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

Sponsor

AbbVie (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03314181

Collaborator

Janssen Research & Development, LLC (Industry)

156

Enrollment

Locations

Arms

88.9

Anticipated Duration (Months)

3.9

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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 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).

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Dexamethasone Drug: Daratumumab Drug: Venetoclax Drug: Bortezomib	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

156 participants

Allocation:

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 :

Apr 2, 2018

Anticipated Primary Completion Date :

Jun 26, 2025

Anticipated Study Completion Date :

Aug 29, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm H: DVd Dose Daratumumab (1800 mg subcutaneous injection (preferred) or 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 on Cycles 1 - 3: Days 1, 2, 4, 5, 8, 9, 11,12 and 15; 40 mg weekly (or 20 mg weekly, if necessary as described in the protocol) on Cycles 4-8: Days 1,2,4,5,8,9,11 and 12; 20 mg monthly for Cycles 9+: Day 1	Drug: Dexamethasone Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
Experimental: Arm G: VenDd Dose Expansion Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta
Experimental: Arm F: VenDd Dose Expansion Venetoclax at a pre-determined dose, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 16 mg/kg 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta
Experimental: Arm E, Part 2b: VenDVd Dose Expansion Venetoclax at dose determined by the dose-escalation phase, administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
Experimental: Arm D, Part 2a: VenDVd Dose Escalation Venetoclax at various doses administered orally QD in combination with daratumumab (1800 mg subcutaneous injection (preferred) or 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta Drug: Bortezomib Injection; Subcutaneous (preferred), Infusion; Intravenous (IV)
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 (1800 mg subcutaneous injection (preferred) or 16 mg/kg 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta
Experimental: Arm A, Part 1a: VenDd Dose Escalation Venetoclax (Ven) various doses administered orally, once daily (QD) in combination with daratumumab (D) (1800 mg subcutaneous injection (preferred) or 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 Infusion; Intravenous (IV), or Tablet; Oral Drug: Daratumumab Injection; Subcutaneous (preferred), Infusion; Intravenous (IV) Drug: Venetoclax Tablet; Oral Other Names: ABT-199 Venclexta

Outcome Measures

Primary Outcome Measures

Overall Response Rate (ORR) [Up to approximately 3.5 years after the last participant is enrolled]
ORR is defined as the percentage of participants with documented partial response (PR) or better based on International Myeloma Working Group (IMWG) criteria.
Very Good Partial Response or Better Response Rate (VGPR) [Up to approximately 3.5 years after the last participant is enrolled]
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.
Complete Response (CR) or Better Rate [Up to approximately 3.5 years after the last participant is enrolled]
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.
Time to Response (TTR) [Up to approximately 3.5 years after the last participant is enrolled]
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.
Duration of Response (DOR) [Up to approximately 3.5 years after the last participant is enrolled]
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.
Time to Progression (TTP) [Up to approximately 3.5 years after the last participant is enrolled]
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.
Progression-Free Survival (PFS) [Up to approximately 3.5 years after the last participant is enrolled]
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.
Overall Survival (OS) [Up to approximately 3.5 years after the last participant is enrolled]
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.

