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

Multiple Myeloma Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03314181
• Other study ID #: M15-654
• Secondary ID: 2017-002099-26
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: April 2, 2018
• Est. completion date: August 28, 2025

Study information

• Verified date: February 2023
• Source: AbbVie
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 3 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); Part 3 includes participants with t(11;14) positive R/R multiple myeloma who will receive venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd). Part 1 and Part 2 are non-randomized and 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. Part 3 will include a randomized, open-label expansion phase with participants receiving venetoclax in combination with daratumumab and dexamethasone (VenDd) or daratumumab, bortezomib, and dexamethasone (DVd).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 156
• Est. completion date: August 28, 2025
• Est. primary completion date: August 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.
• Bone marrow aspirate samples have been collected.
• To qualify for Part 1 and 3, 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
• For participants in Parts 1 and 2: Previous treatment with daratumumab or other anti-CD38 therapy. For participants in Part 3: Prior daratumumab or other anti-CD38

antibody therapy exposure that meets ANY of the following criteria:

• Failure to achieve at least a PR to most recent therapy with daratumumab or other anti-CD38 therapy.
• Daratumumab or other anti-CD38 antibody therapy was discontinued due to toxicity.
• Relapse within 60 days of intensive treatment (at least every other week) of daratumumab or other anti-CD38 antibody therapy.
• Prior treatment with daratumumab or other anti-CD38 antibody within 6 months prior to first dose of study drug.
• For participants in Part 2 and 3:
• 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.
• 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 to first dose.
• Recent corticosteroid therapy at a cumulative dose equivalent to >= 140 mg of prednisone, cumulative dose equivalent to >= 40 mg of dexamethasone, or a single dose equivalent to >= 40 mg of dexamethasone within 2 weeks prior the first dose of study drug.
• Known central nervous system involvement of multiple myeloma.
• Significant history of medical conditions as listed in the protocol.
• History of other active malignancies including myelodysplatic syndromes (MDS) within

the past 3 years with the exceptions of:

• Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin.
• Prostate cancer Gleason grade 6 or lower AND with stable Prostate Specific Antigen (PSA) levels off treatment
• Previous malignancy with no evidence of disease confirmed and surgically resected (or treated with other modalities) with curative intent and unlikely to impact survival during the duration of the study.
• Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
• Has a hypersensitivity or allergy to any of the components of study therapy, excipient or boron.
• Known allergies, hypersensitivities, or intolerance to monoclonal antibodies or human proteins, or their excipients, or known sensitivity to mammalian-derived products (see daratumumab prescribing information).

