Clinical Trial Results:
A Phase 1/2 Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects with Relapsed or Refractory Multiple Myeloma
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Summary
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EudraCT number |
2012-000589-38 |
Trial protocol |
BE |
Global end of trial date |
08 Nov 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Dec 2022
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First version publication date |
15 Dec 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
M13-367
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01794520 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
AbbVie Deutschland GmbH & Co. KG
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Sponsor organisation address |
AbbVie House, Vanwall Business Park, Vanwall Road,, Maidenhead, Berkshire, United Kingdom, SL6-4UB
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Public contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Scientific contact |
Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
08 Nov 2021
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Nov 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
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.
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Protection of trial subjects |
The Investigator or his/her representative explained the nature of the study to the subject and answered all questions regarding this study. Prior to any study-related screening procedure being performed on the subject the informed consent statement was reviewed, signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
10 Oct 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
France: 22
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Country: Number of subjects enrolled |
Norway: 5
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Country: Number of subjects enrolled |
United States: 90
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Worldwide total number of subjects |
117
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EEA total number of subjects |
27
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
60
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From 65 to 84 years |
57
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects underwent screening procedures within approximately 21 days prior to initial study drug administration, with the exception of the skeletal survey which was to be completed within approximately 30 days prior to planned study drug administration. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Phase 1: Venetoclax Dose Escalation/Safety Expansion Cohorts | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Participants in the dose-escalation cohort received daily venetoclax at a designated dose (i.e., 300, 600, 900, or 1200 mg) on Days 1 -21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with progressive disease (PD) may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥75 years) on Days 1, 8, and 15 of each 21-day cycle. Those who completed at least 2 cycles at their designated cohort dose (or current dose) may have progressively escalated their dose to the highest cleared venetoclax dose level or any dose below. Participants in the safety expansion cohort received daily venetoclax at the maximum administered dose (i.e., 1200 mg) on Days 1 - 21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with PD may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥ 75 years) on Days 1, 8, and 15 of each 21-day cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
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Other name |
ABT-199, VENCLEXTA®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets were administered by mouth per the dexamethasone prescribing information.
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Arm title
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Phase 1: Venetoclax-Dexamethasone Combination | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
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Other name |
ABT-199, VENCLEXTA®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets were administered by mouth per the dexamethasone prescribing information.
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Arm title
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Phase 2: Venetoclax-Dexamethasone Combination Expansion | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venetoclax
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Investigational medicinal product code |
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Other name |
ABT-199, VENCLEXTA®
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
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.
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Investigational medicinal product name |
Dexamethasone
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Tablets were administered by mouth per the dexamethasone prescribing information.
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Baseline characteristics reporting groups
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Reporting group title |
Phase 1: Venetoclax Dose Escalation/Safety Expansion Cohorts
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Reporting group description |
Participants in the dose-escalation cohort received daily venetoclax at a designated dose (i.e., 300, 600, 900, or 1200 mg) on Days 1 -21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with progressive disease (PD) may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥75 years) on Days 1, 8, and 15 of each 21-day cycle. Those who completed at least 2 cycles at their designated cohort dose (or current dose) may have progressively escalated their dose to the highest cleared venetoclax dose level or any dose below. Participants in the safety expansion cohort received daily venetoclax at the maximum administered dose (i.e., 1200 mg) on Days 1 - 21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with PD may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥ 75 years) on Days 1, 8, and 15 of each 21-day cycle. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 1: Venetoclax-Dexamethasone Combination
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Reporting group 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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 2: Venetoclax-Dexamethasone Combination Expansion
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Reporting group 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). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Phase 1: Venetoclax Dose Escalation/Safety Expansion Cohorts
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Reporting group description |
Participants in the dose-escalation cohort received daily venetoclax at a designated dose (i.e., 300, 600, 900, or 1200 mg) on Days 1 -21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with progressive disease (PD) may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥75 years) on Days 1, 8, and 15 of each 21-day cycle. Those who completed at least 2 cycles at their designated cohort dose (or current dose) may have progressively escalated their dose to the highest cleared venetoclax dose level or any dose below. Participants in the safety expansion cohort received daily venetoclax at the maximum administered dose (i.e., 1200 mg) on Days 1 - 21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with PD may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥ 75 years) on Days 1, 8, and 15 of each 21-day cycle. | ||
Reporting group title |
Phase 1: Venetoclax-Dexamethasone Combination
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Reporting group 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). | ||
Reporting group title |
Phase 2: Venetoclax-Dexamethasone Combination Expansion
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Reporting group 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). | ||
Subject analysis set title |
300 mg Venetoclax
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received a 300 mg dose of venetoclax administered on the intensive pharmacokinetic sampling day
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Subject analysis set title |
600 mg Venetoclax
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received a 600 mg dose of venetoclax administered on the intensive pharmacokinetic sampling day
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Subject analysis set title |
900 mg Venetoclax
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received a 900 mg dose of venetoclax administered on the intensive pharmacokinetic sampling day
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Subject analysis set title |
1200 mg Venetoclax
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Participants who received a 1200 mg dose of venetoclax administered on the intensive pharmacokinetic sampling day
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End point title |
Number of Participants With Adverse Events [1] | ||||||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
From first dose of study drug until 30 days following last dose of study drug (up to 2482 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive data are summarized for this end point per protocol. |
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| Notes [2] - Safety population: all participants who received at least one dose of study drug [3] - Safety population: all participants who received at least one dose of study drug [4] - Safety population: all participants who received at least one dose of study drug |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Phase 1: Maximum Observed Plasma Concentration (Cmax) of Venetoclax [5] | ||||||||||||||||||||
End point description |
Cmax is the highest concentration that a drug achieves in the blood after administration in a dosing interval.
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End point type |
Primary
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End point timeframe |
Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis results are presented in the endpoint data table, per protocol. |
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| Notes [6] - Phase 1 dose escalation and safety expansion participants with available data [7] - Phase 1 dose escalation and safety expansion participants with available data [8] - Phase 1 dose escalation and safety expansion participants with available data [9] - Phase 1 dose escalation and safety expansion participants with available data |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Phase 1: Time to Maximum Observed Plasma Concentration (Tmax) of Venetoclax [10] | ||||||||||||||||||||
End point description |
Tmax is the the time at which the maximum plasma concentration (Cmax) is observed.
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End point type |
Primary
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End point timeframe |
Cycle 2, Day 1 at predose, 2, 4, 6, 8, and 24 hours postdose
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| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis results are presented in the endpoint data table, per protocol. |
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| Notes [11] - Phase 1 dose escalation and safety expansion participants with available data [12] - Phase 1 dose escalation and safety expansion participants with available data [13] - Phase 1 dose escalation and safety expansion participants with available data [14] - Phase 1 dose escalation and safety expansion participants with available data |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Phase 1: Area Under the Plasma Concentration-Time Curve Over Time From 0 to 24 Hours (AUC0-24) of Venetoclax [15] | ||||||||||||||||||||
End point description |
AUC is a measure of how long and how much drug is present in the body after dosing.
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End point type |
Primary
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End point timeframe |
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)
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| Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis results are presented in the endpoint data table, per protocol. |
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| Notes [16] - Phase 1 dose escalation and safety expansion participants with available data [17] - Phase 1 dose escalation and safety expansion participants with available data [18] - Phase 1 dose escalation and safety expansion participants with available data [19] - Phase 1 dose escalation and safety expansion participants with available data |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Phase 2: Overall Response Rate [20] [21] | ||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
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
|
||||||||
| Notes [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis results are presented in the endpoint data table, per protocol. [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Primary efficacy endpoints were pre-specified for Phase 2 only. |
|||||||||
|
|||||||||
| Notes [22] - Phase 2 participants who received venetoclax and had active disease at baseline and available data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Phase 2: Very Good Partial Response Rate or Better [23] [24] | ||||||||
End point 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.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
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
|
||||||||
| Notes [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The statistical analysis results are presented in the endpoint data table, per protocol. [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Primary efficacy endpoints were pre-specified for Phase 2 only. |
|||||||||
|
|||||||||
| Notes [25] - Phase 2 participants who received venetoclax and had active disease at baseline and available data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Phase 1: Overall Response Rate [26] | ||||||||||||
End point 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.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
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
|
||||||||||||
| Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This efficacy endpoint was pre-specified as secondary for Phase 1 |
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|
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| Notes [27] - All enrolled Phase 1 participants who had active disease at baseline and received venetoclax [28] - All enrolled Phase 1 participants who had active disease at baseline and received venetoclax |
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Time to Response (TTR) | ||||||||||||||||
End point 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. 99999 in the table below denotes a value that is not estimable/calculable due to low number of participants with events.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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
|
||||||||||||||||
|
|||||||||||||||||
| Notes [29] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) [30] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) [31] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Time to Progression (TTP) | ||||||||||||||||
End point 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Estimated median duration of follow-up was 8.1 months for Phase 1 and 31.7 months for Phase 2
|
||||||||||||||||
|
|||||||||||||||||
| Notes [32] - All enrolled participants who received venetoclax [33] - All enrolled participants who received venetoclax |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||||||
End point title |
Duration of Response | ||||||||||||||||
End point 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
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
|
||||||||||||||||
|
|||||||||||||||||
| Notes [34] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) [35] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) [36] - Subjects who rcvd venetoclax, had active disease at baseline, and achieved a response (PR or better) |
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||
End point title |
Phase 2: Progression-Free Survival (PFS) [37] | ||||||||
End point 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Estimated median duration of follow-up was 31.7 months
|
||||||||
| Notes [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only. |
|||||||||
|
|||||||||
| Notes [38] - Phase 2 participants who received venetoclax and had active disease at baseline and available data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Phase 2: Overall Survival (OS) [39] | ||||||||
End point 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.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Estimated median duration of follow-up was 31.7 months
|
||||||||
| Notes [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only |
|||||||||
|
|||||||||
| Notes [40] - Phase 2 participants who received venetoclax and had active disease at baseline and available data |
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||||||||||||||||||||
End point title |
Phase 2: Mean Change From Baseline in Brief Pain Inventory - Short Form (BPI-SF) Worst Pain [41] | ||||||||||||||||||||||||||||||||||
End point 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.
In the table below, 99999 indicates standard deviation not calculable/estimable due to n=1 subject at Cycle 25, Day 1.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||
| Notes [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
| Notes [42] - Subjects who rcvd ≥ 1 dose of study drug; and have baseline and post-baseline values |
|||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
End point title |
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) [43] | ||||||||||||||||||||||||||||||||||
End point 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.
In the table below, 99999 indicates standard deviation not calculable/estimable due to n=1 subject at Cycle 25, Day 1.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||
| Notes [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
| Notes [44] - Subjects who rcvd ≥ 1 dose of study drug; and have baseline and post-baseline values |
|||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
End point title |
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) [45] | ||||||||||||||||||||||||||||||||||
End point 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.
In the table below, 99999 indicates standard deviation not calculable/estimable due to n=1 subject at Cycle 25, Day 1.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||
| Notes [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
| Notes [46] - Subjects who rcvd ≥ 1 dose of study drug; and have baseline and post-baseline values |
|||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
End point title |
Phase 2: Mean Change From Baseline in Patient Reported Outcomes Measurement Information System [PROMIS] Cancer Fatigue Short Form [SF] Score [47] | ||||||||||||||||||||||||||||||||||
End point 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 [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.
In the table below, 99999 indicates standard deviation not calculable/estimable due to n=1 subject at Cycle 25, Day 1.
|
||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||
End point timeframe |
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
|
||||||||||||||||||||||||||||||||||
| Notes [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: This endpoint was pre-specified for Phase 2 only. |
|||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||
| Notes [48] - Subjects who rcvd ≥ 1 dose of study drug; and have baseline and post-baseline values |
|||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
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Timeframe for reporting adverse events |
All-cause mortality is reported from enrollment to 30 days after the last dose of study drug; the median time on follow up was 8.1 months for Phase 1 and 31.7 months for Phase 2.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
TEAEs and SAEs were collected from first dose of study drug until 30 days after last dose of study drug; mean duration on study drug was 279.8 days (MonoVen) and 400.0 days (VenDex) in Phase 1 and 240.3 days in Phase 2 (VenDex).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.1
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Reporting groups
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Reporting group title |
Phase 1: Venetoclax Dose Escalation/Safety Expansion Cohorts
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Reporting group description |
Participants in the dose-escalation cohort received daily venetoclax at a designated dose (i.e., 300, 600, 900, or 1200 mg) on Days 1 -21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with progressive disease (PD) may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥75 years) on Days 1, 8, and 15 of each 21-day cycle. Those who completed at least 2 cycles at their designated cohort dose (or current dose) may have progressively escalated their dose to the highest cleared venetoclax dose level or any dose below. Participants in the safety expansion cohort received daily venetoclax at the maximum administered dose (i.e., 1200 mg) on Days 1 - 21 of each cycle after a 2-week lead-in period, in which venetoclax doses were increased weekly. Those with PD may also have received oral dexamethasone starting at 40 mg (20 mg for those aged ≥ 75 years) on Days 1, 8, and 15 of each 21-day cycle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 1: Venetoclax-Dexamethasone Combination
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Reporting group 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Phase 2: Venetoclax-Dexamethasone Combination Expansion
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Reporting group 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). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Nov 2012 |
Protocol Amendment 1
● Changed Sponsor from Abbott Laboratories to AbbVie
● Increased maximum dose of ABT-199 from 600 mg/day to 1200 mg/day
● Clarified that if at least 1 subject in a dose escalation cohort experiences a DLT, that cohort may enroll up to 6 subjects and cohort size may be expanded beyond 6 at discretion of AbbVie medical monitor
● Extended option for subjects receiving clinical benefit from dosing with ABT-199 for treatment for up to 2 yrs following enrollment of last subject into study
● Exclusion Criterion 5 changed to only reflect exclusion of HIV-positive subjects
● Allowed subjects with serologic evidence of prior vaccination to hepatitis B (HBV) and without evidence of chronic hepatitis B infection to enroll in the study
● Excluded potent CYP3A inducers
● Excluded subjects from receiving live vaccines within 60 days of study entry
● Added lymphocyte enumerations; updated timeframe for completion of all Screening procedures except Skeletal Survey to within 21 days of first dose of ABT-199; clarified expectations for chemistry and hematology sampling for TLS prophylaxis and monitoring; updated assays included as part of Viral Serologies and Viral Polymerase Chain Reaction (PCR) testing; added long bones (i.e., tibiae, fibulae, tibiae, ulnae, radii) to skeletal survey; removed Cytogenetics/FISH sample collection at confirmation of CR/sCR timepoint; added requirement for ABT-199 pharmacokinetic samples to be drawn at time of TLS event and 24 hours TLS event
● Clarified that worsening of an adverse event is to be recorded as a new adverse event
● Added allowance for implementation of a drug interruption for up to 72 hours for transient (< 48 hrs) chemical changes and laboratory TLS
● Changed size of Safety Expansion Cohort to approximately 12
● Added Cairo-Bishop Tumor Lysis Syndrome Definition and Grading for definition of laboratory and clinical TLS
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22 Mar 2013 |
Protocol Amendment 2
