Daratumumab, Ixazomib, & Dexamethasone or Daratumumab, Bortezomib, & Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

NCT03942224 | Active Not Recruiting Phase 2 DMC FDA Drug

• 4 other identifiers: IRB00102336NCI-2018-03615Winship4547-18P30CA138292
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial studies how well daratumumab, ixazomib, and dexamethasone with or without bortezomib work in treating patients with newly diagnosed multiple myeloma. Immunotherapy with monoclonal antibodies, such as daratumumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as ixazomib, dexamethasone, and bortezomib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving daratumumab, ixazomib, and dexamethasone with or without bortezomib may work better in treating patients with multiple myeloma.

Conditions

Plasma Cell Myeloma

Outcome Measures

Primary Outcomes (1)

• ≥ Very good partial response (VGPR) response rate

  This will be defined as the proportion of subjects who achieved a response of VGPR or better (stringent complete response \[sCR\], complete response \[CR\], or VGPR) after induction cycle 8 treatment. Response will be determined by modified International Myeloma Working Group (IMWG) criteria.

  After cycle 8 (224 days)

Secondary Outcomes (7)

• Stem cell mobilization

  After cycle 3 (84 days)

• Best response on study

  Up to 5 years after study start

• Objective response rate (ORR)

  Up to 5 years after study start

• Minimal residual disease (MRD)

  Up to 5 years after study start

• Progression-Free Survival (PFS)

  Up to 5 years after study start

Study Arms (2)

Arm I (DId)

EXPERIMENTAL

INDUCTION: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on days 1, 8, 15, and 22 of cycles 1-2 and on days 1 and 15 of cycles 3-8, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 8 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance. MAINTENANCE: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Biological: Daratumumab; Drug: Dexamethasone; Drug: Ixazomib

Arm II (DVd, DId)

EXPERIMENTAL

INDUCTION CYCLES 1-3: Patients receive dexamethasone IV and PO on days 1, 8, and 15, daratumumab IV on days 1, 8, and 15, and bortezomib subcutaneously (SC) on days 1, 4, 8, and 11. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. INDUCTION CYCLES 4-8: Patients receive dexamethasone IV and PO on days 1, 8, 15, and 22, daratumumab IV on days 1 and 15, and ixazomib PO on days 1, 8, and 15. Treatment repeats every 28 days for 5 cycles in the absence of disease progression or unacceptable toxicity. Eligible patients then undergo stem cell transplant per standard of care. Patients who have at least stable disease after induction and patients who have undergone transplant continue to Maintenance. MAINTENANCE: Patients receive dexamethasone IV on day 1, daratumumab IV on day 1, and ixazomib PO on days 1, 8, and 15. Cycles repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Biological: Daratumumab; Drug: Dexamethasone; Drug: Ixazomib

Interventions

Bortezomib DRUG

Given SC

Also known as: MLN341, PS-341, Velcade

Arm II (DVd, DId)

Daratumumab BIOLOGICAL

Given IV

Also known as: Anti-cluster of differentiation 38 (CD38) Monoclonal Antibody, Darzalex, HuMax-CD38

Arm I (DId); Arm II (DVd, DId)

Dexamethasone DRUG

Given IV and PO

Also known as: Decadron, Dexasone, Diodex, Hexadrol, Maxidex

Arm I (DId); Arm II (DVd, DId)

Ixazomib DRUG

Given PO

Also known as: Ninlaro, MLN2238

Arm I (DId); Arm II (DVd, DId)

Eligibility Criteria

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

You may qualify if:

• Patients must meet the following criteria on screening examination to be eligible to participate in the study. All laboratory assessments should be performed within 21 days of initiation of protocol therapy unless otherwise specified. Subject is, in the investigator's opinion, willing and able to comply with the protocol requirements
• Subject has given voluntary signed written informed consent before performance of any study-related procedure that is not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to their future medical care
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
• Have documented multiple myeloma as defined by the International Myeloma Working Group (IMWG) 2014 criteria including: Clonal bone marrow plasma cells ≥ 10% (If bone marrow has less than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement). In addition, the patient must meet one of the criteria in d1 or d2:
• Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically (one or more of the following):
• Hypercalcemia: serum calcium \> 0.25 mmol/L (\> 1 mg/dL) higher than the upper limit of normal (ULN) or \> 2.75 mmol/L (\> 11 mg/dL)
• Renal insufficiency: Creatinine clearance (CrCl) \< 40 mL/min (measured or estimated by validated equations) or serum creatinine \> 177 umol/L (\> 2 mg/dL)
• Anemia: hemoglobin value of \> 20 g/L below the lower limit of normal, or a hemoglobin value \< 100 g/L
• Bone lesions: 1 or more osteolytic lesions on skeletal radiography, computed tomography (CT), or magnetic resonance imaging (MRI)
• Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used
• Any one or more of the following:
• Clonal bone marrow plasma cell percentage ≥ 60%
• Clonality should be established by showing kappa/lambda-light-chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be used
• Involved:uninvolved serum free light chain (FLC) ratio \> 100
• These values are based on the serum Freelite assay (The Binding Site Group, Birmingham, UK). The involved FLC must be ≥ 100 mg/L

You may not qualify if:

• Diagnosed with smoldering multiple myeloma (MM), monoclonal gammopathy of undetermined significance, Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, amyloidosis or primary or secondary plasma cell leukemia
• Participant has ≥ grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination within 21 days before initiation of protocol therapy
• Renal insufficiency, defined as creatinine clearance ≤ 30 mL/min (either actual or calculated value), within 21 days of initiation of protocol therapy. The Cockcroft-Gault formula should be used for calculating creatinine clearance values
• Platelet count ≤ 75,000 cells/mm³ at time of screening evaluation. Platelet transfusions to help patients meet eligibility criteria are not allowed within 3 days before study enrollment
• Participants with an absolute neutrophil count (ANC) ≤ 1000 cells/mm³ at time of screening evaluation. Growth factors may not be used to meet ANC eligibility criteria within 14 days of obtaining screening evaluation
• Participants with hemoglobin level \< 7.0 g/dL, at time of screening. Transfusion may not be used to meet eligibility criteria within 7 days of obtaining screening evaluation
• Participants with hepatic impairment, defined as bilirubin ≥ 1.5 x institutional upper limit of normal (ULN) or aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\]), alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]), or alkaline phosphatase ≥ 3 x institutional ULN, within 21 days of initiation of protocol therapy
• Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but no more than 10 mg p.o. once daily (q.d.) or its equivalent) for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to study treatment.)
• Steroids more than 160 mg IV equivalents of dexamethasone or bortezomib \> 2 doses of 1.3 mg/m² each dosing equivalents
• Known significant cardiac abnormalities including:
• Congestive heart failure, New York Heart Association (NYHA) class III or IV
• Uncontrolled angina, arrhythmia or hypertension
• Myocardial infarction within the past six months
• Any other uncontrolled or severe cardiovascular condition
• Prior cerebrovascular event with residual neurologic deficit

Sponsors & Collaborators

• Emory University: lead
• Takeda: collaborator
• Janssen, LP: collaborator
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

MeSH Terms

Conditions

Multiple Myeloma

Interventions

Bortezomib; daratumumab; Antibodies, Monoclonal; Dexamethasone; Calcium Dobesilate; ixazomib; MLN2238

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; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; 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

• Ajay Nooka, MD, MPH

  Emory University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 8, 2019
• Study Start: July 3, 2019
• Primary Completion: July 31, 2025
• Study Completion (Estimated): July 31, 2026
• Last Updated: June 21, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)