Secondary Outcome Measures

Minimal Residual Disease (MRD) [Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)]
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.
Cmax of Venetoclax [Up to approximately 1 year]
Maximum observed plasma concentration (Cmax) of venetoclax
Tmax of Venetoclax [Up to approximately 1 year]
Time to Cmax (Tmax) of Venetoclax
AUC0-24 of Venetoclax [Up to approximately 1 year]
Area under the plasma concentration-time curve (AUC) over the dose interval (AUC0-24) of venetoclax.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Colorado Cancer Center /ID# 167331	Aurora	Colorado	United States	80045
2	Moffitt Cancer Center /ID# 169614	Tampa	Florida	United States	33612-9416
3	Emory University, Winship Cancer Institute /ID# 165427	Atlanta	Georgia	United States	30322
4	The University of Chicago Medical Center /ID# 165429	Chicago	Illinois	United States	60637-1443
5	Beth Israel Deaconess Medical Center /ID# 210904	Boston	Massachusetts	United States	02215-5400
6	Dana-Farber Cancer Institute /ID# 166886	Boston	Massachusetts	United States	02215
7	Hackensack Univ Med Ctr /ID# 225111	Hackensack	New Jersey	United States	07601
8	Roswell Park Comprehensive Cancer Center /ID# 169615	Buffalo	New York	United States	14263
9	Weill Cornell Medicine/NYP /ID# 167605	New York	New York	United States	10021-4872
10	Atrium Health Carolinas Medical Center /ID# 164948	Charlotte	North Carolina	United States	28203
11	Duke Cancer Center /ID# 165104	Durham	North Carolina	United States	27710-3000
12	Wake Forest Baptist Health /ID# 224447	Winston-Salem	North Carolina	United States	27157-0001
13	Oregon Health & Science University /ID# 166822	Portland	Oregon	United States	97239-3011
14	University of Washington /ID# 164884	Seattle	Washington	United States	98109
15	The Kinghorn Cancer Centre /ID# 165431	Darlinghurst	New South Wales	Australia	2010
16	St George Hospital /ID# 171063	Kogarah	New South Wales	Australia	2217
17	Royal Adelaide Hospital /ID# 171060	Adelaide	South Australia	Australia	5000
18	Eastern Health /ID# 165850	Box Hill	Victoria	Australia	3128
19	St Vincent's Hospital Melbourne /ID# 165853	Fitzroy Melbourne	Victoria	Australia	3065
20	Peter MacCallum Cancer Ctr /ID# 164742	Melbourne	Victoria	Australia	3000
21	Royal Perth Hospital /ID# 224895	Perth	Western Australia	Australia	6000
22	Tom Baker Cancer Centre /ID# 167822	Calgary	Alberta	Canada	T2N 4N2
23	Cross Cancer Institute /ID# 203114	Edmonton	Alberta	Canada	T6G 1Z2
24	Royal Victoria Hospital / McGill University Health Centre /ID# 167824	Montreal	Quebec	Canada	H4A 3J1
25	Rigshospitalet /ID# 164420	Copenhagen Ø	Hovedstaden	Denmark	2100
26	Aarhus University Hospital /ID# 164509	Aarhus N	Midtjylland	Denmark	8200
27	Odense University Hospital /ID# 164417	Odense C	Syddanmark	Denmark	5000
28	Sygehus Lillebælt, Vejle /ID# 164418	Vejle	Syddanmark	Denmark	7100
29	CHU Limoges - Dupuytren 1 /ID# 224759	Limoges CEDEX 1	Franche-Comte	France	87042
30	CHRU Tours - Hopital Bretonneau /ID# 164795	Tours CEDEX 9	Indre-et-Loire	France	37044
31	CHU de Nantes, Hotel Dieu -HME /ID# 164767	Nantes	Pays-de-la-Loire	France	44000
32	CHU Poitiers - La milétrie /ID# 164806	Poitiers	Poitou-Charentes	France	86000
33	Institut Gustave Roussy /ID# 164807	Villejuif Cedex	Val-de-Marne	France	94805
34	AP-HP - Hopital Saint-Louis /ID# 224758	Paris		France	75010
35	Universitaetsklinikum Freiburg /ID# 166036	Freiburg	Baden-Wuerttemberg	Germany	79106
36	University Hospital Cologne /ID# 166037	Cologne		Germany	50937
37	Nagoya City University Hospital /ID# 225273	Nagoya shi	Aichi	Japan	467-8602
38	Kameda General Hospital /ID# 225246	Kamogawa-shi	Chiba	Japan	296-8602
39	Matsuyama Red Cross Hospital /ID# 225196	Matsuyama-shi	Ehime	Japan	790-8524
40	Gifu Municipal Hospital /ID# 240381	Gifu-shi	Gifu	Japan	500-8513