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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Relapsed/Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: ABT-199
* Drug: bortezomib
* Drug: dexamethasone


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABT-199 + BTZ/Dex Dose Escalation Cohorts<br>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<br>* ABT-199 at cohort-defined dosing schedules and dose levels. ABT-199 at defined dose and schedule for Safety Expansion cohort<br>Drug: bortezomib<br>* Bortezomib at cohort-defined dosing schedules and dose levels. Bortezomib at defined dose and schedule for Safety Expansion cohort<br>Drug: dexamethasone<br>* Dexamethasone at cohort-defined dosing schedules and dose levels. Dexamethasone at defined dose and schedule for Safety Expansion cohort.<br>|
| Experimental: ABT-199 + BTZ/Dex Safety Expansion Cohort<br>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<br>* ABT-199 at cohort-defined dosing schedules and dose levels. ABT-199 at defined dose and schedule for Safety Expansion cohort<br>Drug: bortezomib<br>* Bortezomib at cohort-defined dosing schedules and dose levels. Bortezomib at defined dose and schedule for Safety Expansion cohort<br>Drug: dexamethasone<br>* Dexamethasone at cohort-defined dosing schedules and dose levels. Dexamethasone at defined dose and schedule for Safety Expansion cohort.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed/refractory multiple myeloma, relapsed multiple myeloma, refractory multiple myeloma, multiple myeloma