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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Jan 2018 → ongoing

Decision date (initial)

2024-05-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-506110-43-00

EudraCT number

2017-002099-26

ClinicalTrials.gov

NCT03314181

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Pharmacogenetic, Safety, Pharmacodynamic, Efficacy, Pharmacokinetic, Dose response

1. To evaluate combination therapy with venetoclax, daratumumab, and dexamethasone (VenDd) in subjects with t(11;14) positive relapsed/refractory (R/R) multiple myeloma who have received:
- At least one prior line of multiple myeloma therapy that included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD)
2. To evaluate combination therapy with venetoclax, daratumumab, bortezomib, and dexamethasone (VenDVd) in subjects with R/R multiple myeloma who are:
- Considered non-refractory to PIs AND received 1 to 3 prior lines of multiple myeloma therapy.
3. To evaluate combination therapy with venetoclax, daratumumab, and dexamethasone (VenDd) in subjects with t(11;14) positive R/R multiple myeloma who are:
- Considered non-refractory to PIs AND received at least one prior line of multiple myeloma therapy that included an IMiD

Secondary objectives 3

1. To evaluate the safety profiles of VenDd and VenDVd in the expansion phases.
2. To assess minimal residual disease (MRD) in the bone marrow by next generation sequencing (NGS).
3. To characterize the pharmacokinetic (PK) profile of venetoclax and daratumumab when administered as VenDd or VenDVd and to characterize the immunogenicity to daratumumab when administered with venetoclax.

Conditions and MedDRA coding

Multiple Myeloma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
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.
3. 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.
4. Participant has received previous multiple myeloma treatment as defined in the protocol.
5. Bone marrow aspirate samples have been collected.
6. 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.
7. Participants must have adequate hematologic, renal and hepatic function.

Exclusion criteria 12

1. Previous treatment with venetoclax or other B-Cell Lymphoma 2 (BCL-2) inhibitor
2. 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.
3. 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.
4. 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.
5. Treatment with anti-myeloma monoclonal antibodies within 6 weeks prior to first dose.
6. 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.
7. Known central nervous system involvement of multiple myeloma.
8. Significant history of medical conditions as listed in the protocol.
9. 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.
10. Known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
11. Has a hypersensitivity or allergy to any of the components of study therapy, excipient or boron.
12. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 8

1. Overall response rate (ORR)
2. Very good partial response (VGPR) or better rate
3. Complete response (CR) or better rate
4. Time to response (TTR)
5. Duration of response (DOR)
6. Time to progression (TTP)
7. Progression-free survival (PFS)
8. Overall survival (OS)

Secondary endpoints 2

1. Minimal Residual Disease (MRD)
2. Safety, Pharmacokinetic (PK) and Biomarker Research Variables

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Third parties 9

Locations

3 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 27 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications