Study of Oral IXAZOMIB in Combination With Lenalidomide and Dexamethasone in Participants With Newly Diagnosed Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) in phase 1 and to determine the combined response rate of clinical response CR and very good partial response (VGPR) in phase 2 of oral (PO) ixazomib administered twice-weekly in combination with lenalidomide and low-dose dexamethasone in a 21-day cycle in participants with newly diagnosed multiple myeloma (NDDM).

Detailed Description
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The drug being tested in this study is called ixazomib. Ixazomib was tested to slow disease progression and improve overall survival in participants who have newly diagnosed multiple myeloma (NDMM). This study looked at the safety, tolerability and response in participants when administered in combination with lenalidomide and low-dose dexamethasone. The study enrolled 64 patients. Participants were assigned to one of the 3 treatment groups: Phase 1 Ixazomib 3 mg Phase 1 Ixazomib 3.7 mg Phase 2 Ixazomib 3 mg All participants were administered with Ixazomib capsules, orally, twice-weekly on Days 1, 4, 8, and 11 along with lenalidomide capsules, orally, once daily on Days 1-14 and dexamethasone, capsules, orally, once daily on Days 1, 2, 4, 5, 8, 9, 11, and 12 for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib capsules, orally, twice weekly on Days 1, 4, 8, and 11 in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity. This multi-center trial conducted in the United States. The overall time to participate in this study was 2037 days. Participants will make multiple visits to the clinic, and a final visit after 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 Formulation of IXAZOMIB (MLN9708), Administered Twice-weekly in Combination With Lenalidomide and 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: Male or female patients 18 years or older Symptomatic multiple myeloma or asymptomatic myeloma with myeloma-related organ damage diagnosed according to standard criteria Measurable disease as specified in study protocol Hematologic, liver, and renal function as specified in the study protocol. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse; must also adhere to the guidelines of the lenalidomide pregnancy prevention program Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse AND 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 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 Uncontrolled infection requiring systematic antibiotics within 14 days before the first dose of study drug Diarrhea (> Grade 1) Prior systemic therapy for multiple myeloma, including investigational drugs (prior treatment with corticosteroids or localized radiation therapy dose not disqualify the patient) Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers, or use of Ginkgo biloba or St. John's wort within 14 days before the first dose of study treatment Central nervous system involvement Diagnosis of smoldering multiple myeloma, Waldenstrom's macroglobulinemia, POEMS syndrome, plasma cell leukemia, primary amyloidosis, myelodysplastic syndrome, or myeloproliferative syndrome Evidence of current uncontrolled cardiovascular conditions Prior or concurrent deep vein thrombosis or pulmonary embolism 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 allergy to any of the study medications Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption, or tolerance of IXAZOMIB Diagnosed or treated for another malignancy within 2 years before the first dose or previously diagnosed with another malignancy and have any evidence of residual disease with the exception of nonmelanoma skin cancer or any completely resected carcinoma in situ

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 3 mg or 3.7 mg<br>Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 1. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>Drug: Lenalidomide<br>* Lenalidomide capsules<br>Drug: Dexamethasone<br>* Dexamethasone Tablets<br>|
| Experimental: Phase 2: Ixazomib 3 mg<br>Ixazomib (MLN9708), orally, twice-weekly in combination with lenalidomide orally and dexamethasone orally as prescribed, in 21-day treatment cycles for up to 16 cycles in the absence of disease progression or unacceptable toxicity as induction therapy during Phase 2. Participants with stable or responding disease continued receiving ixazomib (MLN9708) orally, twice weekly in 21-day treatment cycles as maintenance therapy until progressive disease or unacceptable toxicity. | Drug: Ixazomib<br>* Ixazomib capsules<br>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: Maximum Tolerated Dose (MTD) | MTD was highest dose of ixazomib given with combination drugs, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT 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 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; 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 >14 days; <=80% lenalidomide doses administered due to other >=Grade 2 combination study drug-related nonhematologic toxicities requiring therapy discontinuation. | Cycle 1 (21 days) | 
| Phase 1: Recommended Phase 2 Dose (RP2D) | The RP2D of ixazomib was determined after the evaluation of the available data from the phase 1 portion of the trial which included, but was not limited to analyses of efficacy results, toxicity characterization, all grades peripheral neuropathy, and treatment discontinuation. The maximum number of cycles received was 83 cycles (approximately up to 2037 days). | Cycle 1 (21 days) | 
| Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs) | 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 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. A TEAE is defined as an adverse event with an onset that occurs after receiving study drug. | Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days) | 
| Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs) | Laboratory tests included chemistry, hematology and urinalysis. Abnormal laboratory value was assessed as an AE if the value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. | Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days) | 
| Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity | TEAE related to neurotoxicity grading based on common terminology criteria for adverse events (CTACE) version 4.03 are reported. Grade 1= mild; Grade 2= moderate; within normal limits, Grade 3= severe or medically significant but not immediately life-threatening; Grade 4= life-threatening consequences; urgent intervention indicated; Grade 5= death. Only TEAEs related to neurotoxicity with values are reported. | Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days) | 
| Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Vital signs included body temperature, blood pressure and heart rate. | Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days) | 
| Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR) | CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria 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. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events | 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. As per Common Terminology Criteria for Adverse Events v4.0 (CTCAE), Grade 3 = AE with severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living. Grade 4 = AE with life-threatening consequences; urgent intervention indicated and Grade 5 = Death related to AE. | Baseline up to 30 days after the last dose of study drug (approximately 1905 days) | 
| Phase 2: Percentage of Participants Experiencing Serious Adverse Events | A 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. | Baseline up to 30 days after the last dose of study drug (approximately 1905 days) | 
| Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug 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 TEAE is defined as an adverse event with an onset that occurs after receiving study drug. | Baseline up to 30 days after the last dose of study drug (approximately 1905 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib | 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 11 | 
| Phase 1: AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | AUC(0-72) is a measure of the area under the plasma concentration time-curve from time zero to 72 hours post-dose for ixazomib. | Cycle 1, Days 1 and 11 | 
| Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Tmax: Time to reach the first maximum plasma concentration (Cmax), equal to time (hours) to Cmax of ixazomib after administration, obtained directly from the plasma concentration-time curve. | Cycle 1, Days 1 and 11 | 
| Phase 1: Rac: Accumulation Ratio of Ixazomib | The accumulation ratio (Rac) was estimated as the ratio of AUC (0-72) on Day 11 to the AUC (0-72) on Day 1. AUC (0-72) is the area under the plasma concentration-time curve from time zero to 72 hours post-dose for ixazomib. | Cycle 1, Days 1 and 11 | 
| Phase 1: Percentage of Participants With Best Overall Response | CR as per International Myeloma Working Group (IMWG) uniform criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. Partial response(PR):>=50% reduction of serum M-protein,urinary M-protein by >=90%/to <200 mg/24 hr reduction.Near CR(nCR):positive immunofixation of serum/urine;soft tissue plasmacytomas disappearance;<=5% plasma cells in bone marrow. VGPR as per IMWG criteria 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. VGPR was applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein greater than or equal to (>=)1 g/dL; Urine M-protein >=200 mg/24 hours; Serum FLC assay level >=10 mg/dL, provided serum FLC ratio was abnormal. | Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days) | 
| Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR) | Overall response is defined as CR, VGPR or PR based on IMWG Response Criteria for malignant lymphoma. CR: disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. VGPR: serum, urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein+urine M-protein level <100 mg/24h. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16 | CR as per IMWG criteria is defined as negative immunofixation on the serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. VGPR as per IMWG criteria 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. VGPR were applicable only to participants who had measurable disease defined by at least 1 of the following 3 measurements: Serum M-protein; Urine M-protein; Serum FLC assay. | Cycles 4, 8, and 16 | 
| Phase 2: Percentage of Participants With Complete Response (CR) | CR as per IMWG criteria is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Stringent Complete Response (sCR) | sCR as per IMWG criteria is CR plus normal FLC ratio and absence of clonal cells in bone marrow. CR is negative immunofixation on serum and urine and disappearance of soft tissue plasmacytomas and <5% plasma cells in bone marrow. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Very Good Partial Response (VGPR) | VGPR as per IMWG criteria is serum and urine M-protein detectable by immunofixation but not on electrophoresis or >=90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hours. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Near Complete Response (nCR) | nCR as per IMWG criteria is positive immunofixation analysis of serum or urine as the only evidence of disease; appearance of any soft tissue plasmacytomas and <=5% plasma cells in bone marrow. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Partial Response (PR) | PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by 90% or to <200 mg per 24 hours. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Percentage of Participants With Minimal Response (MR) | MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Time to Response | Time to first response is defined as the time from the date of first dose of study treatment to the date of the first documentation of a confirmed response (PR or better) in a participant who responded + 1 day. PR as per IMWG criteria is 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by 90% or to <200 mg per 24 hours. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Phase 2: Duration of Response (DOR) | DOR was measured as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as >=25% increase from lowest value in: serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; development of new bone lesions or soft tissue plasmacytomas development or increase in the size of existing bone lesions or soft tissue plasmacytomas; hypercalcaemia development. | Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days) | 
| Time to Disease Progression (TTP) | Time to progression was defined as the time from the date of first dose of study treatment to the date of first documentation of PD + 1 day. Participants that did not experience PD will be censored at the last response assessment that is SD or better. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved, uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants that received Autologous Stem Cell Transplantation (ASCT) or an alternate cancer therapy were also be censored at the last response assessment that is, SD or better prior to initiation of therapy. Participants without response assessment will be censored at the date of first dose. TTP was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates. | Baseline up to a follow-up of 62.1 months | 
| Progression Free Survival (PFS) | PFS was defined as the time from the date of first dose of study treatment to the date of first documentation of progressive disease or to death due to any cause, whichever occurred first plus 1. PD: >=25% increase from lowest value in:serum/urine M-component; difference between involved,uninvolved FLC levels; bone marrow plasma cell percent; new bone lesions/soft tissue plasmacytomas development/existing bone lesions/soft tissue plasmacytomas size rise; hypercalcaemia development. SD: not meeting criteria for CR, VGPR, PR, or PD. Participants who received ASCT or an alternate anticancer therapy were censored at the last response assessment that was SD or better before initiation of therapy. Participants without a response assessment were censored at the date of first dose. PFS was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates. | Baseline up to a follow-up of 62.1 months | 
| Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1 | The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1. | 1 year after the first dose of study treatment | 
| Overall Survival | Overall survival was measured as the time from the date of first dose of study treatment to the time of death plus 1 day. For participants who did not die, survival was censored at the date of last contact. Overall Survival was analyzed using standard survival analysis techniques based on Kaplan-Meier estimates. | Baseline up to a follow-up of 62.1 months |