Relapsed and Refractory Multiple Myeloma
Conditions
Keywords
Relapsed multiple myeloma, Refractory multiple myeloma, Ixazomib Proteasome inhibitor
Brief summary
This study will determine the safety profile, tolerability, and maximum tolerated dose (MTD) and disease response of Ixazomib administered orally in participants with relapsed and/or refractory multiple myeloma.
Detailed description
The drug being tested in this study is ixazomib. Ixazomib is being tested to treat people who have multiple myeloma. This study will look at the safety and efficacy of ixazomib and will enroll approximately 60 participants. Participants will receive ixazomib by oral capsule twice weekly on Days 1, 4, 8, and 11 of a 21-day cycle. The study will consist of a dose escalation phase to determine the MTD, followed by an expansion phase in which participants will be treated at the MTD. This multi-center trial will be conducted in the United States. The overall time to participate in this study is 8 years.
Interventions
DRUGIxazomib
Ixazomib capsules
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each participant must meet all of the following inclusion criteria to be enrolled in the study: * Multiple myeloma diagnosed according to the standard criteria. * Participants with multiple myeloma who have relapsed following at least 2 lines of therapy. * Participants must have measurable disease. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. * Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse. * Male participants who agree to practice effective barrier contraception or agree to abstain from heterosexual intercourse. * Voluntary written consent. * Suitable venous access for study-required blood sampling.
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 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. |
| Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | 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. |
| Number of Participants With a TEAE of Peripheral Neuropathy | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy. |
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months) | The number of participants with any clinically significant changes in vital signs collected throughout the study that were reported as TEAEs. Measurement of vital signs, included oral temperature, blood pressure, and heart rate. |
| Maximum Tolerated Dose (MTD) of Ixazomib | Cycle 1 (21 days) | MTD was highest dose of Ixazomib, at which \<=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT was defined as any of following considered possibly related to therapy: 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 (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 millisecond \[msec\]);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. |
| Recommended Phase 2 Dose (RP2D) of Ixazomib | Cycle 1 through Cycle 39 (Up to 28.3 months) | The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic data observed in Cycle 1 and beyond. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Plasma Concentration for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (up to 264 hours) postdose | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | — |
| AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | — |
| AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 72 hours) postdose | — |
| λz: Terminal Disposition Phase Rate Constant for Ixazomib | Cycle 1, Day 11: predose and at multiple time points (Up to 264 hours) postdose | — |
| T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | Cycle 1, Day 11: predose and at multiple time points (up to 264 hours) postdose | — |
| CL/F: Blood Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | CL/F is apparent clearance of the drug from the plasma. |
| Emax: Maximum Observed Effect for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | Emax was determined to characterize the whole blood 20S proteasome inhibition parameters. |
| TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib | Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose | TEmax was determined to characterize the whole blood 20S proteasome inhibition parameters. |
| Overall Response Rate (ORR) | Cycle 1 through Cycle 115 (Up to 80.1 months) | ORR is defined as percentage of participants with complete response (CR) or partial response (PR) or minimal response (MR) as assessed by the investigator using International Myeloma Working Group Uniform Response criteria. CR=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to \<200 mg /24 h. MR=25-49% reduction in the serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24-h urinary light chain excretion, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks; for participants with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 5 investigative sites in the United States from 12 October 2009 to 23 May 2017.
Pre-assignment details