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Drug:
• Dexamethasone
Infusion; Intravenous (IV), or Tablet; Oral
• Daratumumab
Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
• Venetoclax
Tablet; Oral
• Bortezomib
Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital /ID# 171060	Adelaide	South Australia
Australia	Eastern Health /ID# 165850	Box Hill	Victoria
Australia	The Kinghorn Cancer Centre /ID# 165431	Darlinghurst	New South Wales
Australia	St Vincent's Hospital Melbourne /ID# 165853	Fitzroy Melbourne	Victoria
Australia	St George Hospital /ID# 171063	Kogarah	New South Wales
Australia	Peter MacCallum Cancer Ctr /ID# 164742	Melbourne	Victoria
Australia	Royal Perth Hospital /ID# 224895	Perth	Western Australia
Canada	Tom Baker Cancer Centre /ID# 167822	Calgary	Alberta
Canada	Cross Cancer Institute /ID# 203114	Edmonton	Alberta
Canada	Royal Victoria Hospital / McGill University Health Centre /ID# 167824	Montreal	Quebec
Denmark	Aarhus University Hospital /ID# 164509	Aarhus N	Midtjylland
Denmark	Rigshospitalet /ID# 164420	Copenhagen Ø	Hovedstaden
Denmark	Odense University Hospital /ID# 164417	Odense C	Syddanmark
Denmark	Sygehus Lillebælt, Vejle /ID# 164418	Vejle	Syddanmark
France	CHU Limoges - Dupuytren 1 /ID# 224759	Limoges CEDEX 1	Franche-Comte
France	CHU de Nantes, Hotel Dieu -HME /ID# 164767	Nantes	Pays-de-la-Loire
France	AP-HP - Hopital Saint-Louis /ID# 224758	Paris
France	CHU Poitiers - La milétrie /ID# 164806	Poitiers	Poitou-Charentes
France	CHRU Tours - Hopital Bretonneau /ID# 164795	Tours CEDEX 9	Indre-et-Loire
France	Institut Gustave Roussy /ID# 164807	Villejuif Cedex	Val-de-Marne
Germany	University Hospital Cologne /ID# 166037	Cologne
Germany	Universitaetsklinikum Freiburg /ID# 166036	Freiburg	Baden-Wuerttemberg
Japan	Gifu Municipal Hospital /ID# 240381	Gifu-shi	Gifu
Japan	Kameda General Hospital /ID# 225246	Kamogawa-shi	Chiba
Japan	Matsuyama Red Cross Hospital /ID# 225196	Matsuyama-shi	Ehime
Japan	Nagoya City University Hospital /ID# 225273	Nagoya shi	Aichi
United States	Emory University, Winship Cancer Institute /ID# 165427	Atlanta	Georgia
United States	Univ of Colorado Cancer Center /ID# 167331	Aurora	Colorado
United States	Beth Israel Deaconess Medical Center /ID# 210904	Boston	Massachusetts
United States	Dana-Farber Cancer Institute /ID# 166886	Boston	Massachusetts
United States	Roswell Park Comprehensive Cancer Center /ID# 169615	Buffalo	New York
United States	Atrium Health Carolinas Medical Center /ID# 164948	Charlotte	North Carolina
United States	The University of Chicago Medical Center /ID# 165429	Chicago	Illinois
United States	Duke Cancer Center /ID# 165104	Durham	North Carolina
United States	Hackensack Univ Med Ctr /ID# 225111	Hackensack	New Jersey
United States	Weill Cornell Medicine/NYP /ID# 167605	New York	New York
United States	Oregon Health & Science University /ID# 166822	Portland	Oregon
United States	University of Washington /ID# 164884	Seattle	Washington
United States	Moffitt Cancer Center /ID# 169614	Tampa	Florida
United States	Wake Forest Baptist Health /ID# 224447	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
AbbVie	Janssen Research & Development, LLC

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Denmark,  France,  Germany,  Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR)	ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Very Good Partial Response or Better Response Rate (VGPR)	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.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Complete Response (CR) or Better Rate	CR or better response is defined as the percentage of participants with documented response of CR or better (stringent complete response [sCR] or CR) based on IMWG criteria.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Time to Response (TTR)	TTR is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented response of PR or better.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Duration of Response (DOR)	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.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Time to Progression (TTP)	TTP is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of first documented PD or death due to MM, whichever occurs first.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Progression-Free Survival (PFS)	PFS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of the first documented PD or death due to any cause, whichever occurs first.	Up to approximately 3.5 years after the last participant is enrolled
Primary	Overall Survival (OS)	OS is defined as the number of days from the date of treatment start (for subjects enrolled prior to randomization start) or randomization (for randomized subjects) to the date of death.	Up to approximately 3.5 years after the last participant is enrolled
Secondary	Minimal Residual Disease (MRD)	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.	Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)
Secondary	Cmax of Venetoclax	Maximum observed plasma concentration (Cmax) of venetoclax	Up to approximately 1 year
Secondary	Tmax of Venetoclax	Time to Cmax (Tmax) of Venetoclax	Up to approximately 1 year
Secondary	AUC0-24 of Venetoclax	Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.	Up to approximately 1 year

External Links

•   This clinical study may be evaluating a usage that is not currently FDA approved. Please see US Prescribing Information for approved uses.