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A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects With Relapsed or Refractory Multiple Myeloma

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ClinicalTrials.gov Identifier: NCT03314181
Recruitment Status : Recruiting
First Posted : October 19, 2017
Last Update Posted : October 9, 2018
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
AbbVie

Brief Summary:

This is a study of venetoclax, daratumumab, and dexamethasone with and without bortezomib combination therapy to evaluate safety, tolerability, and efficacy of these combinations in participants with relapsed or refractory multiple myeloma. The study will consist of 2 distinct parts: Part 1 includes participants with t(11;14) positive relapsed/refractory (R/R) multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd); Part 2 includes participants with R/R multiple myeloma who will receive venetoclax in combination with daratumumab, bortezomib, and dexamethasone (VenDVd).

Each Part will be initiated with a dose-escalation phase in which increasing doses of venetoclax will be given with fixed doses of daratumumab and dexamethasone (Part 1a) or with fixed doses of daratumumab, bortezomib, and dexamethasone (Part 2a). Each dose escalation phase will be followed by a single-arm, open-label expansion phase.


Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Dexamethasone Drug: Daratumumab Drug: Venetoclax Drug: Bortezomib Phase 2

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2, Multicenter, Dose-Escalation and Expansion Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Subjects With Relapsed or Refractory Multiple Myeloma
Actual Study Start Date : March 12, 2018
Estimated Primary Completion Date : November 4, 2020
Estimated Study Completion Date : July 2, 2023


Arm Intervention/treatment
Experimental: Arm B, Part 1b: VenDd Dose Expansion
Venetoclax at a dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (16 mg/kg intravenous [IV]) administered in accordance with prescribing information and dexamethasone (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Drug: Dexamethasone
Oral or intravenous

Drug: Daratumumab
Intravenous

Drug: Venetoclax
Oral
Other Name: ABT-199

Experimental: Arm D, Part 2a: VenDVd Dose Escalation
Venetoclax at various doses administered orally QD in combination with daratumumab (16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection [preferred] or IV) Cycles 1-8, Days 1, 4, 8 and 11), and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.
Drug: Dexamethasone
Oral or intravenous

Drug: Daratumumab
Intravenous

Drug: Venetoclax
Oral
Other Name: ABT-199

Drug: Bortezomib
Subcutaneous (preferred) or intravenous
Other Name: Velcade

Experimental: Arm A, Part 1a: VenDd Dose Escalation
Venetoclax (Ven) various doses administered orally, once daily (QD) in combination with daratumumab (D) (16 mg/kg intravenous [IV]) administered in accordance with prescribing information and dexamethasone (d) (oral or IV) 40 mg weekly (or 20 mg weekly, if necessary, as described in the protocol).
Drug: Dexamethasone
Oral or intravenous

Drug: Daratumumab
Intravenous

Drug: Venetoclax
Oral
Other Name: ABT-199

Experimental: Arm E, Part 2b: VenDVd Dose Expansion
Venetoclax at dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (16 mg/kg IV) administered in accordance with prescribing information, bortezomib (1.3 mg/m2 subcutaneous injection) Cycles 1-8, Days 1, 4, 8 and 11, and dexamethasone (oral or IV) 20 mg Cycles 1 - 3, Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 20 mg Cycles 4-8, Days 1,2,4,5,8,9,11 and 12; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) Cycle 9+.
Drug: Dexamethasone
Oral or intravenous

Drug: Daratumumab
Intravenous

Drug: Venetoclax
Oral
Other Name: ABT-199

Drug: Bortezomib
Subcutaneous (preferred) or intravenous
Other Name: Velcade




Primary Outcome Measures :
  1. Part 1: Objective Response Rate (ORR) [ Time Frame: Up to 3 months ]
    ORR is defined as the proportion of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.

  2. Part 1: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Up to Day 28 ]
    Adverse events occurring following Cycle 1 and evaluated by the Investigator and the sponsor; events that are considered to have a reasonable possibility of relationship to the administration of venetoclax, daratumumab, bortezomib, or dexamethasone, which cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, concurrent illness, or concomitant medication, will be considered a DLT.

  3. Part 2: Number of Participants with Dose Limiting Toxicities (DLT) [ Time Frame: Up to Day 21 ]
    Adverse events occurring following Cycle 1 and evaluated by the Investigator and the sponsor; events that are considered to have a reasonable possibility of relationship to the administration of venetoclax, daratumumab, bortezomib, or dexamethasone, which cannot be attributed by the investigator to a clearly identifiable cause such as disease progression, concurrent illness, or concomitant medication, will be considered a DLT.

  4. Part 2: Complete Response (CR) [ Time Frame: Up to 5 months ]
    CR is defined as the proportion of participants with documented response of CR or better (stringent complete response [sCR] or CR) based on IMWG criteria.

  5. Very Good Partial Response or Better Response Rate (VGPR) [ Time Frame: Up to 5 months ]
    VGPR or better response rate is defined as the proportion of participants with documented VGPR or better (sCR, CR. or VGPR) based on IMWG criteria.


Secondary Outcome Measures :
  1. ORR (Part 2b VenDVd Expansion) [ Time Frame: UP to 3 months ]
    ORR is defined as the proportion of participants with a documented response PR or better based on IMWG.

  2. Trough Concentration (Ctrough) of Daratumumab [ Time Frame: Up to 48 weeks ]
    Observed plasma concentration at trough (Ctrough) of Daratumumab

  3. Cmax of Daratumumab [ Time Frame: Up to 48 weeks ]
    Maximum observed plasma concentration (Cmax) of daratumumab

  4. Time to Progression (TTP) [ Time Frame: Up to 20 months ]
    TTP is defined as the number of days from the date of the first dose of study drug (Arms A,D,E and B) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.

  5. Duration of Response (DOR) [ Time Frame: Up to 20 months ]
    DOR is defined as the number of days from the participant's date of first documented response (PR or better) to the date of first documented disease progression or death due to multiple myeloma, whichever occurs first.

  6. Progression-Free Survival (PFS) [ Time Frame: Up to 2 years ]
    PFS is defined as the number of days from the date of the first dose of study drug (for Arms A,D,E and B) to the date of the first documented disease progression or death due to any cause, whichever occurs first.

  7. Cmax of Venetoclax [ Time Frame: Up to Day 29 ]
    Maximum observed plasma concentration (Cmax) of venetoclax

  8. AUC0-24 of Venetoclax [ Time Frame: Up to Day 29 ]
    Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.

  9. Tmax of Venetoclax [ Time Frame: Up to Day 29 ]
    Time to Cmax (Tmax) of Venetoclax

  10. Minimal Residual Disease (MRD) [ Time Frame: Up to 6 months ]
    MRD negativity in bone marrow aspirates is defined at 10^-5 threshold as assessed by next generation sequencing (NGS) in participants at the time of suspected CR/sCR, and at 6 and 12 months post confirmation of CR/sCR for participants who maintained this response.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) performance status <= 2.
  • Participant has relapsed or refractory multiple myeloma with documented evidence of progression that occurred during or after the participant's last treatment regimen based on investigator's determination of International Myeloma Working Group (IMWG) criteria.
  • Measurable disease confirmed by central lab at Screening, defined by at least 1 of the following:

    • Serum M-Protein >=1.0 g/dL (>=10 g/L), OR
    • Urine M-Protein >= 200 mg/24 hours, OR
    • Serum free light chain (FLC) >= 10 mg/dL, provided serum FLC ratio is abnormal in participants who do not have measurable disease by Serum Protein Electrophoresis (SPEP) or Urine Protein Electrophoresis (UPEP) criteria.
  • Participant has received previous multiple myeloma treatment as defined in the protocol for Part 1 and Part 2 of this study.
  • Bone marrow aspirate samples have been collected.
  • To qualify for Part 1, the participant must be t(11;14) positive as determined by an analytically validated Fluorescent In Situ Hybridization (FISH) assay per central laboratory testing.
  • Participants must have adequate hematologic, renal and hepatic function.

Exclusion Criteria:

  • Previous treatment with venetoclax or other B-Cell Lymphoma 2 (BCL-2) inhibitor OR previous treatment with daratumumab or other anti-CD38 therapy.
  • For participants in Part 2:

    1. Participant is refractory to any proteasome inhibitor, defined as progression on or within 60 days of the last dose of a proteasome inhibitor-containing regimen.
    2. Participant has had prior treatment with proteasome inhibitor within 60 days prior to first dose of study drug.
  • Treatment with anti-myeloma chemotherapy, radiotherapy, biological, immunotherapy or an investigational therapy, including targeted small molecule agents within 2 weeks or 5 half-lives (whichever is longer and/or applicable) before first dose.
  • Treatment with anti-myeloma monoclonal antibodies within 6 weeks prior first dose.
  • Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of prednisone or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior the first dose of study drug.
  • Known meningeal involvement of multiple myeloma.
  • Significant history of medical conditions as listed in the protocol.

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): NCT03314181


Contacts
Contact: ABBVIE CALL CENTER 847.283.8955 abbvieclinicaltrials@abbvie.com

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Sponsors and Collaborators
AbbVie
Janssen Research & Development, LLC
Investigators
Study Director: AbbVie Inc. AbbVie

Additional Information:
Responsible Party: AbbVie
ClinicalTrials.gov Identifier: NCT03314181     History of Changes
Other Study ID Numbers: M15-654
2017-002099-26 ( EudraCT Number )
First Posted: October 19, 2017    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018
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

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:
t(11,14) positive relapsed/refractory (R/R) multiple myeloma
Non-refractory Relapsed Multiple Myeloma
Non-refractory Refractory Multiple Myeloma
Relapsed Multiple Myeloma
Refractory Multiple Myeloma
Multiple Myeloma
Cancer

Additional relevant MeSH terms:
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 acetate
Dexamethasone
Venetoclax
Daratumumab
Bortezomib
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists