Multiple MyelomaPhase 1/2NCT01217957
A Study of Ixazomib Administered in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma
A Phase 1/2 study testing Ixazomib, Lenalidomide and Dexamethasone in people with Multiple Myeloma, run by Millennium Pharmaceuticals, Inc. at 16 sites in United States.
Trial summary
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multiple Myeloma
- What is being tested?
- Ixazomib, Lenalidomide and Dexamethasone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 65 participants
- Where
- 16 sitesUnited States
- Study dates
- 22 Nov 2010to 2 Feb 2018
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
16 sites in 1 country.
16 sites in 1 country
United States16 sites
Emory University
Atlanta, Georgia, 30322
Harry and Jeannette Weinberg Cancer Center at Franklin Square Hospital
Baltimore, Maryland, 21215
Dana Farber Cancer Institute
Boston, Massachusetts, 02115
Rocky Mountain Cancer Center Rose
Denver, Colorado, 80218
Karmanos Cancer Institute
Detroit, Michigan, 48201
Mayo Clinic Jacksonville
Jacksonville, Florida, 32224
Cedars Sinai Medical Center
Los Angeles, California, 90048
Mt Sinai Medical Center
Miami Beach, Florida, 33140
The Medical College of Wisconsin, Inc.
Milwaukee, Wisconsin, 53226
W VA University Mary Babb Randolph Cancer Center
Morgantown, West Virginia, 26506
Sarah Cannon Cancer Center
Nashville, Tennessee, 37203
New York Presbyterian Hospital - Weill-Cornell
New York, New York, 10021
Mayo Clinic
Rochester, Minnesota, 55905
Mayo Clinic Arizona
Scottsdale, Arizona, 85259
Cancer Center of Central Connecticut
Southington, Connecticut, 06489
Washington University
St Louis, Missouri, 63110
About this study
Official title: 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
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.
Read the detailed description
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.
- Conditions
- Multiple Myeloma
- Being tested
- Ixazomib, Lenalidomide, Dexamethasone
- Keywords
- Drug therapy
- Medical subject headings
- Multiple Myeloma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IxazomibDrug
Also called MLN9708, NINLARO®
Ixazomib capsules
LenalidomideDrug
Lenalidomide capsules
DexamethasoneDrug
Dexamethasone tablets
| Study group | Role | What they receive |
|---|---|---|
| Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | 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. Receives: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone |
| Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | 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. Receives: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone |
| Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | 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. Receives: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone |
| Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | 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. Receives: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone |
| Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone | Experimental | 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. Receives: Drug: Ixazomib; Drug: Lenalidomide; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)
Secondary outcomes (15)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 1 year after first dose of study drug
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Oct 2010 (estimated)
- Study start22 Nov 2010
- Primary completion8 Mar 2013
- Study completion2 Feb 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Multiple MyelomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- Millennium Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Monitor, Study director, Millennium Pharmaceuticals, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01217957
- Sponsor's protocol ID
- C16005
- Other IDs
- U1111-1176-7340
- Status last verified
- Mar 2018
- First submitted
- 24 Sep 2010
- Last updated
- 14 Mar 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Gupta N, Yang H, Hanley MJ, Zhang S, Liu R, Kumar S, Richardson PG, Skacel T, Venkatakrishnan K. Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.
PubMed 28803351Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-1512. doi: 10.1016/S1470-2045(14)71125-8. Epub 2014 Nov 14.
PubMed 25456369
Study at a glance
From the registry record, last updated by the sponsor on 14 Mar 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01217957
- Acronym / sponsor ID
- C16005
- Conditions
- Multiple Myeloma
- Keywords
- Drug therapy
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 22 Nov 2010 (actual)
- Primary completion
- 8 Mar 2013 (actual)
- Study completion
- 2 Feb 2018 (actual)
- First posted
- 8 Oct 2010 (estimated)
- Results
- Posted 27 Jan 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 5
| Arm | Type | Receives |
|---|---|---|
| Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | Drug: Ixazomib, Drug: Lenalidomide, Drug: DexamethasoneIn 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. |
| Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | Drug: Ixazomib, Drug: Lenalidomide, Drug: DexamethasoneIn 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. |
| Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | Drug: Ixazomib, Drug: Lenalidomide, Drug: DexamethasoneIn 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. |
| Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone | Experimental | Drug: Ixazomib, Drug: Lenalidomide, Drug: DexamethasoneIn 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. |
| Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone | Experimental | Drug: Ixazomib, Drug: Lenalidomide, Drug: DexamethasoneIn 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IxazomibAlso: MLN9708, NINLARO®Ixazomib capsules | Drug | Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone, Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone |
| LenalidomideLenalidomide capsules | Drug | Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone, Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone |
| DexamethasoneDexamethasone tablets | Drug | Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone, Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone, Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone |
Primary outcome
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability
Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 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 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.
Phase 2: Objective Response Rate (ORR) Following Treatment With the Combination Of Oral Ixazomib, Lenalidomide And Low-Dose Dexamethasone
Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 days)
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.
Phase 1: Recommended Phase 2 Dose of Ixazomib Given in Combination With Lenalidomide and Low-Dose Dexamethasone
Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)
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.
Phase 1: Maximum Tolerated Dose (MTD) of Ixazomib Administered Weekly in Combination With Lenalidomide and Low-Dose Dexamethasone
Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)
MTD of ixazomib will be determined by assessing adverse events and serious adverse events, clinical laboratory values, neurotoxicity grading, and vital sign measurements.
Phase 2: Percentage of Participants With Grade 3 or Higher AEs, SAEs and Treatment Discontinuation
Time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 787 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 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.
15 secondary outcomes
Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 15
Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib
Time frame: 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
Time frame: Cycle 1, Days 1 and 15
Phase 1: Rac: Accumulation Ratio of Ixazomib
Time frame: Cycle 1, Day 15
Phase 1: Emax: Maximum Observed Inhibition of Whole Blood 20S Proteasome
Time frame: 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
Time frame: 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)
Time frame: From the first dose of study treatment to the date of first documented progressive disease (Up to 787 days)
Phase 2: Overall Survival (OS)
Time frame: From the first dose of study treatment to the date of death (up to 787 days)
Phase 2: Overall Response Rate (ORR)
Time frame: Up to 787 days
Phase 2: Percentage of Participants With Complete Response (CR) and Very Good Partial Response (VGPR)
Time frame: 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)
Time frame: Cycles 3, 6, 9 and 12 (Up to 787 days)
Phase 2: Time to Best Response
Time frame: Up to 787 days
Phase 2: Duration of Response (DOR)
Time frame: Up to 787 days
Phase 2: Progression Free Survival (PFS)
Time frame: Up to 787 days
Phase 2: 1 Year Survival Rate
Time frame: 1 year after first dose of study drug
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Mar 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 28803351Gupta N, Yang H, Hanley MJ, Zhang S, Liu R, Kumar S, Richardson PG, Skacel T, Venkatakrishnan K. Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses. Target Oncol. 2017 Oct;12(5):643-654. doi: 10.1007/s11523-017-0524-3.
- Derived from this study: PubMed 25456369Kumar SK, Berdeja JG, Niesvizky R, Lonial S, Laubach JP, Hamadani M, Stewart AK, Hari P, Roy V, Vescio R, Kaufman JL, Berg D, Liao E, Di Bacco A, Estevam J, Gupta N, Hui AM, Rajkumar V, Richardson PG. Safety and tolerability of ixazomib, an oral proteasome inhibitor, in combination with lenalidomide and dexamethasone in patients with previously untreated multiple myeloma: an open-label phase 1/2 study. Lancet Oncol. 2014 Dec;15(13):1503-1512. doi: 10.1016/S1470-2045(14)71125-8. Epub 2014 Nov 14.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Monitor study director
Millennium Pharmaceuticals, Inc.
16 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Ixazomib, Lenalidomide and Dexamethasone in people with Multiple Myeloma, run by Millennium Pharmaceuticals, Inc. at 16 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Mar 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 16 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jan 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability (time frame: Until occurrence of progressive disease or unacceptable toxicity (Up to 336 days)). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01217957, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Mar 2018.