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

NCT01318902 | Completed Phase 1 Results

• 3 other identifiers: C160072010-022497-13U1111-1168-1192
• Study Type: interventional
• Target: 27
• Locations: 5 countries
• Sites: 10

Brief 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.

Conditions

Light-Chain Amyloidosis

Keywords

Drug therapy

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (18)

• 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

Study Arms (4)

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.

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.

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.

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.

Drug: Ixazomib

Interventions

Ixazomib DRUG

Ixazomib capsules.

Also known as: MLN9708

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)

Dexamethasone DRUG

Dexamethasone tablets.

Dose Escalation Cohort: Ixazomib 4.0 mg; Dose Escalation Cohort: Ixazomib 5.5 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (10)

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Barbara Ann Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

Location

University Health Network

Toronto, Ontario, M5G 2M9, Canada

Location

CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis

Limoges, 87042, France

Location

Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie

Heidelberg, D-69120, Germany

Location

Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo

Pavia, 27100, Italy

Location

Related Publications (4)

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  PMID: 28550039 DERIVED

MeSH Terms

Conditions

Immunoglobulin Light-chain Amyloidosis

Interventions

ixazomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Amyloidosis; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Paraproteinemias

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 15, 2011
• First Posted: March 21, 2011
• Study Start: April 27, 2011
• Primary Completion: November 13, 2018
• Study Completion: November 13, 2018
• Last Updated: April 1, 2020
• Results First Posted: April 1, 2020

Record last verified: 2020-03

Data Sharing

• IPD Sharing: Will share

Locations

FR (1); US (6); CA (1); DE (1); IT (1)