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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Light-Chain Amyloidosis

Intervention / Treatment
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* Drug: Ixazomib
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation Cohort: Ixazomib 4.0 mg<br>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<br>* Ixazomib capsules.<br>* Other names: MLN9708;Drug: Dexamethasone<br>* Dexamethasone tablets.<br>|
| Experimental: Dose Escalation Cohort: Ixazomib 5.5 mg<br>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<br>* Ixazomib capsules.<br>* Other names: MLN9708;Drug: Dexamethasone<br>* Dexamethasone tablets.<br>|
| Experimental: Dose Expansion Cohort: Ixazomib 4.0 mg (PI Naive)<br>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<br>* Ixazomib capsules.<br>* Other names: MLN9708;|
| Experimental: Dose Expansion Cohort: Ixazomib 4.0 mg (PI Exposed)<br>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<br>* Ixazomib capsules.<br>* Other names: MLN9708;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy