Study of Oral Ixazomib in Adult Participants With Relapsed and/or Refractory (RR) Multiple Myeloma

Study Overview
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Brief Summary
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This study will determine the safety profile, tolerability, and maximum tolerated dose (MTD) and disease response of Ixazomib administered orally in participants with relapsed and/or refractory multiple myeloma.

Detailed Description
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The drug being tested in this study is ixazomib. Ixazomib is being tested to treat people who have multiple myeloma. This study will look at the safety and efficacy of ixazomib and will enroll approximately 60 participants. Participants will receive ixazomib by oral capsule twice weekly on Days 1, 4, 8, and 11 of a 21-day cycle. The study will consist of a dose escalation phase to determine the MTD, followed by an expansion phase in which participants will be treated at the MTD. This multi-center trial will be conducted in the United States. The overall time to participate in this study is 8 years.

Official Title
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An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Form of Ixazomib (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Relapsed and Refractory Multiple Myeloma

Intervention / Treatment
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* Drug: Ixazomib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each participant must meet all of the following inclusion criteria to be enrolled in the study: Multiple myeloma diagnosed according to the standard criteria. Participants with multiple myeloma who have relapsed following at least 2 lines of therapy. Participants must have measurable disease. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse. Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse. Voluntary written consent. Suitable venous access for study-required blood sampling. Exclusion Criteria: Participants meeting any of the following exclusion criteria are not to be enrolled in the study: Peripheral neuropathy greater than or equal to (>=) Grade 2. Female participants who are lactating or have a positive serum pregnancy test during the screening period. Major surgery within 14 days before the first dose of study drug. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment. Life-threatening illness unrelated to cancer. Diarrhea > Grade 1, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) categorization. Systemic antineoplastic or radiation therapy within 14 days of cytotoxic agents within 21 days before the first dose of study treatment. Treatment with any investigational products within 21 days before the first dose of study treatment. Treatment with any investigational proteasome inhibitor. Systemic treatment with prohibited medication. Ongoing therapy with corticosteroids greater than 10mg of prednisone or its equivalent per day. Inhaled and topical steroids are permitted. Central nervous system involvement. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months. Corrected QT interval (QTc) > 470 milliseconds on a 12-lead electrocardiogram (ECG) obtained during the screening period. Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption of tolerance of ixazomib including difficulty swallowing.

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: Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2<br>Ixazomib 0.24 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 220 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2<br>Ixazomib 0.48 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 270 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2<br>Ixazomib 0.8 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 137 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2<br>Ixazomib 1.2 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 1436 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2<br>Ixazomib 1.68 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 456 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2<br>Ixazomib 2.0 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 1621 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2<br>Ixazomib 2.23 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 2434 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Relapsed and Refractory Expansion Cohort: Ixazomib 2 mg/m^2<br>Ixazomib 2.0 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months, Participants must also be refractory to their most recent therapy as evidenced by PD while on therapy or within 60 days after their last dose of therapy (Up to 1621 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2<br>Ixazomib 2.0 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants with relapsed or refractory disease after >=1 prior therapy but have relapsed after previous Velcade exposure and were not treated with any other proteasome inhibitors (Up to 1573 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2<br>Ixazomib 2.0 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants with relapsed or refractory disease after >=1 prior therapy which must include thalidomide (or lenalidomide) and corticosteroid, but who never received a proteasome inhibitor (Up to 550 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|
| Experimental: Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2<br>Ixazomib 2.0 mg/m^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants who previously received carfilzomib and had relapsed or refractory disease (Up to 123 days). | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: MLN9708;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death;is life-threatening;requires inpatient hospitalization or prolongation of present hospitalization;results in persistent or significant disability/incapacity;is a congenital anomaly/birth defect;or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy. | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 
| Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 
| Number of Participants With a TEAE of Peripheral Neuropathy | Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy. | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | The number of participants with any clinically significant changes in vital signs collected throughout the study that were reported as TEAEs. Measurement of vital signs, included oral temperature, blood pressure, and heart rate. | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 
| Maximum Tolerated Dose (MTD) of Ixazomib | MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT was defined as any of following considered possibly related to therapy: Grade 4 neutropenia (absolute neutrophil count [ANC] <500 cell per cubic millimeter [cells/mm^3]) for >7 days;Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding; platelet count <10,000/mm^3; Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy; Grade 3 QTc prolongation (QTc >500 millisecond [msec]);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia; or <1 week Grade 3 fatigue; delay in initiation of the subsequent therapy cycle by >2 weeks; other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation. | Cycle 1 (21 days) | 
| Recommended Phase 2 Dose (RP2D) of Ixazomib | The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic data observed in Cycle 1 and beyond. | Cycle 1 through Cycle 39 (Up to 28.3 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for Ixazomib |  | Cycle 1, Days 1 and 11: Predose and at multiple time points (up to 264 hours) postdose | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib |  | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | 
| AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib |  | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | 
| AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib |  | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 72 hours) postdose | 
| λz: Terminal Disposition Phase Rate Constant for Ixazomib |  | Cycle 1, Day 11: predose and at multiple time points (Up to 264 hours) postdose | 
| T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib |  | Cycle 1, Day 11: predose and at multiple time points (up to 264 hours) postdose | 
| CL/F: Blood Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Ixazomib | CL/F is apparent clearance of the drug from the plasma. | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | 
| Emax: Maximum Observed Effect for Ixazomib | Emax was determined to characterize the whole blood 20S proteasome inhibition parameters. | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | 
| TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib | TEmax was determined to characterize the whole blood 20S proteasome inhibition parameters. | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | 
| Overall Response Rate (ORR) | ORR is defined as percentage of participants with complete response (CR) or partial response (PR) or minimal response (MR) as assessed by the investigator using International Myeloma Working Group Uniform Response criteria. CR=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200 mg /24 h. MR=25-49% reduction in the serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24-h urinary light chain excretion, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks; for participants with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions. | Cycle 1 through Cycle 115 (Up to 80.1 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed multiple myeloma, Refractory multiple myeloma, Ixazomib Proteasome inhibitor