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

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.

Time frame: Cycle 1 (28 days)

Population: DLT-evaluable population included all participants who received all Cycle 1 doses of ixazomib or experienced a DLT in Cycle 1.

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.

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)

Population: Safety population included all participants who received at least 1 dose of ixazomib.

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.

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)

Population: Safety population included all participants who received at least 1 dose of ixazomib.

Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.

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)

Population: Safety population included all participants who received at least 1 dose 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.

Time frame: Cycle 1 (28 days)

Population: DLT-evaluable population included all participants who received all Cycle 1 doses of ixazomib or experienced a DLT in Cycle 1.

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

Population: PK analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

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

Population: PD analysis population: all participants who received at least 1 dose of ixazomib and had whole blood 20S proteasome inhibition-time data and dosing data to permit calculation of PD parameters. Data was only collected for ixazomib 4.0 mg arm group. Number analyzed is number of participants with evaluable data at given time-point.

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

Population: Pharmacokinetic (PK) analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

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

Population: PK analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.

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.

Time frame: From the date of first documentation of a hematologic response to the date of hematologic disease progression (Up to approximately 12 months)

Population: Hematologic response-evaluable population: all participants who received at least 1 cycle of ixazomib, had measureable disease at baseline, had \>=1 postbaseline hematologic response. No participants had hematologic response for ixazomib 5.5 mg arm group thus were not analyzed. Data is reported for participants evaluable for this outcome measure.

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.

Time frame: From the date of first documentation of a organ response to the date of organ disease progression (Up to approximately 12 months)

Population: Organ Response-Evaluable population included participants who received at least 1 cycle of ixazomib, who had amyloid involvement of at least kidney or heart at baseline, and who had at least 1 postbaseline organ response assessment. Number of participants analyzed is the number of participants with data available for analyses.

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

Population: Pharmacodynamic (PD) analysis population: all participants who received at least 1 dose of ixazomib and had whole blood 20S proteasome inhibition-time data and dosing data to permit calculation of PD parameters. Data was only collected for ixazomib 4.0 mg arm group. Number analyzed is number of participants with evaluable data at given time-point.

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.

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)

Population: Safety population included all participants who received at least 1 dose of ixazomib. Data is reported for participants evaluable for this outcome measure.

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.

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)

Population: Hematologic response-evaluable population included all participants who received at least 1 cycle of ixazomib, had measureable disease at baseline, and had at least 1 postbaseline hematologic response 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.

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)

Population: Organ response-evaluable population included all participants who received at least 1 cycle of ixazomib, had amyloid involvement of at least kidney or heart at baseline, and had at least 1 postbaseline organ response assessment.

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.

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)

Population: Organ Response-Evaluable population included participants who received at least 1 cycle of ixazomib, who had amyloid involvement of at least kidney or heart at baseline, and who had at least 1 postbaseline organ response assessment.

One-year survival, defined as the patient survival probability at 1 year after the date of first dose of ixazomib.

Time frame: From the date of the first dose of ixazomib to the date of hematologic disease progression or death (Up to 1 year)

Population: Safety population included all participants who received at least 1 dose of 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

Population: PD analysis population: all participants who received at least 1 dose of ixazomib and had whole blood 20S proteasome inhibition-time data and dosing data to permit calculation of PD parameters. Data was only collected for ixazomib 4.0 mg arm group. Number analyzed is number of participants with evaluable data at given time-point.

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.

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)

Population: Hematologic response-evaluable population: all participants who received at least 1 cycle of ixazomib, had measureable disease at baseline, had \>=1 postbaseline hematologic response. No participants had hematologic response for ixazomib 5.5 mg arm group thus were not analyzed. Data is reported for participants evaluable for this outcome measure.

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.

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)

Population: Organ Response-Evaluable population included participants who received at least 1 cycle of ixazomib, who had amyloid involvement of at least kidney or heart at baseline, and who had at least 1 postbaseline organ response assessment.

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.

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)

Population: Safety population included all participants who received at least 1 dose of ixazomib. Data is reported for participants evaluable for this outcome measure.

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.

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)

Population: Organ Response-Evaluable population included participants who received at least 1 cycle of ixazomib, who had amyloid involvement of at least kidney or heart at baseline, and who had at least 1 postbaseline organ response assessment.

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

Population: PK analysis population included all participants who received at least 1 dose of ixazomib and had sufficient ixazomib concentration-time data and dosing data to permit calculation of ixazomib plasma PK parameters. Number analyzed is the number of participants with evaluable data at the given time-point.