A Study of Ixazomib+Daratumumab+Dexamethasone (IDd) in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the percentage of participants with a response of very good partial response (VGPR) or better to IDd treatment.

Detailed Description
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The regimen being tested in this study is the combination of ixazomib, daratumumab, and dexamethasone. This study will look at the efficacy and safety of IDd in people who have RRMM. The study will enroll approximately 60 Participants. Participants will be assigned to the treatment group: • Ixazomib 4.0 mg + Daratumumab 16.0 mg/kg + Dexamethasone 20 mg All participants will be asked to take Ixazomib on Days 1, 8 and 15 of each 28-day cycle plus Daratumumab on Days 1, 8, 15 and 22 of each 28-day cycle for Cycles 1 and 2, on Days 1 and 15 of each 28-day cycle for Cycles 3 through 6 and on Day 1 of each 28-day cycle for Cycle 7 and beyond plus Dexamethasone orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle. This multi-center trial will be conducted in the United States, Czech Republic, France, Poland, Greece and the Netherlands. The overall time to participate in this study is approximately 4 years. Participants will make multiple visits to the clinic, and every 12 weeks after PD until death or termination of the study by the sponsor.

Official Title
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A Phase 2, Open-Label Study of Ixazomib+Daratumumab+Dexamethasone (IDd) in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Daratumumab
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have measurable disease by at least 1 of the following measurements: serum M-protein >=1 gram per liter (g/dL) (>=10 g/L). urine M-protein >=200 mg/24 hours. Have documented evidence of PD on or after their last regimen as defined by IMWG criteria. All participants must have received between 1 to 3 prior therapies for MM (a prior therapy is defined as 2 or more cycles of therapy given as a treatment plan for MM [example, a single-agent or combination therapy or a sequence of planned treatments such as induction therapy followed by autologous stem cell transplant (SCT) and then consolidation and/or maintenance therapy]). Have achieved a response (partial response (PR) or better) to at least 1 prior therapy. Have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2. Must meet the following laboratory criteria: Absolute neutrophil count (ANC) >=1000 per cubic millimeter (/mm^3). Platelet count >=75,000/mm^3. Total bilirubin less than or equal to (<=) 1.5*the upper limit of the normal range (ULN) (except for Gilbert syndrome: direct bilirubin <=2*ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3*ULN. Calculated creatinine clearance >=50 mL/min. Exclusion Criteria: Have undergone prior allogenic bone marrow transplantation. Have received prior ixazomib at any time or daratumumab or other anti-CD38 therapies, except as part of initial therapy if this was stopped to move on to SCT and the participant did not progress on anti-CD38 treatment. Are refractory to bortezomib or carfilzomib at the last exposure before this study (defined as participants having PD while receiving bortezomib or carfilzomib therapy or within 60 days after ending bortezomib or carfilzomib therapy). Are planning to undergo SCT prior to PD on this study (ie, these participants should not be enrolled in order to reduce disease burden prior to transplant). Are receiving systemic treatment with strong Cytochrome P450 3A4 (CYP3A) inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, St. John's wort) within 14 days before randomization. Has received autologous SCT within 12 weeks before the date of study treatment. With known chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal. Note: FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal. Participants with Grade 2 or higher residual toxicities from prior therapy (including Grade 2 or higher peripheral neuropathy or any grade neuropathy with pain; excluding alopecia). This includes recovery from any major surgery. Note: Participants with planned surgical to be conducted under local anesthesia may participate. Kyphoplasty or vertebroplasty are not considered major surgery. Has uncontrolled clinically significant cardiac disease, including myocardial infarction within 6 months before date of study entry or unstable or uncontrolled angina, congestive heart failure, New York Heart Association (NYHA) Class III-IV, uncontrolled cardiac arrhythmia (Grade 2 or higher). With ongoing or active systemic infection requiring intravenous IV medical management ; participants with known human immunodeficiency virus- Ribonucleic acid (HIV-RNA) positivity; participants with hepatitis B virus (HBV) surface antigen or core antibody positivity; and participants with known hepatitis C virus-RNA positivity. Note: Participants who have positive hepatitis B core antibody can be enrolled but must have hepatitis B virus- deoxyribonucleic acid (DNA) negative. Participants who have positive hepatitis C antibody can be enrolled but must have hepatitis C virus-RNA negativity. Note: Participants who are already enrolled at the