● Updated protocol with the most current information released in Investigator's Brochure Edition 4
● Inclusion Criteria: added requirement for AbbVie medical monitor approval for subjects at high TLS risk
● Exclusion Criteria: clarified time frame for significant medical history; updated time frame for prior use of monoclonal antibodies for anti-neoplastic intent from 30 days to 8 weeks prior to the first dose of study drug
● Clarified TLS management time points; adjusted pharmacokinetic blood collection time points
● Updated vital signs, chemistry and hematology to align with new TLS prophylaxis and management; replaced use of central laboratory with local laboratory for all testing except IMWG, viral PCR and viral serologies; reduced time points for reticulocyte counts
● Removed hepatitis B, C, and D testing from viral PCR assay
● Updated sample collection for ABT-199 Assay to reflect additional 8 hour post-dose timepoints at Lead-in Days 1 and 8, Cycle 1 Day 1 and optional collections for Intrasubject Dose Escalation
● Updated Adverse Events to include reporting laboratory abnormalities that meet one criterion within the Cairo-Bishop criteria for TLS (after a first dose or escalation dose) as an AE (or SAE) and instructions for documenting these laboratory abnormalities on the appropriate
● Updated expectations for subjects regarding contraceptive use and requested data collection for partners of study subjects that become pregnant during the study
● Clarified requirements for dose reductions following TLS; updated Management of Tumor Lysis Syndrome to reflect more stringent procedures for high-risk subjects, and revise procedures for other subjects to further mitigate the risk of TLS
● Added Appendix G, Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) in Multiple Myeloma Subjects
● Revised Appendix F Cairo-Bishop Tumor Lysis Syndrome Definition and Grading
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03 Mar 2014 |
Protocol Amendment 3
● Allowed for use of low-dose (20 mg) weekly dexamethasone in the presence of progressive disease while on ABT-199 monotherapy
● Revised number of subjects to be enrolled in the safety expansion cohort to 36, and increased number of sites to approximately 11
● Inclusion Criteria: allowed for enrollment of subjects with a history of allogenic stem cell transplant; removed explicit percentage of disease infiltrate in the bone marrow; revised platelet count down to 30,000/mm3 for entry
● Exclusion Criterion 3: Added statement that, for subjects who have required an intervention for a condition within the significant history items noted within the previous 6 months, a discussion between the investigator and AbbVie medical monitor must occur.
● Added detailed uric acid analysis procedure for subjects taking rasburicase
● Updated windows for Screening procedures to reflect "approximately" 3 months for skeletal survey and "approximately" 21 days or 3 weeks for all other procedures
● Updated window for completion of testing for IMWG assessments to approximately 1 week prior to the scheduled assessment to facilitate result availability during the subject's scheduled visit
● Added allowance for consideration of direct thrombin inhibitors in lieu of warfarin to allow for use of newer anticoagulation therapies within this subject population
● Revised pharmacodynamic testing: added minimal residual disease (MRD) testing for all subjects at Screening, confirmation of CR or sCR, and relapse time points to determine residual disease present in the bone marrow
● Clarified that AbbVie does not allow intentional/prospective protocol deviations
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01 Dec 2014 |
Protocol Amendment 4
● Updated the tumor lysis syndrome (TLS) prophylaxis guidelines in recognition that no clinical or laboratory incidences of TLS had been observed in this study
● Revised number of subjects to be enrolled in the dose escalation phase to account for increased subject enrollment in earlier cohorts
● Clarified that subjects enrolled in the safety expansion cohort will receive the recommended Phase 2 dose and added information to state how the RPTD was determined
● Removed requirement for "< 4 separate lines of therapy" during safety expansion phase enrollment; clarified that subjects may receive blood transfusions to meet hemoglobin eligibility; clarified collection period for subject's medical history, reporting of serious adverse events relative to the time the informed consent is signed; and criteria when a laboratory test value should be considered an adverse event
● Clarified criteria for Grade 3 and Grade 4 adverse events; clarified expected adverse events due to disease; and clarified adverse event collection period
● Updated statistical rationale for number of subjects expected to be enrolled in the safety expansion cohort
● Added the Howard definition of laboratory tumor lysis syndrome to further clarify criteria for defining TLS as provided by the Cairo-Bishop definition
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23 Apr 2016 |
Protocol Amendment 5
● Added venetoclax-dexamethasone combination portion to investigate venetoclax with dexamethasone treatment in 18 subjects with t(11;14)-positive multiple myeloma
● Updated dexamethasone dose from 20 mg to 40 mg and classification of dexamethasone as Investigational Product for subjects who enroll in venetoclax-dexamethasone combination portion
● Updated pharmacodynamic and pharmacogenetic terminology with standardized biomarker and exploratory language
● Added minimal residual disease (MRD) collection at Cycle 5, Day 1 and updated sampling collection volume
● Updated drug-drug interaction (DDI) information for venetoclax and provide additional guidance for concomitant medications and allowed treatments
● Updated guidance for dose modifications based on updated DDI information for venetoclax and for general treatment
● Clarified hepatitis eligibility and eliminate redundancy
● Clarified that intrasubject dose escalation only applies to subjects enrolled to the dose escalation portion
● Clarified bone marrow biopsy collection to confirm complete response or stringent complete response
● Clarified assessments that are not sufficient to determine progressive disease
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05 Oct 2017 |
Protocol Amendment 6
● Updated protocol to reflect expansion of the study based on preliminary efficacy data from the VenDex combination cohort for a Phase 2 portion to investigate overall response rate and very good partial response or better rate of venetoclax with dexamethasone treatment in approximately 80 subjects with t(11;14)-positive multiple myeloma
● Revised Inclusion and Exclusion Criteria to align with venetoclax MM program
● Clarified timing of prior and concomitant medication use
● Updated drug-drug interaction (DDI) information for venetoclax and guidance for concomitant medications and allowed treatments
● Clarified sample collection based on subject cohort
● Included IMWG 2016 response criteria for Phase 2 cohort subjects to be assessed based on the most recent response criteria available
● Clarified IMWG response assessments are to be based on central laboratory results and specify an independent review committee will be utilized for Phase 2 subjects
● Specified dosing instructions and investigational product for the Phase 2 cohort.
● Specified subject population for VenDex combination and Phase 2 cohorts
● Provided rationale for the 800 mg selected venetoclax dose
● Specified hospitalizations after study discontinuation for subsequent line of therapy will not be recorded as a serious adverse event, and reporting of cytopenias as adverse events
● Specified medical outcome for either mother or infant, meeting any serious criteria is considered a serious adverse event
● Revised dosing information sections to be consistent with venetoclax MM program guidance
● Updated Appendix F to remove Cairo-Bishop Criteria for Tumor Lysis Syndrome
● Corrected error in Appendix G, Recommendations for Initial Management of Electrolyte Imbalances and Prevention of Tumor Lysis Syndrome (TLS) in Multiple Myeloma Subjects
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11 Jan 2018 |
Protocol Amendment 7
● Added patient reported outcomes (PRO) to the Phase 2 portion to measure quality indicators throughout study
● Revised Inclusion Criteria 3, noting that Phase 2 subjects must have been treated with prior daratumumab combination therapies
● Increased bone marrow aspirate volume collection and prioritization for BCL-2 analysis
● Provided additional guidance for TLS management for subjects considered high risk
● Updated TLS management guidelines in accordance with current venetoclax and therapeutic specific guidelines
● Specified Phase 2 subgroup analysis and clarified Phase 1 portion of the study is dose escalation
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30 May 2018 |
Protocol Amendment 8
● Clarified that the study is sponsored by AbbVie in collaboration with Roche/Genentech
● Updated to reflect an increase number of Phase 2 subjects from 80 to approximately 80 to 100, and total number of subjects from 166 to approximately 166 to 186
● Clarified inclusion criteria to allow subjects with two prior lines of therapy and to allow non US subjects who have been treated with Daratumumab monotherapy to be eligible and to require central laboratory confirming t11;14 status to be eligible
● Revised priority sampling of bone marrow aspirate sample
● Added informed consent as a study activity and allowed for subject visits to be scheduled within 4 days due to operational or logistical reasons
● Updated the information in the most current investigator brochure
● Clarified benefit and risk associated with venetoclax and dexamethasone
● Corrected sample volume to align with standardized tube size available for collection
● Clarified skeletal survey results must be obtained within < 30 days prior to planned first dose, to remove reference to legally acceptable representative, and to remove secondary malignancies as part of overall survival information
● Clarified that dexamethasone should be protected from moisture
● Removed limitation of 48 months for treatment duration based on updated information
● Clarified that events with an outcome of death will be included in progression-free survival
● Ensured consistent use of statistical terms and to clarified determination of sample size effect on primary efficacy Phase 2 endpoints
● Revised Appendix G to correct an error
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15 Mar 2019 |
Protocol Amendment 9
● Provided guidance to reduce the risk of serious infections in patients treated with venetoclax, to align with similar recommendations made due to findings on a recent Phase III combination study (Study M14-031)
● Updated Exclusion Criterion 1 to exclude subjects with acute infection, regardless of therapy required, within 14 days of first dose
● Updated clinical and safety data per the most recent investigator brochure
● Clarified that the tympanic method for body temperature is acceptable
● Updated guidance in cases of vomiting with current venetoclax safety risk language
● Clarified that the number of deaths summarized was to include all deaths in this study regardless of the number of days after the last dose of study drug
● Corrected timing of screening skeletal survey in line with schedule of assessments
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24 Sep 2019 |
Protocol Amendment 10
● Modified guidance to study procedures to reflect Sponsor decision to stop enrolling subjects in the study
● Added information about the use of and the timing for prophylactic antibiotics and recommendations for the administration of intravenous immunoglobulin (IVIG)
● Added the requirement of pneumococcal and influenza vaccinations
● Added text clarifying allowable corticosteroid use while on study treatment
● Clarified IMWG assessments, bone marrow collections, and overall survival assessments
● Updated Adverse Event Collection Period to include any additional relevant clinical information leading to a death in survival is to be reported on the appropriate eCRF for Phase 2 subjects during the follow up period and to specify TLS as an adverse event of special interest.
● Added information about the new Safety Review Committee
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03 Nov 2020 |
Protocol Amendment 11
● Updated Pretreatment Guidance for required pneumococcal and influenza vaccinations
● Updated Excluded and Cautionary Medications to add excluded food
● Updated to Overall Survival assessments to provide a ± 2-week window time frame for the 12 week Overall Survival Follow Up assessment intervals
● Update to Pregnancy testing to define classification of not of childbearing potential female subjects
● Added Non-Treatment Emergent Death Collection details
● Updated to Study Procedures-Pro Assessments to discontinue further PRO assessment collections with Amendment 10
● Updated Discontinuation of Individual Subjects to explain that study staff may still use available public records to obtain information about survival status only, as appropriate per local regulations
● Updated Subject Information and Consent to reflect expected informed consent process to collect pharmacogenetic testing's and updated proceedings if subject withdraws consent
● Update to Source Documents to reflect Investigator responsibilities and conduct of clinical monitoring.
● Discontinued further Cytogenetics/FISH, Immunophenotyping and Translational Research collection at Final Visit
● Added SARS-CoV-2 test at any timepoint if clinically indicated per Investigator's discretion.
● Incorporated protocol modifications due to the COVID-19 pandemic to incorporate interruption/discontinuation of study drug due to confirmed or suspected COVID-19 Infection guidance
• Noted that remote monitoring may be employed if allowed by the local regulatory authority, IRB/IEC, and the study site
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17 Feb 2021 |
Protocol Amendment 12
• Updated to clarify subjects will continue on treatment until the end of study provided they continue to tolerate venetoclax, have no evidence of disease progression, and do not meet any criteria for subject discontinuation
• Updated to clarify that the end of study is defined as the date of the last subject's last visit, including Safety Follow Up
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
