NCT01794520 · REGISTRY CONDITION SEARCH

Study Evaluating ABT-199 in Participants With Relapsed or Refractory Multiple Myeloma

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: COMPLETED
Registry last update: 2023-04-10

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Participants With Adverse Events

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outcome · POSTED

Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax

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outcome · POSTED

Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax

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outcome · POSTED

Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax

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outcome · POSTED

Phase 2: Overall Response Rate

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outcome · POSTED

Phase 2: Very Good Partial Response Rate or Better

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outcome · POSTED

Phase 1: Overall Response Rate

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outcome · POSTED

Time to Response (TTR)

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outcome · POSTED

Time to Progression (TTP)

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outcome · POSTED

Duration of Response

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outcome · POSTED

Phase 2: Progression-Free Survival (PFS)

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outcome · POSTED

Phase 2: Overall Survival (OS)

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outcome · POSTED

Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain

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outcome · POSTED

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)

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outcome · POSTED

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)

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outcome · POSTED

Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility Criteria: 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
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.
intervention Names
Drug: Venetoclax
label
Phase 1: Venetoclax 300 mg
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Venetoclax
label
Phase 1: Venetoclax 600 mg
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Venetoclax
label
Phase 1: Venetoclax 900 mg
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Venetoclax
label
Phase 1: Venetoclax 1200 mg
type
EXPERIMENTAL
description
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.
intervention Names
Drug: Venetoclax
label
Phase 1 Safety Expansion: Venetoclax 1200 mg
type
EXPERIMENTAL
description
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).
intervention Names
Drug: Venetoclax
Drug: Dexamethasone
label
Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
type
EXPERIMENTAL
description
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).
intervention Names
Drug: Venetoclax
Drug: Dexamethasone
label
Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
type
EXPERIMENTAL

interventions

arm Group Labels
Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
Phase 1 Safety Expansion: Venetoclax 1200 mg
Phase 1: Venetoclax 1200 mg
Phase 1: Venetoclax 300 mg
Phase 1: Venetoclax 600 mg
Phase 1: Venetoclax 900 mg
Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
description
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.
name
Venetoclax
other Names
ABT-199
VENCLEXTA®
type
DRUG
arm Group Labels
Phase 1 Combination: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
Phase 2 Expansion: Venetoclax 800 mg/Dexamethasone 20 or 40 mg
description
Tablets were administered by mouth per the dexamethasone prescribing information.
name
Dexamethasone
type
DRUG

Study design

allocation

NON_RANDOMIZED

intervention Model

SEQUENTIAL

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 117
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
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.
measure
Number of Participants With Adverse Events
time Frame
From first dose of study drug until 30 days following last dose of study drug (up to 2482 days)
description
Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval.
measure
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax
time Frame
Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
description
Tmax is the the time at which the maximum plasma concentration (Cmax) is observed.
measure
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax
time Frame
Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
description
AUC is a measure of how long and how much drug is present in the body after dosing.
measure
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax
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)
description
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.
measure
Phase 2: Overall Response Rate
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
description
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.
measure
Phase 2: Very Good Partial Response Rate or Better
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

secondary Outcomes

description
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.
measure
Phase 1: Overall Response Rate
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
description
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.
measure
Time to Response (TTR)
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
description
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.
measure
Time to Progression (TTP)
time Frame
Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
description
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.
measure
Duration of Response
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
description
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.
measure
Phase 2: Progression-Free Survival (PFS)
time Frame
Estimated median duration of follow-up was 31.7 months
description
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.
measure
Phase 2: Overall Survival (OS)
time Frame
Estimated median duration of follow-up was 31.7 months
description
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.
measure
Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain
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
description
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.
measure
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)
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
description
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.
measure
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)
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
description
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.
measure
Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score
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

Full study description

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.

Source references

references

citation
Badawi M, Coppola S, Eckert D, Gopalakrishnan S, Engelhardt B, Doelger E, Huang W, Dobkowska E, Kumar S, Menon RM, Salem AH. Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety. Hematol Oncol. 2024 Jan;42(1):e3222. doi: 10.1002/hon.3222. Epub 2023 Sep 23.
pmid
37740931
type
DERIVED
citation
Kumar S, Kaufman JL, Gasparetto C, Mikhael J, Vij R, Pegourie B, Benboubker L, Facon T, Amiot M, Moreau P, Punnoose EA, Alzate S, Dunbar M, Xu T, Agarwal SK, Enschede SH, Leverson JD, Ross JA, Maciag PC, Verdugo M, Touzeau C. Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma. Blood. 2017 Nov 30;130(22):2401-2409. doi: 10.1182/blood-2017-06-788786. Epub 2017 Oct 10.
pmid
29018077
type
DERIVED