A Study of IXAZOMIB in Adult Patients With Lymphoma

The MTD was defined as the highest dose of ixazomib that generated dose limiting toxicity (DLT) during Cycle 1 in 0 of 3 or 1 of 6 participants. DLT defined as any of the following considered possibly related to therapy by investigator: Grade 4 neutropenia (absolute neutrophil count \[ANC\] \<500 cell per cubic millimeter \[cells/mm\^3\]) for \>7 days; Grade 3 neutropenia with fever or infection; Grade 4 thrombocytopenia for \>7 days; platelet count \<25,000 cells/mm\^3; 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 maximal supportive therapy; Grade 3 QTc prolongation\>500 millisecond (msec);any \>=Grade 3 nonhematologic toxicity except arthralgia/myalgia; \<1 week fatigue; delay in the initiation of the subsequent therapy cycle by \>=7 days ; other Grade 2 ixazomib-related nonhematologic toxicities requiring therapy discontinuation.

Time frame: Treatment Cycle 1

Population: DLT-Evaluable Population included participants who received all Cycle 1 doses of MLN9708 and who completed Cycle 1. If Cycle 1 was interrupted by a DLT, the participant was included in this population.

The number of participants with any markedly abnormal standard safety laboratory values collected throughout study. Hematology, clinical chemistry and urinalysis were performed. TEAEs related to laboratory assessment observed at any time-points were reported under 3 system organ classes: blood and lymphatic system disorders, metabolism and nutrition disorders, and investigations.

Time frame: Baseline and Days 1, 8, and 15 of each treatment cycle (up to Cycle 45)

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

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Time frame: Baseline up to 30 days after last dose of study drug

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

Vital signs included body temperature, weight, systolic and diastolic blood pressure and heart rate.

Time frame: Baseline and Days 1, 8, 15 of each treatment cycle up to 45 treatment cycles

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

The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK), pharmacodynamic and preliminary efficacy data observed in Cycles 1 and 2 and beyond.

Time frame: Baseline up to Treatment Cycle 45

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

Ae (0-4) is the total amount of drug excreted in the urine from 0 to 4 hours postdose.

Time frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose

Population: The PK analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 15 assessments were available.

AUC(0-168) is a measure of the area under the plasma concentration time-curve from time 0 to 168 hours postdose

Time frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)

Population: The PK analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 15 assessments were available. AUC(0-168) is not reported for ixazomib 0.125 and 0.25 mg/m\^2 as the participants were not evaluable for this parameter.

C0 is the plasma drug concentration at time zero following bolus intravenous injection, obtained from the plasma concentration-time curve.

Time frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 336 hours postdose)

Population: The pharmacokinetic (PK) analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 15 assessments were available.

CLr is the volume of plasma from which the drug is completely removed by the kidney in a given amount of time, calculated as the amount of drug excreted in the urine divided by the area under the plasma concentration-time curve, expressed in liter per hour (L/hr).

Time frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose

Population: The PK analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters where Days 1 and 15 assessments were available. CLr is not reported for ixazomib 0.125 and 0.25 mg/m\^2 as the participants were not evaluable for this parameter.

Emax is the maximum inhibition of 20S proteasome activity in whole blood.

Time frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)

Population: The pharmacodynamic analysis population included participants who had sufficient dosing data and effect-time data to permit calculation of pharmacodynamic parameters where Days 1 and 15 assessments were available.

Fe (0-4) is the fraction of the dose excreted unchanged in the urine from 0 to 4 hours postdose, calculated as percentage of the exact dose administered.

Time frame: Cycle 1, Days 1 and 15: 0 to 4 hours postdose

Population: The PK analysis population was defined as participants who had sufficient dosing data and ixazomib concentration-time data to permit the calculation of PK parameters where Days 1 and 15 assessments were available.

Overall best response is the best response observed for a participant during the study based on International Working Group (IWG) Response Criteria for malignant lymphoma. Complete response (CR) as per IWG is complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response (PR) is a minimum of 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses and no increase in the size of other nodes. Stable disease (SD) is when a participant fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD. PD is any new lesion or increase by \>50% of previously involved sites from nadir.

Time frame: Baseline up to Cycle 45

Population: Response-evaluable population included participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 postbaseline disease assessment for analyses of response.

Rac was estimated as the ratio of AUC (0-168) on Day 15 and AUC (0-168) on Day 1. AUC (0-168) is the area under the plasma concentration-time curve from time 0 to 168 hours postdose.

Time frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)

Population: The PK analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters. Rac is reported for ixazomib 1.4, 2.34 and 3.11 mg/m\^2 groups only as it could not be estimated for the other dosing groups.

TEmax: Time to reach the maximum observed effect (Emax), equal to time (hours) to Emax.

Time frame: Cycle 1 Days 1 and 15: Predose and at multiple time points (up to 168 hours postdose)

Population: The pharmacodynamic analysis population included participants who had sufficient dosing data and effect-time data to permit calculation of pharmacodynamic parameters where Days 1 and 15 assessments were available.

Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.

Time frame: Cycle 1 Day 15: Predose and at multiple time points (up to 336 hours postdose)

Population: The PK analysis population included all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of PK parameters.T1/2 is not reported for ixazomib 0.125 and 0.25 mg/m\^2 as the participants were not evaluable for this parameter.