time of Amendment 02 should have local HBV testing performed as soon as possible for HBV surface antigen, e antigen, core antibody, and DNA. If any of these tests is positive, consult a physician with expertise in managing HBV for guidance regarding stopping daratumumab, starting HBV antiviral therapy, and remaining on study. Diagnosed or treated for another malignancy within 2 years before randomization or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ixazomib 4 mg + Daratumumab 16 mg/kg + Dexamethasone 20 mg<br>Ixazomib, 4 mg, capsules, orally, on Days 1, 8 and 15 of each 28-day cycle along with daratumumab, 16 mg/kg, intravenously (IV), on Days 1, 8, 15 and 22 of Cycles 1 and 2, on Days 1 and 15 (every 2 weeks) for Cycles 3 to 6 and on Day 1 (every 4 weeks) for Cycle 7 and beyond along with dexamethasone, 20 mg, tablets, orally on Days 1, 2, 8, 9, 15, 16, 22 and 23 of each 28-day cycle until progressive disease (PD), unacceptable toxicity, or withdrawal of consent, or until the sponsor terminates the study or when the study has completed (approximately up to 4 years). | Drug: Ixazomib<br>* Ixazomib capsule.<br>* Other names: NINLARO;Drug: Daratumumab<br>* Daratumumab IV infusion.<br>Drug: Dexamethasone<br>* Dexamethasone tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Very Good Partial Response (VGPR) or Better (Complete Response + VGPR) | Response was assessed using International Myeloma Working Group (IMWG) Criteria. VGPR is defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level< 100 milligram (mg) per 24 hours. The percentage of participants were rounded off to the single decimal point. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is defined as time from date of first dose of drug to date of first documentation of progressive disease (PD) or death from any cause, whichever occurs first. Participant without documentation of PD or death were censored at the date of last response assessment that is stable disease (SD) or better. PD is defined as increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase ≥0.5 g/dl); or urine M-component (absolute increase ≥200 mg/24-hour); difference between involved and uninvolved FLC levels (absolute increase >10 mg/dl); or bone marrow plasma cell percentage (absolute plasma cell percentage ≥10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. SD is defined as not meeting criteria for other responses. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 
| Time to Progression (TTP) | TTP is defined as the time from the first dose of any study drug treatment to the date of the first documented PD. PD is defined as increase of 25% of lowest response value in one or more of following criteria: serum M-component (absolute increase ≥0.5 g/dl); or urine M-component (absolute increase ≥200 mg/24-hour); difference between involved and uninvolved FLC levels (absolute increase >10 mg/dl); or bone marrow plasma cell percentage (absolute plasma cell percentage ≥10%); development of new/ increase in size of existing bone lesions or soft tissue plasmacytoma; or development of hypercalcemia that can be attributed solely to plasma cell proliferative disorder. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 
| Overall Survival (OS) | OS is defined as the time from the date of first dose of any study drug treatment to the date of death. Participant without documentation of death at the time of analysis will be censored at the last visit at which s/he was known to be alive. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 
| Overall Response Rate (ORR) | ORR is defined as percentage of participants with complete response (CR), VGPR and partial response (PR). CR: Negative immunofixation of serum and urine, disappearance of any soft tissue plasmacytomas, and <5% plasma cells in bone marrow; normal free light chain (FLC) ratio of 0.26-1.65; VGPR: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein + urine M-protein level <100 mg/24 hours; and PR: >=50% reduction of serum M protein and reduction in 24-hour urinary M protein by >=90%/to <200 mg/24 hours; In addition, if present at baseline, >=50% reduction in size of soft tissue plasmacytomas; no known evidence of progressive/new bone lesions. The percentage of participants were rounded off to the single decimal point. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 
| Time To Response (TTR) | TTR is defined as the time from first dose of any study drug treatment to the date of first documentation of PR or better. PR is defined as >=50% reduction of serum M protein and reduction in 24-hour urinary M protein by >=90%/to <200 mg/24 hours; In addition, if present at baseline, >=50% reduction in size of soft tissue plasmacytomas; no known evidence of progressive/new bone lesions. | Up to data cut-off: 1 January 2022 (Approximately 4 years) | 
| Duration of Response (DOR) | DOR is defined as the time from the date of first documentation of PR or better to the date of the first documented PD among participants who responded to the treatment. | Up to data cut-off: 1 January 2022 (Up to approximately 4 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy, Ixazomib, Daratumumab, Dexamethasone