 25, Day 1; Final visit
Population: Intent-to-Treat (ITT) population: all participants who received at least one dose of study drug; participants who have both baseline and post-baseline values are included in the analysis at each visit
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 3, Day 1 | -3.7 units on a scale | Standard Deviation 21.9 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 5, Day 1 | 4.0 units on a scale | Standard Deviation 15.78 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 7, Day 1 | 8.3 units on a scale | Standard Deviation 11.13 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 9, Day 1 | 8.3 units on a scale | Standard Deviation 11.13 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 11, Day 1 | 15.2 units on a scale | Standard Deviation 9.97 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 13, Day 1 | 11.4 units on a scale | Standard Deviation 14.76 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 15, Day 1 | 14.3 units on a scale | Standard Deviation 11.17 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 17, Day 1 | 8.9 units on a scale | Standard Deviation 13.11 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 19, Day 1 | -0.0 units on a scale | Standard Deviation 11.55 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 21, Day 1 | -13.3 units on a scale | Standard Deviation 28.28 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 23, Day 1 | -3.3 units on a scale | Standard Deviation 14.14 |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Cycle 25, Day 1 | 6.7 units on a scale | — |
| Phase 1: Venetoclax 300 mg | Phase 2: Mean Change From Baseline in Physical Functioning Scale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) | Final visit | -5.0 units on a scale | Standard Deviation 19.4 |
Secondary
Phase 2: Overall Survival (OS)
OS is defined as the number of days from the date of the first dose of study drug to the date of death due to any cause. If a participant was not known to have died, OS was censored at the last known alive date. The distribution of OS was estimated using Kaplan-Meier methodology.
Time frame: Estimated median duration of follow-up was 31.7 months
Population: All enrolled Phase 2 participants who received venetoclax; this endpoint was pre-specified for Phase 2 only, data are reported for all participants with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Overall Survival (OS) | 18.4 months |
Secondary
Phase 2: Progression-Free Survival (PFS)
PFS is defined as the number of days from the date of the first dose of study treatment to the date of first documented disease progression or death due to any cause, whichever occurs first. PFS was analyzed by Kaplan-Meier methodology.
Time frame: Estimated median duration of follow-up was 31.7 months
Population: All enrolled Phase 2 participants who received venetoclax and had active disease at baseline; this endpoint was pre-specified for Phase 2 only, data are reported for all participants with available data
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Phase 2: Progression-Free Survival (PFS) | 11.2 months |
Secondary
Time to Progression (TTP)
TTP is defined as the number of days from the date of first dose of study drug to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first. TTP was analyzed by Kaplan- Meier (K-M) methodology.
Time frame: Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
Population: All enrolled participants who received venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 300 mg | Time to Progression (TTP) | 5.0 months |
| Phase 1: Venetoclax 600 mg | Time to Progression (TTP) | 2.0 months |
| Phase 1: Venetoclax 900 mg | Time to Progression (TTP) | 1.2 months |
| Phase 1: Venetoclax 1200 mg | Time to Progression (TTP) | 1.9 months |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Time to Progression (TTP) | 4.2 months |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Time to Progression (TTP) | 12.2 months |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Time to Progression (TTP) | 11.2 months |
Secondary
Time to Response (TTR)
TTR is defined as the number of days from the date of first dose of study drug until the date of their first favorable response of Partial Response (PR) or better (PR, Very good partial response \[VGPR\], Complete response \[CR\], or Stringent complete response \[sCR\]) per 2011 International Myeloma Working Group (IMWG) criteria (Phase 1) or 2016 IMWG criteria (Phase 2). If a participant did not experience a favorable response, they were to be censored at the date of last adequate assessment. TTR was analyzed by Kaplan- Meier (K-M)\\ methodology.
Time frame: Response was assessed at Cycle 2, Day 1, and on Day 1 of every cycle thereafter; Estimated median time on follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
Population: All enrolled participants who received venetoclax, had active disease at baseline, and achieved a response (PR or better)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: Venetoclax 600 mg | Time to Response (TTR) | NA months |
| Phase 1: Venetoclax 900 mg | Time to Response (TTR) | NA months |
| Phase 1 Safety Expansion: Venetoclax 1200 mg | Time to Response (TTR) | 9.0 months |
| Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Time to Response (TTR) | 2.6 months |
| Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg | Time to Response (TTR) | 0.8 months |