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

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Ixazomib; Drug: Daratumumab; Drug: Dexamethasone

Detailed Description

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 5 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.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia, 625 00
    • Fakultni nemocnice Brno
  • Praha, Czechia, 128 08
    • Onkologická klinika Všeobecná fakultní nemocnice v Praze a 1
  • Olomoucky
    • Olomouc, Olomoucky, Czechia, 77900
      • Fakultni nemocnice Olomouc
  • Praha
    • Praha 10, Praha, Czechia, 100 34
      • Fakultni nemocnice Kralovske Vinohrady
  • Severomoravsky KRAJ
    • Ostrava - Poruba, Severomoravsky KRAJ, Czechia, 708 52
      • Fakultni Nemocnice Ostrava
• France
  • Ile-de-france
    • Paris, Ile-de-france, France, 75012
      • Hopital Saint-Antoine
  • NORD Pas-de-calais
    • Lille Cedex, NORD Pas-de-calais, France, 59037
      • Hopital Claude Huriez
  • PAYS DE LA Loire
    • Nantes Cedex 1, PAYS DE LA Loire, France, 44093
      • Hôpital Hôtel Dieu
  • Rhone-alpes
    • Pierre Benite Cedex, Rhone-alpes, France, 69495
      • Centre Hospitalier Lyon Sud
• Greece
  • Attica
    • Athens, Attica, Greece, 10676
      • Evaggelismos General Hospital
    • Athens, Attica, Greece, 11528
      • Alexandra General Hospital of Athens
  • Peloponnese
    • Patras, Peloponnese, Greece, 26504
      • University General Hospital of Patras Panagia I Voithia
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
  • Friesland
    • Leeuwarden, Friesland, Netherlands, 8934 AD
      • Medisch Centrum Leeuwarden
  • Noord-holland
    • Amsterdam, Noord-holland, Netherlands, 1081 HV
      • Vrije Universiteit Medisch Centrum
  • South Holland
    • Dordrecht, South Holland, Netherlands, 3300 AK
      • Albert Schweitzer Ziekenhuis Dordwijk
  • Zuid-holland
    • Rotterdam, Zuid-holland, Netherlands, 3015 CE
      • Erasmus Medisch Centrum
• Poland
  • Lodzkie
    • Lodz, Lodzkie, Poland, 93-510
      • Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w Lodzi
  • Malopolskie
    • Krakow, Malopolskie, Poland, 31-501
      • Szpital Uniwersytecki w Krakowie
  • Podkarpackie
    • Brzozow, Podkarpackie, Poland, 36-200
      • Szpital Specjalistyczny w Brzozowie Podkarpacki Osrodek Onkologiczny im. ks. B. Markiewicza
  • Pomorskie
    • Gdynia, Pomorskie, Poland, 81-519
      • Szpitale Pomorskie spolka z ograniczona odpowiedzialnoscia
  • Slaskie
    • Chorzow, Slaskie, Poland, 41-500
      • Samodzielny Publiczny Zaklad Opieki Zdrowotnej Zespol Szpitali Miejskich
• United States
  • California
    • Anaheim, California, United States, 92801
      • Pacific Cancer Medical Center
  • Colorado
    • Denver, Colorado, United States, 80218
      • Colorado Blood Cancer Institute
  • Florida
    • Tallahassee, Florida, United States, 32308
      • SCRI - Florida Cancer Specialists - Panhandle
  • Missouri
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center - Kansas City
  • Tennessee
    • Nashville, Tennessee, United States, 58014
      • SCRI - Tennessee Oncology - Nashville - Centennial
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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.
2. 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]).
3. Have achieved a response (partial response (PR) or better) to at least 1 prior therapy.
4. Have an Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2.

5. 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:

1. Have undergone prior allogenic bone marrow transplantation.
2. 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.
3. 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).
4. 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).
5. 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.
6. Has received autologous SCT within 12 weeks before the date of study treatment.

7. 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.
8. 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).

9. 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.

10. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ixazomib 4 mg + Daratumumab 16 mg/kg + Dexamethasone 20 mg; 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 up to 5 years.

Drug: Ixazomib; Ixazomib capsule.; Other Names: NINLARO; Drug: Daratumumab; Daratumumab IV infusion.; Drug: Dexamethasone; Dexamethasone tablets.

What is the study measuring?

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 5 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 5 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 5 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 5 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 5 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 5 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 5 years

Collaborators and Investigators

• Sponsor: Takeda
• Investigators: Study Director: Medical Director, Takeda

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2018
• Primary Completion (Actual): January 1, 2022
• Study Completion (Actual): June 26, 2023

Study Registration Dates

• First Submitted: February 14, 2018
• First Submitted That Met QC Criteria: February 14, 2018
• First Posted (Actual): February 20, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: June 7, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Drug Therapy; Daratumumab; Dexamethasone; Ixazomib
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Daratumumab; Ixazomib
• Other Study ID Numbers: C16047; U1111-1202-6022 (Other Identifier: WHO); 2017-003977-32 (Registry Identifier: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement
• IPD Sharing Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes