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

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ClinicalTrials.gov Identifier: NCT01217957
Recruitment Status : Completed
First Posted : October 8, 2010
Results First Posted : January 27, 2016
Last Update Posted : March 14, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief 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). 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.

Condition or disease Intervention/treatment Phase
Multiple Myeloma Drug: Ixazomib Drug: Lenalidomide Drug: Dexamethasone Phase 1 Phase 2

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 65 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 22, 2010
Actual Primary Completion Date : March 8, 2013
Actual Study Completion Date : February 2, 2018


Arm Intervention/treatment
Experimental: Phase 1: Ixazomib 1.68 mg/m^2 + Lenalidomide + Dexamethasone
In phase 1, ixazomib 1.68 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 1.68 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • MLN9708
  • NINLARO®

Drug: Lenalidomide
Lenalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets

Experimental: Phase 1: Ixazomib 2.23 mg/m^2 + Lenalidomide + Dexamethasone
In phase 1, ixazomib 2.23 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.23 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • MLN9708
  • NINLARO®

Drug: Lenalidomide
Lenalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets

Experimental: Phase 1: Ixazomib 2.97 mg/m^2 + Lenalidomide + Dexamethasone
In phase 1, ixazomib 2.97 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 2.97 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • MLN9708
  • NINLARO®

Drug: Lenalidomide
Lenalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets

Experimental: Phase 1: Ixazomib 3.95 mg/m^2 + Lenalidomide + Dexamethasone
In phase 1, ixazomib 3.95 mg/m^2, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 3.95 mg/m^2, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • MLN9708
  • NINLARO®

Drug: Lenalidomide
Lenalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets

Experimental: Phase 2: Ixazomib 4.0 mg + Lenalidomide + Dexamethasone
In phase 2, ixazomib 4.0 mg fixed dose, capsules, orally, once, on Days 1, 8 and 15; plus dexamethasone 40 mg, tablets, orally, once on Days 1, 8, 15 and 22; and lenalidomide 25 mg, capsules, orally, once on Days 1 through 21 of a 28-day cycle for up to 12 cycles. Cycle 13 and beyond, single agent ixazomib 4.0 mg fixed dose, capsules, orally, once on Days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
Drug: Ixazomib
Ixazomib capsules
Other Names:
  • MLN9708
  • NINLARO®

Drug: Lenalidomide
Lenalidomide capsules

Drug: Dexamethasone
Dexamethasone tablets




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.


Secondary Outcome Measures :
  1. Phase 1: Cmax: Maximum Observed Plasma Concentration for Ixazomib [ Time Frame: Cycle 1, Days 1 and 15 ]
    Cmax: Maximum Observed Plasma Concentration (Cmax) is the peak plasma concentration of ixazomib obtained directly from the plasma concentration-time curve.

  2. Phase 1: Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for Ixazomib [ Time Frame: Cycle 1, Days 1 and 15 ]
    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.

  3. 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 ]
    AUC(0-168) is a measure of the area under the plasma concentration-time curve from time 0 to 168 hours postdose for Ixazomib.

  4. Phase 1: Rac: Accumulation Ratio of Ixazomib [ Time Frame: Cycle 1, Day 15 ]
    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.

  5. 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 ]
    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.

  6. 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 ]
    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.

  7. 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) ]
    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).

  8. Phase 2: Overall Survival (OS) [ Time Frame: From the first dose of study treatment to the date of death (up to 787 days) ]
    OS was measured as the time in months from the first dose of study treatment to the date of death + 1 day.

  9. Phase 2: Overall Response Rate (ORR) [ Time Frame: Up to 787 days ]
    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.

  10. 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) ]
    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.

  11. 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) ]
    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.

  12. Phase 2: Time to Best Response [ Time Frame: Up to 787 days ]
    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.

  13. Phase 2: Duration of Response (DOR) [ Time Frame: Up to 787 days ]
    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.

  14. Phase 2: Progression Free Survival (PFS) [ Time Frame: Up to 787 days ]
    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.

  15. Phase 2: 1 Year Survival Rate [ Time Frame: 1 year after first dose of study drug ]
    1-year survival rate is defined as the percentage of participants still alive at year after the first dose of stud drug.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Each patient must meet all of the following eligibility criteria to be enrolled in the study:

  • Male or female patients 18 years or older
  • Previously untreated multiple myeloma diagnosed according to standard criteria requiring systemic treatment
  • Patients must have measurable disease
  • Nonsecretory multiple myeloma based upon standard M-component criteria (i.e., measurable serum/urine M-component) is not allowed unless the baseline serum free light chain level (Freelite™) is evaluated Patients must meet clinical laboratory criteria as specified in study protocol
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
  • Female and male patients MUST adhere to the guidelines of the lenalidomide pregnancy prevention program
  • Must be able to take concurrent aspirin 325 mg daily
  • Voluntary written consent

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

  • Peripheral neuropathy that is greater or equal to Grade 2
  • Female patients who are lactating or pregnant
  • Major surgery or radiotherapy within 14 days before the first dose of study drug
  • Serious infection requiring systemic antibiotic therapy within 14 days before the first dose of study drug
  • Diarrhea greater than Grade 1 based on the National Cancer Institute Common Terminology Criteria for Adverse Events
  • Central nervous system involvement.
  • Evidence of current uncontrolled cardiovascular conditions within the past 6 months
  • Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
  • Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
  • Known gastrointestinal condition that could interfere with swallowing or the oral absorption or tolerance of ixazomib
  • No other prior malignancy within 2 years except nonmelanoma skin cancer or carcinoma in situ of any type if they have undergone complete resection

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01217957


Locations
United States, Arizona
Mayo Clinic Arizona
Scottsdale, Arizona, United States, 85259
United States, California
Cedars Sinai Medical Center
Los Angeles, California, United States, 90048
United States, Colorado
Rocky Mountain Cancer Center Rose
Denver, Colorado, United States, 80218
United States, Connecticut
Cancer Center of Central Connecticut
Southington, Connecticut, United States, 06489
United States, Florida
Mayo Clinic Jacksonville
Jacksonville, Florida, United States, 32224
Mt Sinai Medical Center
Miami Beach, Florida, United States, 33140
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Maryland
Harry and Jeannette Weinberg Cancer Center at Franklin Square Hospital
Baltimore, Maryland, United States, 21215
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, Michigan
Karmanos Cancer Institute
Detroit, Michigan, United States, 48201
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University
Saint Louis, Missouri, United States, 63110
United States, New York
New York Presbyterian Hospital - Weill-Cornell
New York, New York, United States, 10021
United States, Tennessee
Sarah Cannon Cancer Center
Nashville, Tennessee, United States, 37203
United States, West Virginia
W VA University Mary Babb Randolph Cancer Center
Morgantown, West Virginia, United States, 26506
United States, Wisconsin
The Medical College of Wisconsin, Inc.
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT01217957     History of Changes
Other Study ID Numbers: C16005
U1111-1176-7340 ( Registry Identifier: WHO )
First Posted: October 8, 2010    Key Record Dates
Results First Posted: January 27, 2016
Last Update Posted: March 14, 2018
Last Verified: March 2018

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Lenalidomide
Ixazomib
Thalidomide
BB 1101
Glycine
Proteasome Inhibitors
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones