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

Phase 1

Completed

Conditions: Multiple Myeloma

Interventions: Drug: Ixazomib
Drug: Lenalidomide
Drug: Dexamethasone

Registration Number: NCT01383928

Lead Sponsor: Millennium Pharmaceuticals, Inc.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1: Ixazomib 3 mg or 3.7 mg	Ixazomib	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.
Phase 1: Ixazomib 3 mg or 3.7 mg	Lenalidomide	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.
Phase 1: Ixazomib 3 mg or 3.7 mg	Dexamethasone	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.
Phase 2: Ixazomib 3 mg	Lenalidomide	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.
Phase 2: Ixazomib 3 mg	Dexamethasone	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.
Phase 2: Ixazomib 3 mg	Ixazomib	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.

Primary Outcome Measures

Name	Time	Method
Phase 1: Maximum Tolerated Dose (MTD)	Cycle 1 (21 days)	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.
Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAE) Related to Neurotoxicity	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)	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.
Phase 1: Recommended Phase 2 Dose (RP2D)	Cycle 1 (21 days)	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).
Phase 1: Number of Participants With Markedly Abnormal Laboratory Values Reported as Treatment Emergent Adverse Events (TEAEs)	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)	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.
Phase 2: Percentage of Participants With Complete Response (CR) + Very Good Partial Response (VGPR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 2: Percentage of Participants With Grade 3 or Higher Adverse Events	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)	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.
Phase 1: Percentage of Participants Experiencing 1 or More Treatment-Emergent Adverse Events (TEAEs) or Serious Adverse Events (SAEs)	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)	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.
Phase 1: Number of Participants With Clinically Significant Change From Baseline in Vital Signs	Baseline up to 30 days after last dose of study drug (Up to Cycle 83 - approximately 2067 days)	Vital signs included body temperature, blood pressure and heart rate.
Phase 2: Percentage of Participants Experiencing Serious Adverse Events	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)	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.
Phase 2: Percentage of Participants With Treatment-Emergent Adverse Events Resulting in Study Drug Discontinuation	Baseline up to 30 days after the last dose of study drug (approximately 1905 days)	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.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Percentage of Participants With Partial Response (PR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 2: Duration of Response (DOR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Time to Disease Progression (TTP)	Baseline up to a follow-up of 62.1 months	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.
Progression Free Survival (PFS)	Baseline up to a follow-up of 62.1 months	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.
Phase 2: Percentage of Participants With Complete Response (CR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 2: Percentage of Participants With Stringent Complete Response (sCR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 2: Percentage of Participants With Minimal Response (MR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	MR as per IMWG criteria is 25%-49% reduction in serum paraprotein and 50%-89% reduction in urine light chain excretion for 6 weeks.
Phase 1: 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	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.
Phase 1: Percentage of Participants With Best Overall Response	Baseline until end of study treatment (Up to treatment Cycle 83 - approximately 2037 days)	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.
Phase 2: Percentage of Participants With Very Good Partial Response (VGPR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 1: Cmax: Maximum Plasma Concentration for Ixazomib	Cycle 1, Days 1 and 11	Maximum observed plasma concentration (Cmax) is the peak plasma concentration of ixazomib, obtained directly from the plasma concentration-time curve.
Phase 1: Rac: Accumulation Ratio of Ixazomib	Cycle 1, Days 1 and 11	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.
Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR) After Cycles 4, 8, and 16	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.
Phase 2: Time to Response	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Overall Survival	Baseline up to a follow-up of 62.1 months	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.
Phase 1: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib	Cycle 1, Days 1 and 11	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.
Phase 2: Percentage of Participants With Overall Response (CR+VGPR+PR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Phase 2: Percentage of Participants With Near Complete Response (nCR)	Baseline until end of treatment (Up to treatment Cycle 74 - approximately 1875 days)	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.
Kaplan-Meier Estimate of Percentage of Participants Achieving Survival at Year 1	1 year after the first dose of study treatment	The Kaplan-Meier estimate reports the percentage of participants surviving at Year 1.

Trial Locations

Locations (20): Virginia Cancer Specialists PC
🇺🇸
Fairfax, Virginia, United States
Ohio State University
🇺🇸
Columbus, Ohio, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Baylor Sammons Cancer Center
🇺🇸
Dallas, Texas, United States
Mercy St Anne Hospital
🇺🇸
Toledo, Ohio, United States
Stanford University
🇺🇸
Stanford, California, United States
UCSF Medical Center
🇺🇸
Berkeley, California, United States
University of Chicago Medical Center
🇺🇸
Chicago, Illinois, United States
Associates of Oncology/Hematology PC
🇺🇸
Rockville, Maryland, United States
Michigan State University
🇺🇸
Lansing, Michigan, United States
Mount Sinai Hospital
🇺🇸
New York, New York, United States
Virginia Cancer Care Specialist
🇺🇸
Fairfax, Virginia, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
Hackensack University Medical Center
🇺🇸
Hackensack, New Jersey, United States
H Lee Moffitt Cancer Center and Research Institute
🇺🇸
Tampa, Florida, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
SCRI Tennessee Oncology Nashville
🇺🇸
Nashville, Tennessee, United States