Daratumumab, Bortezomib, and Dexamethasone With or Without Venetoclax in Treating Patients With Relapsed or Refractory Multiple Myeloma

NCT03701321 | Withdrawn Phase 1 DMC FDA Drug

• 3 other identifiers: NCI-2018-02131EAA172U10CA180820
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 3

Brief Summary

This phase I/II trial studies the side effects and best dose of venetoclax when given together with daratumumab, bortezomib, and dexamethasone, and how well they work in treating patients with multiple myeloma that has come back (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as venetoclax and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as daratumumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving venetoclax with daratumumab, bortezomib, and dexamethasone may work better in treating patients with relapsed or refractory multiple myeloma compared to standard of care treatment, including chemotherapy.

Conditions

Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose of venetoclax in combination with daratumumab, bortezomib and dexamethasone (Phase I)

  Highest dose at which fewer than one-third of patients experience a dose-limiting toxicity.

  Up to 35 days

• Minimal residual disease (MRD) negative status (Phase II)

  Per revised International Myeloma Working Group (IMWG) response criteria for next-generation sequencing (NGS) methods.

  After cycle 8

Secondary Outcomes (5)

• Overall survival (OS) (Phase II)

  From randomization to death due to any cause, or censored at the date last known alive, assessed up to 10 years

• Progression-free survival (PFS) (Phase II)

  From randomization until the earlier of progression or death due to any cause, or censored at date of last disease evaluation, assessed up to 10 years

• Best response (Phase II)

  Up to cycle 8

• Time to progression (TTP) (Phase II)

  From randomization to progression, or censored at the date of last disease evaluation, assessed up to 10 years

• Incidence of adverse events (Phase II)

  Up to 10 years

Other Outcomes (4)

• Duration of treatment (Phase II)

  From time of randomization to date off treatment, or censored at date of last treatment, assessed up to 10 years

• Cumulative dose (Phase II)

  Up to 10 years

• Dose intensity (Phase II)

  Up to 10 years

Study Arms (3)

Phase I (DVd, venetoclax)

EXPERIMENTAL

Patients receive daratumumab IV on days 1, 8, and 15 of cycles 1-3 and on day 1 of subsequent cycles, bortezomib SC on days 1, 8, and 15 of cycles 1-8, dexamethasone PO on days 1, 8, and 15 of cycles 1-8, and venetoclax PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Biological: Daratumumab; Drug: Dexamethasone; Drug: Venetoclax

Phase II Arm D (DVd, venetoclax)

EXPERIMENTAL

Patients receive venetoclax PO QD on days 1-21, daratumumab IV on days 1, 8, and 15 of cycles 1-3 and on day 1 of subsequent cycles, bortezomib SC on days 1, 8, and 15 of cycles 1-8, and dexamethasone PO on days 1, 8, and 15 of cycles 1-8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Biological: Daratumumab; Drug: Dexamethasone; Drug: Venetoclax

Phase II Arm E (DVd)

ACTIVE COMPARATOR

Patients receive daratumumab IV on days 1, 8, and 15 of cycles 1-3 and on day 1 of subsequent cycles, bortezomib SC on days 1, 8, and 15 of cycles 1-8, and dexamethasone PO on days 1, 8, and 15 of cycles 1-8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Biological: Daratumumab; Drug: Dexamethasone

Interventions

Bortezomib DRUG

Given SC

Also known as: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade

Phase I (DVd, venetoclax); Phase II Arm D (DVd, venetoclax); Phase II Arm E (DVd)

Daratumumab BIOLOGICAL

Given IV

Also known as: Anti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414

Phase I (DVd, venetoclax); Phase II Arm D (DVd, venetoclax); Phase II Arm E (DVd)

Dexamethasone DRUG

Given PO

Also known as: Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex

Phase I (DVd, venetoclax); Phase II Arm D (DVd, venetoclax); Phase II Arm E (DVd)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Phase I (DVd, venetoclax); Phase II Arm D (DVd, venetoclax)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• PHASE I (ARMS A, B, C) - STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• PHASE I (ARMS A, B, C) - STEP 1: Patients must have been diagnosed with symptomatic relapsed/refractory multiple myeloma.
• NOTE: Relapsed/refractory myeloma is defined as a disease which becomes non-responsive or progressive on therapy or within 60 days of the last treatment in patients who had achieved a minimal response (MR) or better on prior therapy.
• PHASE I (ARMS A, B, C) - STEP 1: t(11;14) status must be determined.
• PHASE I (ARMS A, B, C) - STEP 1: Patients must not have bortezomib refractory disease. Prior lenalidomide refractory patients are allowed.
• PHASE I (ARMS A, B, C) - STEP 1: Patients must have been treated with 1 or more lines of therapy. 1 prior line of systemic therapy is defined as 1 or more planned cycles of single agent or combination therapy, as well as a planned series of treatment regimens administered in a sequential manner (e.g. lenalidomide, bortezomib and dexamethasone induction therapy for 4 cycles followed by autologous stem cell transplantation and then lenalidomide maintenance therapy would be considered 1 line of prior therapy). Auto stem cell transplant is allowed provided the patient is 100 days out from stem cell infusion. Patients must not have had prior venetoclax. Allogeneic stem cell transplantation (SCT) patients are excluded.
• PHASE I (ARMS A, B, C) - STEP 1: Patients must have measurable disease as defined by having one or more of the following, obtained within 14 days prior to randomization:
• \>= 0.5 g/dL monoclonal protein (M-protein) on serum protein electrophoresis.
• \>= 200 mg/24 hrs of monoclonal protein (M-protein) on a 24 hour urine protein electrophoresis.
• Involved free light chain \>= 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (\< 0.26 or \> 1.65).
• PHASE I (ARMS A, B, C) - STEP 1: Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assay are required to be performed within 14 days prior to randomization.
• NOTE: UPEP (on a 24 hour collection) is required, no substitute method is acceptable. Urine must be followed monthly if the baseline urine M-spike is \>= 200 mg/24 hr and urine in addition to serum must be followed in order to confirm a very good partial response (VGPR) or higher response.
• NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine. Measurable disease in the serum is defined as having a serum M-spike \>= 0.5 g/dL. Measurable disease in the urine is defined as having a urine M-spike \>= 200 mg/24 hr.
• PHASE I (ARMS A, B, C) - STEP 1: Platelet count \>= 100,000 cells/mm\^3 (within 14 days prior to randomization).
• PHASE I (ARMS A, B, C) - STEP 1: Absolute neutrophil count \>= 1000 cells/mm\^3 (within 14 days prior to randomization).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (3)

Indiana University/Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Aurora Cancer Care-Milwaukee West

Wauwatosa, Wisconsin, 53226, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Bortezomib; daratumumab; Dexamethasone; Calcium Dobesilate; auricularum; dexamethasone acetate; dexamethasone 21-phosphate; venetoclax

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated; Benzenesulfonates; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Arylsulfonates; Arylsulfonic Acids; Sulfonic Acids; Sulfur Acids; Sulfur Compounds

Study Officials

• Michael A Thompson

  ECOG-ACRIN Cancer Research Group

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Model Details: 3 arms in phase I, 2 arms in phase II

Study Record Dates

• First Submitted: October 8, 2018
• First Posted: October 10, 2018
• Study Start: January 25, 2019
• Primary Completion: May 28, 2020
• Study Completion: May 28, 2020
• Last Updated: September 26, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will share

Locations

US (3)