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NCT00963820 · REGISTRY CONDITION SEARCH

Study Evaluating the Safety and Tolerability of Weekly Dosing of Oral IXAZOMIB in Adult Patients With Relapsed and Refractory Multiple Myeloma

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase
PHASE1
Status at capture
COMPLETED
Registry last update
2018-01-10

The primary objective of this study is to determine the safety profile, tolerability, and maximum tolerated dose of ixazomib citrate (MLN9708) when taken orally on a weekly dosing schedule by patients with relapsed and refractory multiple myeloma (RRMM). Secondary objectives include pharmacokinetics and response rates.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Number of Participants Reporting One or More Treatment-Emergent Adverse Events and Serious Adverse Events

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outcome · POSTED

Cmax: Maximum Observed Plasma Concentration for MLN2238

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outcome · POSTED

Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238

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outcome · POSTED

AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238

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outcome · POSTED

Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238

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outcome · POSTED

Terminal Elimination Rate Constant (λz) for MLN2238

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outcome · POSTED

Terminal Phase Elimination Half-life (T1/2) for MLN2238

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outcome · POSTED

Emax: Maximum Inhibition

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outcome · POSTED

TEmax: Time of Occurrence of Emax

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outcome · POSTED

Overall Response to Treatment With Ixazomib Citrate Based on Investigator's Evaluation Over Time

