Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis

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.

Study Overview

• Status: Completed
• Conditions: Light-Chain Amyloidosis
• Intervention / Treatment: Drug: Dexamethasone; Drug: Ixazomib

• Study Type: Interventional
• Enrollment (Actual): 27
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • University Health Network
• France
  • Limoges Cedex, France, 87042
    • CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis
• Germany
  • Heidelberg, Germany, D-69120
    • Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie
• Italy
  • Pavia, Italy, 27100
    • Amyloidosis Research & Treatment Center, Fondazione Irccs Policlinico San Matteo
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Fox Chase Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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
• 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

Exclusion Criteria

• 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
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Cohort: Ixazomib 4.0 mg; 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.	Drug: Dexamethasone; Dexamethasone tablets.; Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Dose Escalation Cohort: Ixazomib 5.5 mg; 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.	Drug: Dexamethasone; Dexamethasone tablets.; Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive); 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.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708
Experimental: Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed); 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.	Drug: Ixazomib; Ixazomib capsules.; Other Names: MLN9708

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	Cycle 1 (28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: Maximum Observed Plasma Concentration for Ixazomib		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		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		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		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		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		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		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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Publications and helpful links

General 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. Erratum In: Blood. 2020 Mar 26;135(13):1071.

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2011
• Primary Completion (Actual): November 13, 2018
• Study Completion (Actual): November 13, 2018

Study Registration Dates

• First Submitted: March 15, 2011
• First Submitted That Met QC Criteria: March 18, 2011
• First Posted (Estimate): March 21, 2011

Study Record Updates

• Last Update Posted (Actual): April 1, 2020
• Last Update Submitted That Met QC Criteria: March 18, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Drug therapy
• Additional Relevant MeSH Terms: Metabolic Diseases; Proteostasis Deficiencies; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Dexamethasone; Ixazomib
• Other Study ID Numbers: C16007; 2010-022497-13 (EudraCT Number); U1111-1168-1192 (Registry Identifier: WHO (UTN ))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: 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.