A Study of Ixazomib Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of Phase 1 of this study was to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral ixazomib administered in combination with lenalidomide and low-dose dexamethasone in participants with newly diagnosed multiple myeloma (NDMM). The purpose of Phase 2 of this study was to determine the overall response rate (ORR) and further evaluate the tolerability and toxicity of the combination of oral ixazomib, lenalidomide, and low-dose dexamethasone in patients with NDMM.

Detailed Description
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The drug being tested in this study is called ixazomib. Ixazomib was being tested to treat people who had newly diagnosed multiple myeloma who had not previously received systemic treatment. This study was conducted in two Phases. Phase 1 looked at side effects and lab results in people who took ixazomib to determine the MTD and RP2D. Phase 2 looked at overall response rates and side effects in people who took ixazomib. The study enrolled 15 patients in Phase 1 and 50 patients in Phase 2. Participants in Phase 1 were assigned to cohorts and received ixazomib 1.68, 2.23, 2.97, or 3.95 mg/m^2 in addition to dexamethasone 40 mg and lenalidomide 25 mg. Participants in Phase 2 received ixazomib 4.0 mg fixed dose in addition to dexamethasone 40 mg and lenalidomide 25 mg. In both Phases study treatment was administered in 28-day Cycles as follows: ixazomib Days 1, 8 and 15, dexamethasone Days 1, 8, 15 and 22, and lenalidomide 25 mg Days 1 through 21. This multi-center trial was conducted in the United States. The overall time to participate in this study was 12, 28-day cycles with the option to continue into a maintenance portion in the absence of disease progression or unacceptable toxicity. Participants made multiple visits to the clinic and a final visit 30 days after last dose of study drug for a follow-up assessment.

Official Title
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An Open-Label, Dose-Escalation, Phase 1/2 Study of the Oral Form of Ixazomib (MLN9708), a Second-Generation Proteasome Inhibitor, Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Requiring Systemic Treatment

