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

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ClinicalTrials.gov Identifier: NCT01794520
Recruitment Status : Active, not recruiting
First Posted : February 20, 2013
Last Update Posted : August 26, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
AbbVie

Brief Summary:

The phase 1 primary objectives of this study are 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 subjects with relapsed or refractory multiple myeloma. This study will also assess the safety profile and PK of venetoclax in combination with dexamethasone in subjects with t(11;14)-positive multiple myeloma.

The phase 2 primary objective is to further evaluate the objective response rate (ORR) and very good partial response or better rate (VGPR+) in subjects with t(11;14)-positive multiple myeloma.


Condition or disease Intervention/treatment Phase
Relapsed/Refractory Multiple Myeloma Drug: Dexamethasone Drug: ABT-199 Phase 1 Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 117 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study Evaluating the Safety and Pharmacokinetics of ABT-199 in Subjects With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : October 10, 2012
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021


Arm Intervention/treatment
Experimental: ABT-199 Safety Expansion Cohort Drug: ABT-199
ABT-199 dosed at cohort-defined dosing schedules

Experimental: Phase 2 Cohort
Venetoclax-Dexamethasone Combination Expansion
Drug: ABT-199
ABT-199 dosed at cohort-defined dosing schedules

Experimental: Venetoclax-Dexamethasone Combination Drug: Dexamethasone
Dexamethasone at defined dose and schedule for Venetoclax-Dexamethasone combination cohort.

Drug: ABT-199
ABT-199 dosed at cohort-defined dosing schedules

Experimental: ABT-199 Dose Escalation Cohorts Drug: ABT-199
ABT-199 dosed at cohort-defined dosing schedules




Primary Outcome Measures :
  1. Determination of peak concentration (Cmax) of ABT-199 [ Time Frame: Dose Escalation:Lead-in Day 1 & 8,Cycle 2 Day 2, Day 1 of Cycle 1, 3, 5, 7 & 9; 5 times on Cycle 2 Day 1. Safety Expansion:Lead-in Day 1 & 8, Day 1 of Cycle 1, 2, 3, 5, 7 & 9.ABT-199-Dex:once on Day 1 of Cycle 1, 2, 3, 5, 7 & 9. Each cycle is 21 days. ]
    Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints

  2. Calculation of objective response rate [ Time Frame: Up to approximately 48 months from first randomization ]
    The proportion of subjects with documented PR or better response using standard IMWG 2016 response criteria will be determined for all Phase 2 subjects with active disease at baseline by an independent review committee

  3. Determine dose and schedule of ABT-199 [ Time Frame: Minimum first cycle of dosing (21 days) ]
    ABT-199 will be dose escalated until the largest dose is reached that is felt to be safe based on adverse event reporting and dose-limiting toxicities information from all subjects

  4. Number and percentage of subjects with adverse events [ Time Frame: From subject's first dose of ABT-199 until 30 days after the subject's last dose of ABT-199; up to 2 years after last subject's first dose ]
    Collect all adverse events at each visit

  5. Calculation of very good partial response rate or better [ Time Frame: Measured at Day 0, Cycle 2, Day 1 and Day 1 of every cycle thereafter until disease progression. Each cycle is 21 days. ]
    The proportion of subjects with documented VGPR response or better using standard IMWG 2016 criteria will be computed for all Phase 2 subjects with active disease at baseline by an independent review committee.

  6. Determination of trough concentration (Ctrough) of ABT-199 [ Time Frame: Dose Escalation:Lead-in Day 1 & 8,Cycle 2 Day 2, Day 1 of Cycle 1, 3, 5, 7 & 9; 5 times on Cycle 2 Day 1. Safety Expansion:Lead-in Day 1 & 8, Day 1 of Cycle 1, 2, 3, 5, 7 & 9.ABT-199-Dex:once on Day 1 of Cycle 1, 2, 3, 5, 7 & 9. Each cycle is 21 days. ]
    Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints

  7. Determination of area under the concentration versus time curve (AUC) of ABT-199 [ Time Frame: Dose Escalation:Lead-in Day 1 & 8,Cycle 2 Day 2, Day 1 of Cycle 1, 3, 5, 7 & 9; 5 times on Cycle 2 Day 1. Safety Expansion: Lead-in Day 1 & 8, Day 1 of Cycle 1, 2, 3, 5, 7 & 9.ABT-199-Dex:once on Day 1 of Cycle 1, 2, 3, 5, 7 & 9. Each cycle is 21 days. ]
    Blood samples for pharmacokinetic analysis of ABT-199 will be collected at designated timepoints


Secondary Outcome Measures :
  1. Calculation of Objective Response Rate [ Time Frame: Up to approximately 48 months from first randomization ]
    The proportion of Phase 1 subjects with response using IMWG (International Myeloma Working Group) response criteria will be computed for all subjects with active disease at baseline

  2. Calculation of Time to Response (TTR) [ Time Frame: Up to approximately 48 months from first randomization ]
    Number of days from day of initial treatment to the day of initial response is objectively documented.

  3. Calculation of Overall Survival [ Time Frame: Measured at Day 0 and Day 1 of every cycle until date of death documented. Each cycle is 21 days. ]
    Number of days from the date Phase 2 subject is randomized to the date of the subject's death due to any cause.

  4. Calculation of Duration of Response [ Time Frame: Up to approximately 48 months from first randomization ]
    Number of days from the day of initial response is objectively documented to the day that disease progression is objectively documented.

  5. Calculation of time to disease progression [ Time Frame: Up to approximately 48 months from first randomization ]
    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.

  6. Progression Free Survival [ Time Frame: Up to approximately 48 months from first randomization ]
    Number of days from the date of the first dose of study drug to the date of the first documented progressive disease or death due to any cause, whichever occurs first.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • ECOG (Eastern Cooperative Oncology Group) performance score of 1 or 0. Subjects in the Phase 2 portion: ECOG performance score of 2, 1, or 0.
  • Diagnosis of multiple myeloma previously treated with at least one prior line of therapy. Induction therapy followed by stem cell transplant and maintenance therapy will be considered a single line of therapy. For Safety Expansion, subjects must have been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide). For Venetoclax-Dexamethasone Combination, subjects must have been been previously treated with a proteasome inhibitor (e.g., bortezomib) and an immunomodulatory agent (e.g., thalidomide, lenalidomide) AND have t(11;14)-positive multiple myeloma per the central lab testing. For Phase 2, subjects must have MM positive for the t(11;14) translocation, as determined by an analytically validated fluorescence in situ hybridization (FISH) assay per the central laboratory testing (enrollment with local t(11;14)-positive FISH results only will be considered at the discretion of the TA MD) Subjects must have evidence of disease progression on or within 60 days of last dose of most recent previous treatment based on IMWG criteria AND Subject must have previously received at least 2 lines of therapy, including an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib or ixazomib), daratumumab, and glucocorticoids.

    • For US subjects: Daratumumab combination regimen must be one of the prior lines of therapy (for this study, daratumumab plus corticosteroids will not be considered a combination regimen)
    • For Non-US Subjects: Either daratumumab monotherapy or combination therapy is acceptable. Daratumumab monotherapy will be limited to approximately 20 percent of the total number of Phase 2 subjects.
  • Measurable disease at Screening: Serum monoclonal protein of at least 1.0 g/dL (10g/L) by protein electrophoresis or at least 200 mg of monoclonal protein in the urine on 24-hr electrophoresis or serum immunoglobulin free light chain of at least 10 mg/dL and abnormal serum immunoglobulin kappa to lambda free light chain ratio.
  • Subjects with a history of autologous or allogenic stem cell transplantation must have adequate peripheral blood counts independent of any growth factor support, and have recovered from any transplant related toxicity(s) and be at least 100 days post-autologous transplant prior to first dose of study drug or at least 6 months post-allogenic transplant prior to first dose of study drug and not have active graft-versus-host disease (GVHD), i.e., requiring treatment.
  • Meet the following laboratory parameters, per the reference range, at least once during the screening period: ANC of at least 1000/μL (Subjects may use growth factor support to achieve ANC eligibility criteria), AST and ALT not higher than 3 x ULN, Calculated creatinine clearance of at least 30 mL/min using a modified Cockcroft-Gault calculation, platelet count of at least 30,000 mm³ (independent of transfusion for 2 weeks), hemoglobin of at least 8.0 g/dL (subjects may receive blood transfusion to achieve hemoglobin eligibility criteria), and total bilirubin not higher than 1.5 x ULN (subjects with Gilbert's Syndrome may have bilirubin higher 1.5 x ULN).

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 3.
  • Significant history of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular or hepatic disease, within the last 6 months that, in the opinion of the investigator, would adversely affect his/her participation in the study.
  • History of other active malignancies other than multiple myeloma within the past 3 years prior to study entry, with the following exceptions: adequately treated in situ carcinoma of the cervix uteri, basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin, localized prostate cancer Gleason grade 6 or lower AND with stable prostate specific antigen (PSA) levels off treatment, previous malignancy confined and surgically resected (or treated with other modalities) with curative intent.
  • Known HIV infection.
  • Active hepatitis B or C infection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01794520


  Show 32 Study Locations
Sponsors and Collaborators
AbbVie
Genentech, Inc.
Investigators
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Study Director: AbbVie Inc. AbbVie

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT01794520     History of Changes
Other Study ID Numbers: M13-367
2012-000589-38 ( EudraCT Number )
First Posted: February 20, 2013    Key Record Dates
Last Update Posted: August 26, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual and trial-level data (analysis data sets), as well as other information (e.g., protocols and clinical study reports), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Data requests can be submitted at any time and the data will be accessible for 12 months, with possible extensions considered.
Access Criteria: Access to this clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). For more information on the process, or to submit a request, visit the following link.
URL: https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-sharing/data-and-information-sharing-with-qualified-researchers.html

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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
Keywords provided by AbbVie:
relapsed multiple myeloma
refractory multiple myeloma
multiple myeloma
relapsed/refractory multiple myeloma
Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Venetoclax
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Protease Inhibitors