Clinical trial NCT03314181: A Study of Combination Therapy With Venetoclax, Daratumumab and Dexamethasone (With and Without Bortezomib) in Participants With Relapsed or Refractory Multiple Myeloma
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: 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
Venetoclax
Venclexta
Lead sponsor: AbbVie
Sponsor class: INDUSTRY
Collaborators: name: Janssen Research & Development, LLC
First posted: 2017-10-19
Enrollment: 156
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility 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.
* 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).

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Very Good Partial Response or Better Response Rate (VGPR)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Complete Response (CR) or Better Rate
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Time to Response (TTR)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Duration of Response (DOR)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Time to Progression (TTP)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Progression-Free Survival (PFS)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
measure: Overall Survival (OS)
timeFrame: Up to approximately 3.5 years after the last participant is enrolled
Secondary outcomes:
measure: Minimal Residual Disease (MRD)
timeFrame: Up to 12 months after confirmation of Complete Response (CR) or Stringent Complete Response (sCR)
measure: Cmax of Venetoclax
timeFrame: Up to approximately 1 year
measure: Tmax of Venetoclax
timeFrame: Up to approximately 1 year
measure: AUC0-24 of Venetoclax
timeFrame: Up to approximately 1 year
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Univ of Colorado Cancer Center /ID# 167331
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center /ID# 169614
state: Florida
city: Atlanta
country: United States
facility: Emory University, Winship Cancer Institute /ID# 165427
state: Georgia
city: Chicago
country: United States
facility: The University of Chicago Medical Center /ID# 165429
state: Illinois
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center /ID# 210904
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute /ID# 166886
state: Massachusetts
city: Hackensack
country: United States
facility: Hackensack Univ Med Ctr /ID# 225111
state: New Jersey
city: Buffalo
country: United States
facility: Duplicate_Roswell Park Comprehensive Cancer Center /ID# 169615
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine/NYP /ID# 167605
state: New York
city: Charlotte
country: United States
facility: Atrium Health Carolinas Medical Center /ID# 164948
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Center /ID# 165104
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health /ID# 224447
state: North Carolina
city: Portland
country: United States
facility: Oregon Health and Science University /ID# 166822
state: Oregon
city: Seattle
country: United States
facility: University of Washington /ID# 164884
state: Washington
city: Darlinghurst
country: Australia
facility: The Kinghorn Cancer Centre /ID# 165431
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital /ID# 171063
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital /ID# 171060
state: South Australia
city: Box Hill
country: Australia
facility: Eastern Health /ID# 165850
state: Victoria
city: Fitzroy Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne /ID# 165853
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Ctr /ID# 164742
state: Victoria
city: Perth
country: Australia
facility: Duplicate_Royal Perth Hospital /ID# 224895
state: Western Australia
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre /ID# 167822
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute /ID# 203114
state: Alberta
city: Montreal
country: Canada
facility: Royal Victoria Hospital / McGill University Health Centre /ID# 167824
state: Quebec
city: Copenhagen Ø
country: Denmark
facility: Rigshospitalet /ID# 164420
state: Hovedstaden
city: Aarhus N
country: Denmark
facility: Duplicate_Aarhus University Hospital /ID# 164509
state: Midtjylland
city: Odense
country: Denmark
facility: Odense University Hospital /ID# 164417
state: Syddanmark
city: Vejle
country: Denmark
facility: Sygehus Lillebalt, Vejle /ID# 164418
state: Syddanmark
city: Limoges CEDEX 1
country: France
facility: CHU Limoges - Dupuytren 1 /ID# 224759
state: Franche-Comte
city: Tours CEDEX 9
country: France
facility: CHRU Tours - Hopital Bretonneau /ID# 164795
state: Indre-et-Loire
city: Nantes
country: France
facility: CHU de Nantes, Hotel Dieu -HME /ID# 164767
state: Pays-de-la-Loire
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy /ID# 164807
state: Val-de-Marne
city: Poitiers
country: France
facility: CHU Poitiers - La miletrie /ID# 164806
state: Vienne
city: Paris
country: France
facility: AP-HP - Hopital Saint-Louis /ID# 224758
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg /ID# 166036
state: Baden-Wuerttemberg
city: Cologne
country: Germany
facility: University Hospital Cologne /ID# 166037
city: Nagoya shi
country: Japan
facility: Nagoya City University Hospital /ID# 225273
state: Aichi
city: Kamogawa-shi
country: Japan
facility: Kameda General Hospital /ID# 225246
state: Chiba
city: Matsuyama-shi
country: Japan
facility: Matsuyama Red Cross Hospital /ID# 225196
state: Ehime
city: Gifu-shi
country: Japan
facility: Gifu Municipal Hospital /ID# 240381
state: Gifu
Study officials:
affiliation: AbbVie
name: ABBVIE INC.
role: STUDY_DIRECTOR
References:
citation: Bahlis NJ, Baz R, Harrison SJ, Quach H, Ho SJ, Vangsted AJ, Plesner T, Moreau P, Gibbs SD, Coppola S, Yang X, Al Masud A, Ross JA, Bueno O, Kaufman JL. Phase I Study of Venetoclax Plus Daratumumab and Dexamethasone, With or Without Bortezomib, in Patients With Relapsed or Refractory Multiple Myeloma With and Without t(11;14). J Clin Oncol. 2021 Nov 10;39(32):3602-3612. doi: 10.1200/JCO.21.00443. Epub 2021 Aug 13.