Conditions
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Multiple Myeloma

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each patient must meet all of the following eligibility criteria to be enrolled in the study: Male or female patients 18 years or older Previously untreated multiple myeloma diagnosed according to standard criteria requiring systemic treatment Patients must have measurable disease Nonsecretory multiple myeloma based upon standard M-component criteria (i.e., measurable serum/urine M-component) is not allowed unless the baseline serum free light chain level (Freelite™) is evaluated Patients must meet clinical laboratory criteria as specified in study protocol Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Female and male patients MUST adhere to the guidelines of the lenalidomide pregnancy prevention program Must be able to take concurrent aspirin 325 mg daily Voluntary written consent Exclusion Criteria Patients meeting any of the following exclusion criteria are not to be enrolled in the study: Peripheral neuropathy that is greater or equal to Grade 2 Female patients who are lactating or pregnant Major surgery or radiotherapy within 14 days before the first dose of study drug Serious infection requiring systemic antibiotic therapy within 14 days before the first dose of study drug Diarrhea greater than Grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events Central nervous system involvement. Evidence of current uncontrolled cardiovascular conditions within the past 6 months Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection 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 condition that could interfere with swallowing or the oral absorption or tolerance of ixazomib No other prior malignancy within 2 years except nonmelanoma skin cancer or carcinoma in situ of any type 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone<br>In phase 1, ixazomib 1.68 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 1.68 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Experimental: Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone<br>In phase 1, ixazomib 2.23 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.23 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Experimental: Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone<br>In phase 1, ixazomib 2.97 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.97 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Experimental: Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone<br>In phase 1, ixazomib 3.95 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 3.95 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone tablets<br>|
| Experimental: Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone<br>In phase 2, ixazomib 4.0 mg fixed dose, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 4.0 mg fixed dose, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>* Other names: NINLARO®;Drug: Lenalidomide<br>* Lenalidomide capsules<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 |
| --- | --- | --- |
| Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. | Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days) | 
| Phase 2: Objective Response Rate (ORR) Following Treatment With the Combination Of Oral Ixazomib, Lenalidomide And Low-Dose Dexamethasone | ORR was defined as the percentage of participants with Complete (CR) + Very Good Partial Response (VGPR) assessed by the investigatory using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. VGPR=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 mg per 24 hours. | Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days) | 
| Phase 1: Recommended Phase 2 Dose of Ixazomib Given in Combination With Lenalidomide and Low-Dose Dexamethasone | RP2D will be determined based on number and type of adverse event and serious adverse events, assessments of clinical laboratory values, neurotoxicity grading, and treatment discontinuation. | Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days) | 
| Phase 1: Maximum Tolerated Dose (MTD) of Ixazomib Administered Weekly in Combination With Lenalidomide and Low-Dose Dexamethasone | MTD of ixazomib will be determined by assessing adverse events and serious adverse events, clinical laboratory values, neurotoxicity grading, and vital sign measurements. | Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days) | 
| Phase 2: Percentage of Participants With Grade 3 or Higher AEs, SAEs and Treatment Discontinuation | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. | Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cmax: Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of ixazomib obtained directly from the plasma concentration-time curve. | Cycle 1, Days 1 and 15 | 
| Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib | Tmax: Time to reach the first maximum observed plasma concentration (Cmax), equal to time (hours) to Cmax, obtained directly from the plasma concentration-time curve. | Cycle 1, Days 1 and 15 | 
| Phase 1: AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for Ixazomib | AUC(0-168) is a measure of the area under the plasma concentration-time curve from time 0 to 168 hours postdose for Ixazomib. | Cycle 1, Days 1 and 15 | 
| Phase 1: Rac: Accumulation Ratio of Ixazomib | The accumulation ratio (Rac) was estimated as the ratio of AUC(0-168) on Day 15 to the AUC(0-168) on Day 1. AUC(0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose for ixazomib. | Cycle 1, Day 15 | 
| Phase 1: Emax: Maximum Observed Inhibition of Whole Blood 20S Proteasome | Emax is the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported. | Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose | 
| Phase 1: TEmax: Time to the Maximum Observed Inhibition of Whole Blood 20S Proteasome | TEmax is the time to the maximum observed inhibition of whole blood 20S proteasome. The pharmacodynamics 20S Proteasome samples were collected and the assays were performed; however, concerns about the third-party laboratory's performance of the blood 20S proteasome activity assay were identified that precluded the ability to confirm the accuracy of the data so no data is reported. | Day 1 predose and at multiple time points (up to 168 hours) postdose and Day 15 predose and at multiple time points (up to 336 hours) postdose | 
| Phase 2: Time to Progression (TTP) | TTP was measured as the time in months from the first dose of study treatment to the date of the first documented progressive disease (PD). | From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days) | 
| Phase 2: Overall Survival (OS) | OS was measured as the time in months from the first dose of study treatment to the date of death + 1 day. | From the first dose of study treatment to the date of death (up to 787 days) | 
| Phase 2: Overall Response Rate (ORR) | ORR was defined as the percentage of participants with CR, VGPR and Partial Response (PR) assessed by the investigator using IMWG criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. PR=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by 90% or to < 200 mg per 24 hours. VGPR= 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 mg per 24 hours. | Up to 787 days | 
| Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) | Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR is defined as negative immunofixation on the serum and urine and; disappearance of any soft tissue plasmacytomas and; < 5% plasma cells in bone marrow. 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 mg per 24 hours. | After Cycles 3, 6 and 9 (Up to 787 days) | 
| Phase 2: Percentage of Participants With Complete Response (CR), Stringent Complete Response (sCR), Very Good Partial Response (VGPR), Near Complete Response (nCR), Partial Response (PR) and Minimal Response (MR) | Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR=Negative immunofixation on the serum and urine + Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. sCR= CR + Normal free light chain (FLC) ratio and Absence of clonal cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to < 200 mg per 24 hours. VGPR= 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 mg per 24 hours. nCR=Positive immunofixation analysis of serum or urine as the only evidence of disease. Disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. MR=25% to 49% reduction in serum paraprotein and 50% to 89% reduction in urine light chain excretion for 6 weeks. | Cycles 3, 6, 9 and 12 (Up to 787 days) | 
| Phase 2: Time to Best Response | Time to Best Response was measured as the time in months from the first dose of study treatment to the date of first documented documentation of a confirmed response of partial response (PR) or better. | Up to 787 days | 
| Phase 2: Duration of Response (DOR) | DOR was measured as the time in months from the date of first documentation of a confirmed response (CR + PR+ VGPR) to the date of the first documented disease progression (PD). Response was assessed by the investigator using International Myeloma Working Group (IMWG) Criteria. CR=negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. VGPR=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 mg per 24 hours. | Up to 787 days | 
| Phase 2: Progression Free Survival (PFS) | PFS was measured as the time in months from the first dose of study treatment to the date of the first documented PD or death. | Up to 787 days | 
| Phase 2: 1 Year Survival Rate | 1-year survival rate is defined as the percentage of participants still alive at year after the first dose of stud drug. | 1 year after first dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy