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Multiple MyelomaPhase 1NCT00963820

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

A Phase 1 study testing Ixazomib citrate in people with Multiple Myeloma, run by Millennium Pharmaceuticals, Inc. at 6 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. 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 citrate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
6 sitesUnited States
Study dates
Oct 2009to Jan 2014
Phase
Phase 1
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:
  • 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.

Who cannot join

  • 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.
Show all 13Show fewer
  • 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.

Trial locations and contacts

6 sites in 1 country.

6 sites in 1 country

United States6 sites

  • University of Chicago

    Chicago, Illinois, 60637

  • Weill-Cornell Medical College

    New York, New York, 10011

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • Mayo Clinic- Scottsdale

    Scottsdale, Arizona, 85259

  • Fred Hutchinson Cancer Research Center

    Seattle, Washington, 98109

  • James R. Berenson, MD, Inc

    West Hollywood, California, 90069

Other trials in United States

About this study

Official title: An Open-Label, Dose-Escalation, Phase 1 Study Evaluating the Safety and Tolerability of Weekly Dosing of the Oral Form of MLN9708, a Second-Generation Proteasome Inhibitor, in Adult Patients With Relapsed and Refractory Multiple Myeloma

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.

Read the 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.

Being tested
Ixazomib citrate
Keywords
Relapsed multiple myeloma, Refractory multiple myeloma, 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.

  • Ixazomib citrateDrug

    Also called MLN9708

    Ixazomib citrate capsules

Study groups in NCT00963820
Study groupRoleWhat they receive
0.24 mg/m^2ExperimentalIxazomib 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
Receives: Drug: Ixazomib citrate
0.48 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
0.80 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
1.20 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
1.68 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
2.23 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
2.97 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
3.95 mg/m^2ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
Relapsed and Refractory (RR)ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
VELCADE-Relapsed (VR)ExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
PI naïveExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate
CarfilzomibExperimentalIxazomib 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.
Receives: Drug: Ixazomib citrate

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    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.

    Measured: 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. Neurotoxicity Grading

    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.

    Measured: Cycle 1 Day 1 and End of Study (Up to 354 days)

Secondary outcomes (9)

  1. Cmax: Maximum Observed Plasma Concentration for MLN2238

    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).

    Measured: Days 1 and 15 of Cycle 1

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

    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).

    Measured: Days 1 and 15 of Cycle 1

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

    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).

    Measured: Days 1 and 15 of Cycle 1

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

    MLN2238 is the complete hydrolysis product of the study drug ixazomib citrate (MLN9708).

    Measured: Day 15 of Cycle 1

  5. Terminal Elimination Rate Constant (λz) for MLN2238

    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).

    Measured: Day 15 of Cycle 1

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

    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).

    Measured: Day 15 of Cycle 1

  7. Emax: Maximum Inhibition

    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.

    Measured: Days 1 and 15 of Cycle 1

  8. TEmax: Time of Occurrence of Emax

    Measured: Days 1 and 15 of Cycle 1

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

    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.

    Measured: Up to 354 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted24 Aug 2009 (estimated)
  2. Study startOct 2009
  3. Primary completionSep 2012
  4. Study completionJan 2014

Resources

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
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00963820
Sponsor's protocol ID
C16004
Other IDs
U1111-1166-8401
Status last verified
Dec 2017
First submitted
20 Aug 2009
Last updated
10 Jan 2018
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 28803351

  • 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.

    PubMed 24904120

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Ixazomib citrate in people with Multiple Myeloma, run by Millennium Pharmaceuticals, Inc. at 6 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 8 inclusion and 13 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 10 Jan 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 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 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.

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 28 Aug 2015). 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?

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)). The study lists 2 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 NCT00963820, 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 10 Jan 2018.

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