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outcome · POSTED

Neurotoxicity Grading

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: Each patient must meet all of the following eligibility criteria to be enrolled in the study: * Adult patients with multiple myeloma who have relapsed following at least 2 lines of therapy. * Patients must have measurable disease. * Appropriate functional status, including the recovery from the effects of prior antineoplastic therapy, and acceptable organ function as described in the protocol. * Female patients who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse. * Male patients who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse. * Willing and able to give written informed consent. * Suitable venous access for study-required blood sampling. Exclusion Criteria: * Peripheral neuropathy that is greater or equal to Grade 2. * Major surgery or, serious infections, or infections that required systemic antibiotic therapy within 14 days before the first dose of study drug. * Life-threatening illness unrelated to cancer. * Diarrhea that is greater than Grade 1 as outlined in the protocol * Systemic antineoplastic or radiation therapy within 14 days or cytotoxic agents, or treatment with any investigational products within 21 days before the first dose of study treatment. * Treatment with any investigational proteasome inhibitor. * Systemic treatment with prohibited medications that are outlined in the protocol within 14 days of study treatment. * Ongoing therapy with corticosteroids greater than 10mg of prednisone or its equivalent per day. * Central nervous system involvement. * Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction 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 (GI) disease or GI procedure that could interfere with the oral absorption of tolerance of IXAZOMIB including difficulty swallowing.
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    Ixazomib citrate, 0.24 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate
    intervention Names
    1. Drug: Ixazomib citrate
    label
    0.24 mg/m^2
    type
    EXPERIMENTAL
  2. description
    Ixazomib citrate, 0.48 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    0.48 mg/m^2
    type
    EXPERIMENTAL
  3. description
    Ixazomib citrate, 0.80 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    0.80 mg/m^2
    type
    EXPERIMENTAL
  4. description
    Ixazomib citrate, 1.20 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    1.20 mg/m^2
    type
    EXPERIMENTAL
  5. description
    Ixazomib citrate, 1.68 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    1.68 mg/m^2
    type
    EXPERIMENTAL
  6. description
    Ixazomib citrate, 2.23 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    2.23 mg/m^2
    type
    EXPERIMENTAL
  7. description
    Ixazomib citrate, 2.97 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    2.97 mg/m^2
    type
    EXPERIMENTAL
  8. description
    Ixazomib citrate, 3.95 mg/m\^2, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the dose escalation period. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    3.95 mg/m^2
    type
    EXPERIMENTAL
  9. description
    Ixazomib citrate, 2.97 mg/m\^2 established Maximum Tolerated Dose (MTD), capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the Relapsed and Refractory (RR) expansion cohort. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    Relapsed and Refractory (RR)
    type
    EXPERIMENTAL
  10. description
    Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the VELCADE-relapsed (VR) expansion cohort. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    VELCADE-Relapsed (VR)
    type
    EXPERIMENTAL
  11. description
    Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in expansion cohort of participants who were proteasome inhibitor-naïve (PI naïve). All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    PI naïve
    type
    EXPERIMENTAL
  12. description
    Ixazomib citrate, 2.97 mg/m\^2 established MTD, capsules, orally, once weekly on Days 1, 8, and 15 of a 28-day cycle in the expansion cohort of participants who received their last dose of carfilzomib between 21 and 60 days prior to the first dose of ixazomib citrate. All dose amounts are expressed as the dose of ixazomib, the biologically active moiety of ixazomib citrate.
    intervention Names
    1. Drug: Ixazomib citrate
    label
    Carfilzomib
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. 0.24 mg/m^2
    2. 0.48 mg/m^2
    3. 0.80 mg/m^2
    4. 1.20 mg/m^2
    5. 1.68 mg/m^2
    6. 2.23 mg/m^2
    7. 2.97 mg/m^2
    8. 3.95 mg/m^2
    9. Carfilzomib
    10. PI naïve
    11. Relapsed and Refractory (RR)
    12. VELCADE-Relapsed (VR)
    description
    Ixazomib citrate capsules
    name
    Ixazomib citrate
    other Names
    1. MLN9708
    type
    DRUG
Study design
allocation
NON_RANDOMIZED
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
60
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    An Adverse Event 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 (eg, 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 treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) was any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
    measure
    Number of Participants Reporting One or More Treatment-Emergent Adverse Events and Serious Adverse Events
    time Frame
    From the first dose through 30 days after last dose of ixazomib citrate or until the start of subsequent antineoplastic therapy (Up to 354 days)
  2. description
    Neurotoxicity is graded using participant responses to 11 functional questions on a 5-point scale, where 0=Not at all and 4=Very much, using the Functional Assessment of Cancer Therapy/Gynecology Oncology Group - Neurotoxicity Questionnaire, Version 4.0(14). Neurotoxicity subscale is a sum of 11 reversed item scores where each original score is transformed as (4 - score). The highest possible score is 44, and a higher score indicates more neurotoxicity.
    measure
    Neurotoxicity Grading
    time Frame
    Cycle 1 Day 1 and End of Study (Up to 354 days)
secondary Outcomes
  1. description
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    Cmax: Maximum Observed Plasma Concentration for MLN2238
    time Frame
    Days 1 and 15 of Cycle 1
  2. description
    Tmax: Time to reach the maximum observed plasma concentration (Cmax), equal to time to Cmax. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    Tmax: Time to Reach the Maximum Observed Plasma Concentration (Cmax) for MLN2238
    time Frame
    Days 1 and 15 of Cycle 1
  3. description
    AUC(0-168) is a measure of the area under the plasma concentration-time curve over the dosing interval (tau) (AUC\[0-tau\]), where tau is the length of the dosing interval - 168 hours in this study). MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    AUC(0-168): Area Under the Plasma Concentration-Time Curve From Time 0 to 168 Hours Postdose for MLN2238
    time Frame
    Days 1 and 15 of Cycle 1
  4. description
    MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    Accumulation Ratio: Day 15 AUC0-168 / Day 1 AUC0-168 for MLN2238
    time Frame
    Day 15 of Cycle 1
  5. description
    Terminal elimination rate constant (λz) is the rate at which drugs are eliminated from the body and the values were used for calculation of T1/2. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    Terminal Elimination Rate Constant (λz) for MLN2238
    time Frame
    Day 15 of Cycle 1
  6. description
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).
    measure
    Terminal Phase Elimination Half-life (T1/2) for MLN2238
    time Frame
    Day 15 of Cycle 1
  7. description
    A Whole Blood 20S Proteasome Inhibition Parameter. There were no subjects in the Pharmacodynamic (PD) Analysis Set for the 2.23 mg/m\^2 cohort, so PD tables do not include that arm.
    measure
    Emax: Maximum Inhibition
    time Frame
    Days 1 and 15 of Cycle 1
  8. measure
    TEmax: Time of Occurrence of Emax
    time Frame
    Days 1 and 15 of Cycle 1
  9. description
    Responses were based on International Myeloma Working Group Uniform Criteria. Complete Response (CR)=Negative immunofixation on serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Partial Response (PR)= reduction in M-Protein ≥50% in serum and ≥90% in 24-hour urine. If M-protein unmeasurable, ≥50% decrease in difference of involved and uninvolved Free Light Chain (FLC). If M-protein and FLC unmeasurable, ≥50% reduction in plasma cells is required, if baseline bone marrow plasma cell ≥30%. And ≥50% reduction in the size of soft tissue plasmacytomas. Minimal Response (MR)= 25-49% reduction in serum paraprotein for 6 weeks. 50-89% reduction in 24 hour urinary light chain excretion for 6 weeks. For Non-secretory myeloma patients, 25-49 % reduction in plasma cells in bone marrow and trephine biopsy for a 6 weeks. 25-49% reduction in the size of soft tissue plasmacytomas. No increase in the size or number of lytic bone lesions.
    measure
    Overall Response to Treatment With Ixazomib Citrate Based on Investigator's Evaluation Over Time
    time Frame
    Up to 354 days
Full study description
brief Summary
The primary objective of this study is to determine the safety profile, tolerability, and maximum tolerated dose of ixazomib citrate (MLN9708) when taken orally on a weekly dosing schedule by patients with relapsed and refractory multiple myeloma (RRMM). Secondary objectives include pharmacokinetics and response rates.
detailed Description
The drug being tested in this study is called ixazomib citrate (MLN9708). Ixazomib citrate is being tested for people who have multiple myeloma who have relapsed after treatment or become unresponsive to treatment. This study will determine the maximum tolerated dose (MTD) of ixazomib citrate using a dose escalation scheme. Once MTD is established, participants will be enrolled at MTD into one of the 4 expansion cohorts to characterize the safety, tolerability and efficacy of MLN9708. Blood samples for safety labs, hematology, serum chemistry and pharmacokinetic evaluations will be obtained at the timepoints specified. Disease response assessment is to be performed on the first day of every other cycle beginning with Cycle 3. The study will enroll approximately 60 patients. All participants will receive treatment with ixazomib citrate. This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 60 days, and participants will make 12-16 visits to the clinic for study procedures.
Source references
references
  1. citation
    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.
    pmid
    28803351
    type
    DERIVED
  2. citation
    Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, Hui AM, Gupta N, Di Bacco A, Yu J, Shou Y, Niesvizky R. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood. 2014 Aug 14;124(7):1047-55. doi: 10.1182/blood-2014-01-548941. Epub 2014 Jun 5.
    pmid
    24904120
    type
    DERIVED
Source notices and limitations
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    Preserved source evidence · Not medical advice