Clinical trial NCT01318902: Study of Oral Ixazomib in Adult Participants With Relapsed or Refractory Light Chain Amyloidosis
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Light-Chain Amyloidosis
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-03-21
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With at Least One Treatment Emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
timeFrame: 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)
measure: Number of Participants With Clinically Significant Abnormal Laboratory Values Reported as TEAE
timeFrame: 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)
measure: Number of Participants With Peripheral Neuropathy Reported as a TEAE
timeFrame: 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)
measure: Maximum Tolerated Dose (MTD) of Ixazomib
timeFrame: Cycle 1 (28 days)
measure: Recommended Phase 2 Dose (RP2D) of Ixazomib
timeFrame: Cycle 1 (28 days)
Secondary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for Ixazomib
timeFrame: 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
measure: Tmax: Time of First Occurrence of Cmax for Ixazomib
timeFrame: 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
measure: Ctrough: Plasma Concentration Immediately Prior to Dosing for Ixazomib
timeFrame: 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
measure: AUC0-168: Area Under the Plasma Concentration-time Curve From Time 0 to 168 Hours Post-dose for Ixazomib
timeFrame: 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
measure: Emax: Maximum Observed Percent Inhibition of Whole Blood 20S Proteasome
timeFrame: 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
measure: TEmax: Time to Maximum Observed Effect (Emax) of Whole Blood 20S Proteasome Inhibition for Ixazomib
timeFrame: 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
measure: AUE0-168: Area Under Effect Curve of Whole Blood 20S Proteasome Inhibition From Zero to Concentration at 168 Hours for Ixazomib
timeFrame: 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
measure: Number of Participants With Best Organ Response to Treatment Based on Investigators Assessment
timeFrame: 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)
measure: Number of Participants With Best Hematologic Response to Treatment Based on Investigators Assessment
timeFrame: 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)
measure: Time to First Hematologic Response
timeFrame: From the date of the first dose of ixazomib to the date of first documentation of a hematologic response (Up to approximately 12 months)
measure: Time to First Organ Response
timeFrame: From the date of the first dose of ixazomib to the date of first documentation of a organ response (Up to approximately 12 months)
measure: Duration of Hematologic Response
timeFrame: From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)
measure: Duration of Organ Response
timeFrame: From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)
measure: Time to Hematologic Disease Progression
timeFrame: From the date of the first dose of ixazomib to the date of first documented hematologic disease progression (Up to approximately 12 months)
measure: Time to Organ Disease Progression
timeFrame: From the date of the first dose of ixazomib to the date of first documented organ disease progression (Up to approximately 12 months)
measure: Hematologic Disease Progression-Free Survival (PFS)
timeFrame: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to approximately 12 months)
measure: Organ Disease Progression-Free Survival (PFS)
timeFrame: From the date of the first dose of ixazomib to the date of organ disease progression or death (Up to approximately 12 months)
measure: Percentage of Participants With One Year Hematologic Disease PFS
timeFrame: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Tufts Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Limoges Cedex
country: France
facility: CHU Limoges, Department of Hematology and Cell Therapy, Reference Center for AL amyloidosis
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg Innere Medizin V; Hamatologie, Onkologie und Rheumatologie
city: Pavia
country: Italy
facility: Amyloidosis Research & Treatment Center, Fondazione IRCCS Policlinico San Matteo
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.