Light-Chain AmyloidosisPhase 1NCT01318902
Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis
A Phase 1 study testing Ixazomib and Dexamethasone in people with Light-Chain Amyloidosis, run by Millennium Pharmaceuticals, Inc. at 10 sites in 5 countries.
Trial summary
This study will include participants with previously treated systemic relapsed or refractory light-chain (AL) amyloidosis who require further therapy and will be aimed at determining the safety profile and the maximum tolerated dose/recommended phase 2 dose of MLN9078 (Ixazomib) administered orally. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Light-Chain Amyloidosis
- What is being tested?
- Ixazomib and Dexamethasone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 27 participants
- Where
- 10 sitesin 5 countries
- Study dates
- 27 Apr 2011to 13 Nov 2018
- 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
- Male or female participants 18 years or older
- Biopsy-proven systemic relapsed or refractory light-chain (AL) amyloidosis, which after at least 1 prior therapy, in the investigator's opinion, requires further treatment
- If received stem cell transplant, must be at least 3 months posttransplantation and recovered from side effects
- Must have measurable disease defined as serum differential free light chain concentration ≥ 40 mg/L
- Must have objective measurable organ (heart or kidney) amyloid involvement
- Must have cardiac biomarker risk stage I or II disease
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- Must have adequate hematologic, hepatic, and renal function
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
- Female participants who are postmenopausal, surgically sterile, or agree to practice 2 effective methods of contraception or agree to abstain from heterosexual intercourse
- Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse
- Voluntary written consent
Who cannot join
- Peripheral neuropathy that is greater or equal to Grade 2
- Cardiac status as described in protocol
- Severe diarrhea (≥ Grade 3) not controllable with medication or requires administration of total parenteral nutrition
- Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
- Uncontrolled infection requiring systematic antibiotics
- Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
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- Presence of other active malignancy with the exception of nonmelanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limit, or any completely resected carcinoma in situ
- Female participants who are lactating or pregnant
- Major surgery within 14 days before the first dose of study drug
- Serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to the protocol
Trial locations and contacts
10 sites in 5 countries.
10 sites in 5 countries
United States6 sites
Tufts Medical Center
Boston, Massachusetts, 02111
Boston Medical Center
Boston, Massachusetts, 02118
Barbara Ann Karmanos Cancer Institute
Detroit, Michigan, 48201
Mount Sinai Medical Center
New York, New York, 10029
Fox Chase Cancer Center
Philadelphia, Pennsylvania, 19111
Mayo Clinic
Rochester, Minnesota, 55905
France1 site
CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis
Limoges, 87042
Germany1 site
Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie
Heidelberg, D-69120
Italy1 site
Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo
Pavia, 27100
About this study
Official title: An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) Amyloidosis Who Require Further Treatment
This study will include participants with previously treated systemic relapsed or refractory light-chain (AL) amyloidosis who require further therapy and will be aimed at determining the safety profile and the maximum tolerated dose/recommended phase 2 dose of MLN9078 (Ixazomib) administered orally.
- Conditions
- Light-Chain Amyloidosis
- Being tested
- Ixazomib, Dexamethasone
- Keywords
- Drug therapy
- Medical subject headings
- Immunoglobulin Light-chain Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IxazomibDrug
Also called MLN9708
Ixazomib capsules.
DexamethasoneDrug
Dexamethasone tablets.
| Study group | Role | What they receive |
|---|---|---|
| Dose Escalation Cohort: Ixazomib 4.0 mg | Experimental | Ixazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. Receives: Drug: Ixazomib; Drug: Dexamethasone |
| Dose Escalation Cohort: Ixazomib 5.5 mg | Experimental | Ixazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. Receives: Drug: Ixazomib; Drug: Dexamethasone |
| Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive) | Experimental | Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Receives: Drug: Ixazomib |
| Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed) | Experimental | Ixazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Receives: Drug: Ixazomib |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Measured: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE
The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.
Measured: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Number of Participants With Peripheral Neuropathy Reported as a TEAE
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Measured: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Maximum Tolerated Dose (MTD) of Ixazomib
MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT). DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events, v 4.03 as: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days;Grade 3 neutropenia with fever or infection;Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding;platelet count <10,000/mm^3;Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy;Grade 3 QTc prolongation (QTc >500 msec);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia;or <1 week Grade 3 fatigue;delay in initiation of the subsequent therapy cycle by >2 weeks;other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation, considered possibly related to therapy as assessed by Investigator.
Measured: Cycle 1 (28 days)
Recommended Phase 2 Dose (RP2D) of Ixazomib
The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). The RP2D of Ixazomib was determined in dose escalation group on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) data observed in Cycle 1.
Measured: Cycle 1 (28 days)
Secondary outcomes (18)
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Tmax: Time of First Occurrence of Cmax for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib
Measured: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment
Organ response rate was estimated as the number of participants with documented organ response (ie. Heart or kidney ). Treatment response of amyloid-related organs were identified based on national cancer institute, common terminology criteria for adverse events (NCI CTCAE) Version 4.02 criteria.
Measured: At Cycles 3, 6, 9, and 12; every 6 months thereafter until disease progression or the initiation of subsequent antineoplastic therapy and at end of treatment (EOT) visit (Up to approximately 12 months)
Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment
The overall hematologic response rate is defined as number of participants with complete response (CR) or partial response (PR) or very good partial response (VGPR) as assessed by the investigator. Response is determined according to standardized criteria using a central laboratory. CR=serum and urine negative for monoclonal protein by immunofixation; or free light chain ratio normal; < 5% plasma cells in bone marrow without clonal dominance. PR=reduction in dFLC > 50%. VGPR= dFLC < 40 mg/L.
Measured: Day 22 to 28 in each cycle and end of treatment visit; then every 6 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy (Up to approximately 12 months)
Time to First Hematologic Response
Time to first hematologic response, measured as the time from the first dose of ixazomib to the date of first documentation of a hematologic response.
Measured: From the date of the first dose of ixazomib to the date of first documentation of a hematologic response (Up to approximately 12 months)
Time to First Organ Response
Time to first organ response, measured as the time from the first dose of ixazomib to the date of first documentation of a organ response.
Measured: From the date of the first dose of ixazomib to the date of first documentation of a organ response (Up to approximately 12 months)
Duration of Hematologic Response
Duration of hematologic response, measured as the time from the date of first documentation of a hematologic response to the date of hematologic disease progression.
Measured: From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)
Duration of Organ Response
Duration of organ response, measured as the time from the date of first documentation of a organ response to the date of organ disease progression.
Measured: From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)
Time to Hematologic Disease Progression
Time to hematologic progression, measured as the time from the date of the first dose of ixazomib to the date of first documented hematologic disease progression.
Measured: From the date of the first dose of ixazomib to the date of first documented hematologic disease progression (Up to approximately 12 months)
Time to Organ Disease Progression
Time to organ disease progression, measured as the time from the date of the first dose of ixazomib to the date of first documented organ disease progression.
Measured: From the date of the first dose of ixazomib to the date of first documented organ disease progression (Up to approximately 12 months)
Hematologic Disease Progression-Free Survival (PFS)
Hematologic disease PFS, measured as the time from the date of the first dose of ixazomib to the date of hematologic disease progression or death.
Measured: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to approximately 12 months)
Organ Disease Progression-Free Survival (PFS)
Organ disease PFS, measured as the time from the date of the first dose of ixazomib to the date of organ disease progression or death.
Measured: From the date of the first dose of ixazomib to the date of organ disease progression or death (Up to approximately 12 months)
Percentage of Participants With One Year Hematologic Disease PFS
One-year survival, defined as the patient survival probability at 1 year after the date of first dose of ixazomib.
Measured: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Mar 2011 (estimated)
- Study start27 Apr 2011
- Primary completion13 Nov 2018
- Study completion13 Nov 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 (4)Papers the sponsor has linked to this study.
- Other trials for Light-Chain AmyloidosisStudies 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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 27 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
- NCT01318902
- Sponsor's protocol ID
- C16007
- Other IDs
- 2010-022497-13, U1111-1168-1192
- Status last verified
- Mar 2020
- First submitted
- 15 Mar 2011
- Last updated
- 1 Apr 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- Yes: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
Publications
Sanchorawala V, Comenzo R, Zonder J, Kukreti V, Cohen A, Dispenzieri A, et al. MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed or refractory lightchain (AL) amyloidosis. Clinical Lymphoma Myeloma and Leukemia 2013;13(suppl 1):S153-4; abstr P-229.
Sanchorawala V, Zonder J, Comenzo R, Schönland S, Dispenzieri A, Berg D, et al. Poster Presentation: Phase 1 study of MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012.
Merlini G, Sanchorawala V, Zonder J, Kukreti V, Schonland S, Jaccard A, et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): results of a phase 1 study. In: 54th ASH Annual Meeting and Exposition; 2012 8-11 December; Atlanta, GA; p. abstr 731.
Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schonland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 May 26.
PubMed 28550039
Study at a glance
From the registry record, last updated by the sponsor on 1 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Open-Label, Dose-Escalation, Phase 1 Study of the Oral Formulation of MLN9708 Administered Weekly in Adult Patients With Relapsed or Refractory Light-Chain (AL) Amyloidosis Who Require Further Treatment
- ClinicalTrials.gov ID
- NCT01318902
- Acronym / sponsor ID
- C16007
- Conditions
- Light-Chain Amyloidosis
- Keywords
- Drug therapy
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 27 participants (actual)
- Lead sponsor
- Millennium Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 27 Apr 2011 (actual)
- Primary completion
- 13 Nov 2018 (actual)
- Study completion
- 13 Nov 2018 (actual)
- First posted
- 21 Mar 2011 (estimated)
- Results
- Posted 1 Apr 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study will include participants with previously treated systemic relapsed or refractory light-chain (AL) amyloidosis who require further therapy and will be aimed at determining the safety profile and the maximum tolerated dose/recommended phase 2 dose of MLN9078 (Ixazomib) administered orally.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Dose Escalation Cohort: Ixazomib 4.0 mg | Experimental | Drug: Ixazomib, Drug: DexamethasoneIxazomib 4.0 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. |
| Dose Escalation Cohort: Ixazomib 5.5 mg | Experimental | Drug: Ixazomib, Drug: DexamethasoneIxazomib 5.5 mg, capsule, orally, once weekly on Days 1, 8 and 15 during each 28-day treatment cycle for 3 cycles. If there was no hematologic response, dexamethasone 40 mg, tablet, orally was added once on Days 1 to 4 of every cycle, beginning in Cycle 4 for 3 additional cycles. If there was no hematologic response the participant was discontinued. Participants with hematologic response continued treatment up to maximum 12 cycles. |
| Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive) | Experimental | Drug: IxazomibIxazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until progressive disease (PD) or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were not treated with any other proteasome inhibitor (PI). Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. |
| Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed) | Experimental | Drug: IxazomibIxazomib 4.0 mg, capsule, orally, on Days 1, 8 and 15 during a 28-day treatment cycle until PD or unacceptable toxicity, for participants with relapsed or refractory amyloidosis and who were previously treated with any other PI. Duration of treatment was up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Male or female participants 18 years or older
- Biopsy-proven systemic relapsed or refractory light-chain (AL) amyloidosis, which after at least 1 prior therapy, in the investigator's opinion, requires further treatment
- If received stem cell transplant, must be at least 3 months posttransplantation and recovered from side effects
- Must have measurable disease defined as serum differential free light chain concentration ≥ 40 mg/L
- Must have objective measurable organ (heart or kidney) amyloid involvement
Key exclusion criteria (10 listed)
- Peripheral neuropathy that is greater or equal to Grade 2
- Cardiac status as described in protocol
- Severe diarrhea (≥ Grade 3) not controllable with medication or requires administration of total parenteral nutrition
- Known gastrointestinal condition or procedure that could interfere with swallowing or the oral absorption of tolerance of MLN9708
- Uncontrolled infection requiring systematic antibiotics
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: MLN9708Ixazomib capsules. | Drug | Dose Escalation Cohort: Ixazomib 4.0 mg, Dose Escalation Cohort: Ixazomib 5.5 mg, Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed), Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive) |
| DexamethasoneDexamethasone tablets. | Drug | Dose Escalation Cohort: Ixazomib 4.0 mg, Dose Escalation Cohort: Ixazomib 5.5 mg |
Primary outcome
Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Time frame: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
An AE is any untoward medical occurrence in a participant administered a medicinal investigational drug. The untoward medical occurrence does not necessarily have to have a causal relationship with treatment. An SAE is any untoward medical occurrence that results in death; is life-threatening; requires inpatient hospitalization or prolongation of present hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is a medically important event that may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the participant or may require intervention to prevent one of other outcomes listed in definition above, or involves suspected transmission via a medicinal product of an infectious agent. A TEAE is defined as an AE that occurs after administration of first dose of study drug and through 30 days after last dose of study drug or until start of subsequent antineoplastic therapy.
Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE
Time frame: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
The number of participants with any clinically significant abnormal standard safety laboratory values collected throughout the study reported as TEAEs. Parameters assessed were hematology, serum chemistry and urinalysis. Abnormal laboratory values were assessed as an AE if that value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered by the investigator to be a clinically significant change from baseline.
Number of Participants With Peripheral Neuropathy Reported as a TEAE
Time frame: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Maximum Tolerated Dose (MTD) of Ixazomib
Time frame: Cycle 1 (28 days)
MTD was highest dose of Ixazomib, at which <=1 of 6 participants experienced dose-limiting toxicity (DLT). DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events, v 4.03 as: Grade 4 neutropenia (absolute neutrophil count <500 cells/mm^3) for >7 days;Grade 3 neutropenia with fever or infection;Grade 4 thrombocytopenia (platelets < 25,000/mm^3) for >7 days;Grade 3 thrombocytopenia with clinically significant bleeding;platelet count <10,000/mm^3;Grade 2 peripheral neuropathy with pain or >=Grade 3 peripheral neuropathy; >=Grade 3 nausea/emesis, diarrhea controlled by supportive therapy;Grade 3 QTc prolongation (QTc >500 msec);any >=Grade 3 nonhematologic toxicity except Grade 3 arthralgia/myalgia;or <1 week Grade 3 fatigue;delay in initiation of the subsequent therapy cycle by >2 weeks;other >=Grade 2 study drug-related nonhematologic toxicities requiring therapy discontinuation, considered possibly related to therapy as assessed by Investigator.
Recommended Phase 2 Dose (RP2D) of Ixazomib
Time frame: Cycle 1 (28 days)
The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable participants experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of Cycle 1). The RP2D of Ixazomib was determined in dose escalation group on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) data observed in Cycle 1.
18 secondary outcomes
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Tmax: Time of First Occurrence of Cmax for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib
Time frame: Cycle 1: Day 1 (MTD cohort participants only, 4.0 mg) and Day 15 (all participants enrolled in the study): predose (within 1 hour (hr) before dosing), and postdose at multiple timepoints up to 168 hr
Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment
Time frame: At Cycles 3, 6, 9, and 12; every 6 months thereafter until disease progression or the initiation of subsequent antineoplastic therapy and at end of treatment (EOT) visit (Up to approximately 12 months)
Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment
Time frame: Day 22 to 28 in each cycle and end of treatment visit; then every 6 weeks thereafter until disease progression or initiation of subsequent antineoplastic therapy (Up to approximately 12 months)
Time to First Hematologic Response
Time frame: From the date of the first dose of ixazomib to the date of first documentation of a hematologic response (Up to approximately 12 months)
Time to First Organ Response
Time frame: From the date of the first dose of ixazomib to the date of first documentation of a organ response (Up to approximately 12 months)
Duration of Hematologic Response
Time frame: From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)
Duration of Organ Response
Time frame: From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)
Time to Hematologic Disease Progression
Time frame: From the date of the first dose of ixazomib to the date of first documented hematologic disease progression (Up to approximately 12 months)
Time to Organ Disease Progression
Time frame: From the date of the first dose of ixazomib to the date of first documented organ disease progression (Up to approximately 12 months)
Hematologic Disease Progression-Free Survival (PFS)
Time frame: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to approximately 12 months)
Organ Disease Progression-Free Survival (PFS)
Time frame: From the date of the first dose of ixazomib to the date of organ disease progression or death (Up to approximately 12 months)
Percentage of Participants With One Year Hematologic Disease PFS
Time frame: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Apr 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publicationSanchorawala V, Comenzo R, Zonder J, Kukreti V, Cohen A, Dispenzieri A, et al. MLN9708, an investigational oral proteasome inhibitor (PI), in relapsed or refractory lightchain (AL) amyloidosis. Clinical Lymphoma Myeloma and Leukemia 2013;13(suppl 1):S153-4; abstr P-229.
- Results publicationSanchorawala V, Zonder J, Comenzo R, Schönland S, Dispenzieri A, Berg D, et al. Poster Presentation: Phase 1 study of MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis. XIII International Symposium on Amyloidosis, Groningen, The Netherlands 2012.
- Results publicationMerlini G, Sanchorawala V, Zonder J, Kukreti V, Schonland S, Jaccard A, et al. MLN9708, a novel, investigational oral proteasome inhibitor, in patients with relapsed or refractory light-chain amyloidosis (AL): results of a phase 1 study. In: 54th ASH Annual Meeting and Exposition; 2012 8-11 December; Atlanta, GA; p. abstr 731.
- Derived from this study: PubMed 28550039Sanchorawala V, Palladini G, Kukreti V, Zonder JA, Cohen AD, Seldin DC, Dispenzieri A, Jaccard A, Schonland SO, Berg D, Yang H, Gupta N, Hui AM, Comenzo RL, Merlini G. A phase 1/2 study of the oral proteasome inhibitor ixazomib in relapsed or refractory AL amyloidosis. Blood. 2017 Aug 3;130(5):597-605. doi: 10.1182/blood-2017-03-771220. Epub 2017 May 26.
- Individual participant dataSharing planned: Yes. Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.
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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.
10 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Ixazomib and Dexamethasone in people with Light-Chain Amyloidosis, run by Millennium Pharmaceuticals, Inc. at 10 sites in 5 countries.
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 11 inclusion and 10 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 1 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in United States, Canada, France, Germany, Italy. 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 1 Apr 2020). 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 With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) (time frame: From the first dose of study drug plus 30 days after last dose of study drug or until the initiation of subsequent antineoplastic therapy (Up to approximately 13 months)). 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 NCT01318902, which also lists 4 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 1 Apr 2020.