A Study Evaluating ABT-199 in Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Standard Therapy

A Phase 1b Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Relapsed or Refractory Multiple Myeloma Subjects Who Are Receiving Bortezomib and Dexamethasone as Their Standard Therapy

The primary objectives of this study are to assess the safety profile, characterize pharmacokinetics (PK) and determine the dosing schedule, maximum tolerated dose (MTD), and the recommended phase two dose (RPTD) of ABT-199 when administered in subjects with relapsed /refactory multiple myeloma who are receiving bortezomib and dexamethasone as their standard therapy.

Study Overview

• Status: Completed
• Conditions: Relapsed/Refractory Multiple Myeloma
• Intervention / Treatment: Drug: ABT-199; Drug: bortezomib; Drug: dexamethasone

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Ctr /ID# 79553
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital /ID# 79533
• France
  • Nantes, France, 44093
    • CHU de Nantes, Hotel Dieu -HME /ID# 78773
  • Hauts-de-France
    • Lille CEDEX, Hauts-de-France, France, 59045
      • CHRU Lille - Hôpital Claude Huriez /ID# 77234
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719-1478
      • University of Arizona Cancer Center - North Campus /ID# 117876
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic /ID# 121495
  • Illinois
    • Chicago, Illinois, United States, 60611-2927
      • Northwestern University Feinberg School of Medicine /ID# 117477
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Hospitals /ID# 80353
  • Minnesota
    • Rochester, Minnesota, United States, 55905-0001
      • Mayo Clinic - Rochester /ID# 77235

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance score less than or equal to 1
• Diagnosis of multiple myeloma previously treated with at least 1 prior line of therapy (dose escalation only) or (safety expansion only) received treatment with a proteasome inhibitor or an IMiD(r) or immunomodulatory agent (e.g., thalidomide, lenalidomide). Induction therapy and following stem cell transplant are considered a single line of therapy.
• Measurable disease at Screening: Serum monoclonal protein greater than or equal to 1 g/dL by protein electrophoresis, or greater than or equal to 200 mg monoclonal protein in the urine on 24-hr electrophoresis, or serum immunoglobulin free light chain greater than or equal to 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio.
• Subjects with a history of autologous or allogenic stem cell transplant must have adequate bone marrow independent of any growth factor support, and have recovered from any transplant related toxicity(s); and either greater than 100 days post-autologous transplant (prior to first dose of study drug) or greater than or equal to 6 months post-allogenic transplant (prior to first dose of study drug) and not have active graft-versus-host disease (i.e., requiring treatment).
• Subject must have adequate coagulation, renal, and hepatic function, per laboratory reference range at Screening.

Exclusion Criteria:

• Exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to: uncontrolled systemic infection (viral, bacterial, or fungal), diagnosis of fever and neutropenia within 1 week prior to first dose of study drug
• Cardiovascular disability status of New York Heart Association Class greater than or equal to 2. Class 2 is defined as cardiac disease in which patients are comfortable at rest but ordinary physical activity results in fatigue, palpitations, dyspnea or anginal pain.
• Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, pulmonary or hepatic disease, 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, previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
• Tested positive for HIV or hepatitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ABT-199 + BTZ/Dex Dose Escalation Cohorts; Evaluate the safety and pharmacokinetics profile of ABT-199 administered with standard therapy bortezomib and dexamethasone in a dose escalation scheme in approximately 54 subjects.	Drug: ABT-199; ABT-199 at cohort-defined dosing schedules and dose levels. ABT-199 at defined dose and schedule for Safety Expansion cohort; Drug: bortezomib; Bortezomib at cohort-defined dosing schedules and dose levels. Bortezomib at defined dose and schedule for Safety Expansion cohort; Drug: dexamethasone; Dexamethasone at cohort-defined dosing schedules and dose levels. Dexamethasone at defined dose and schedule for Safety Expansion cohort.
Experimental: ABT-199 + BTZ/Dex Safety Expansion Cohort; Safety expansion cohort to further evaluate recommended phase two dose (RPTD) of ABT-199 administered with standard therapy bortezomib and dexamethasone in approximately 12 subjects.	Drug: ABT-199; ABT-199 at cohort-defined dosing schedules and dose levels. ABT-199 at defined dose and schedule for Safety Expansion cohort; Drug: bortezomib; Bortezomib at cohort-defined dosing schedules and dose levels. Bortezomib at defined dose and schedule for Safety Expansion cohort; Drug: dexamethasone; Dexamethasone at cohort-defined dosing schedules and dose levels. Dexamethasone at defined dose and schedule for Safety Expansion cohort.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determination of peak concentration (Cmax) of ABT-199	Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints	Approximately 5 days in Cycle 1 then on Day 1 of Cycles 2,4,6,8
Determine maximum tolerated dose (MTD), and recommended phase two dose (RPTD) of ABT-199	ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicities information from all subjects.	Minimum first cycle of dosing (21 days)
Number of participants with adverse events	Collect all adverse events at each visit.	From subject's first dose of ABT-199 until 30 days after subject's last dose of ABT-199; up to 2 years following last subject first dose.
Determination of trough concentration (Ctrough) of ABT-199	Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints	Approximately 5 days in Cycle 1 then on Day 1 of Cycles 2,4,6,8
Determination of area under the concentration versus time curve (AUC) of ABT-199	Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints	Approximately 5 days in Cycle 1 then on Day 1 of Cycles 2,4,6,8
Determine recommended phase two dose (RPTD) of ABT-199	ABT-199 will be dose-escalated until the largest dose is reached that is determined to be safe based on adverse event reporting and dose-limiting toxicities information from all subjects.	Minimum first cycle of dosing (21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response	Number of days from the day of initial response is objectively documented to the day that disease progression is objectively documented	Measured up to 48 months after the last subject has enrolled in the study
Objective Response Rate	The proportion of subjects with response using International Myeloma Working Group (IMWG) response criteria will be computed for all subjects with active disease at baseline (in the opinion of the investigator)	Measured up to 48 months after the last subject has enrolled in the study
Time to Disease Progression	Number of days from the date of the first dose of ABT-199 to the date of the subject's disease progression.	Measured up to 48 months after the last subject has enrolled in the study

Collaborators and Investigators

• Sponsor: AbbVie
• Collaborators: Genentech, Inc.

Publications and helpful links

General Publications

• Moreau P, Chanan-Khan A, Roberts AW, Agarwal AB, Facon T, Kumar S, Touzeau C, Punnoose EA, Cordero J, Munasinghe W, Jia J, Salem AH, Freise KJ, Leverson JD, Enschede SH, Ross JA, Maciag PC, Verdugo M, Harrison SJ. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017 Nov 30;130(22):2392-2400. doi: 10.1182/blood-2017-06-788323. Epub 2017 Aug 28.
• Matulis SM, Gupta VA, Nooka AK, Hollen HV, Kaufman JL, Lonial S, Boise LH. Dexamethasone treatment promotes Bcl-2 dependence in multiple myeloma resulting in sensitivity to venetoclax. Leukemia. 2016 May;30(5):1086-93. doi: 10.1038/leu.2015.350. Epub 2015 Dec 28.

Study record dates

Study Major Dates

• Study Start (Actual): November 19, 2012
• Primary Completion (Actual): July 16, 2019
• Study Completion (Actual): July 16, 2019

Study Registration Dates

• First Submitted: December 13, 2012
• First Submitted That Met QC Criteria: February 15, 2013
• First Posted (Estimate): February 20, 2013

Study Record Updates

• Last Update Posted (Actual): August 2, 2021
• Last Update Submitted That Met QC Criteria: July 29, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: multiple myeloma; refractory multiple myeloma; relapsed multiple myeloma; relapsed/refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Venetoclax; Bortezomib
• Other Study ID Numbers: M12-901; 2011-004626-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No