60 participants with a diagnosis of relapsed and/or refractory (RR) multiple myeloma were enrolled in 1 of 7 ixazomib dose escalation groups (26 participants) and/or 1 of 4 ixazomib dose expansion groups (40 participants). 6 Participants in 2.0 mg/m\^2 dose escalation cohort were also included in the expansion group: 5 in RR, 1 in VR arms.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 Ixazomib 0.24 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 220 days). | 3 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 Ixazomib 0.48 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 270 days). | 3 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 Ixazomib 0.8 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 137 days). | 3 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 Ixazomib 1.2 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 1436 days). | 3 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 Ixazomib 1.68 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 456 days). | 3 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 Ixazomib 2.0 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 1621 days). | 1 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 Ixazomib 2.23 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months (Up to 2434 days). | 4 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 Ixazomib 2.0 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months, Participants must also be refractory to their most recent therapy as evidenced by PD while on therapy or within 60 days after their last dose of therapy (Up to 1621 days). | 20 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 Ixazomib 2.0 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants with relapsed or refractory disease after \>=1 prior therapy but have relapsed after previous Velcade exposure and were not treated with any other proteasome inhibitors (Up to 1573 days). | 12 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 Ixazomib 2.0 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants with relapsed or refractory disease after \>=1 prior therapy which must include thalidomide (or lenalidomide) and corticosteroid, but who never received a proteasome inhibitor (Up to 550 days). | 6 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 Ixazomib 2.0 mg/m\^2, capsule, orally, on Days 1, 4, 8 and 11 during a 21-day treatment cycle until progressive disease (PD) or unacceptable toxicity up to 12 months unless the investigator and sponsor determined the participant would benefit from therapy beyond 12 months. Participants who previously received carfilzomib and had relapsed or refractory disease (Up to 123 days). | 2 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1 (Dose Escalation) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Part 1 (Dose Escalation) | Other | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Part 1 (Dose Escalation) | Progressive Disease | 3 | 2 | 2 | 2 | 3 | 5 | 2 | 0 | 0 | 0 | 0 |
| Part 1 (Dose Escalation) | Withdrawal by Participant | 0 | 1 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Part 2 (Dose Expansion) | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 1 | 1 | 0 |
| Part 2 (Dose Expansion) | Progressive Disease | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 14 | 8 | 3 | 2 |
| Part 2 (Dose Expansion) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 3 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.2 years STANDARD_DEVIATION 8.25 | 71.5 years STANDARD_DEVIATION 3.54 | 64.0 years STANDARD_DEVIATION 6.84 | 65.4 years STANDARD_DEVIATION 8.02 | 64.4 years STANDARD_DEVIATION 9.58 | 65.3 years STANDARD_DEVIATION 7.02 | 61.3 years STANDARD_DEVIATION 6.81 | 64.3 years STANDARD_DEVIATION 7.5 | 78 years | 64.0 years STANDARD_DEVIATION 9.85 | 66.0 years STANDARD_DEVIATION 7 | 69.3 years STANDARD_DEVIATION 12.1 |
| Body Surface Area | 1.92 meter square STANDARD_DEVIATION 0.291 | 1.74 meter square STANDARD_DEVIATION 0.495 | 2.09 meter square STANDARD_DEVIATION 0.265 | 1.82 meter square STANDARD_DEVIATION 0.237 | 1.88 meter square STANDARD_DEVIATION 0.342 | 2.05 meter square STANDARD_DEVIATION 0.192 | 1.82 meter square STANDARD_DEVIATION 0.1 | 1.97 meter square STANDARD_DEVIATION 0.335 | 2.02 meter square | 1.93 meter square STANDARD_DEVIATION 0.071 | 2.34 meter square STANDARD_DEVIATION 0.229 | 1.86 meter square STANDARD_DEVIATION 0.062 |
| Height | 167.5 centimeter (cm) STANDARD_DEVIATION 11.07 | 156.7 centimeter (cm) STANDARD_DEVIATION 6.08 | 169.3 centimeter (cm) STANDARD_DEVIATION 9.16 | 165.7 centimeter (cm) STANDARD_DEVIATION 13.26 | 165.8 centimeter (cm) STANDARD_DEVIATION 11.28 | 173.1 centimeter (cm) STANDARD_DEVIATION 9.63 | 167.5 centimeter (cm) STANDARD_DEVIATION 7.6 | 169.7 centimeter (cm) STANDARD_DEVIATION 12.18 | 178 centimeter (cm) | 165.4 centimeter (cm) STANDARD_DEVIATION 7.9 | 180.1 centimeter (cm) STANDARD_DEVIATION 14.25 | 167.4 centimeter (cm) STANDARD_DEVIATION 4.54 |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 55 Participants | 2 Participants | 6 Participants | 9 Participants | 20 Participants | 3 Participants | 2 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 54 Participants | 2 Participants | 6 Participants | 12 Participants | 18 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 60 Participants | 2 Participants | 6 Participants | 12 Participants | 20 Participants | 3 Participants | 3 Participants | 4 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 28 Participants | 2 Participants | 1 Participants | 6 Participants | 12 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 32 Participants | 0 Participants | 5 Participants | 6 Participants | 8 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants |
| Time Since Primary Diagnosis to First Dose | 57.4 months | 76.1 months | 71.9 months | 42.7 months | 56.9 months | 59.1 months | 61.8 months | 35.2 months | 44.62 months | 38.4 months | 80.4 months | 45.8 months |
| Weight | 80.27 kilogram (kg) STANDARD_DEVIATION 19.946 | 71.70 kilogram (kg) STANDARD_DEVIATION 36.77 | 93.20 kilogram (kg) STANDARD_DEVIATION 16.811 | 72.60 kilogram (kg) STANDARD_DEVIATION 15.579 | 77.81 kilogram (kg) STANDARD_DEVIATION 23.76 | 87.50 kilogram (kg) STANDARD_DEVIATION 12.56 | 71.03 kilogram (kg) STANDARD_DEVIATION 5.937 | 82.98 kilogram (kg) STANDARD_DEVIATION 21.532 | 82.3 kilogram (kg) | 80.77 kilogram (kg) STANDARD_DEVIATION 2.542 | 109.90 kilogram (kg) STANDARD_DEVIATION 12.76 | 74.87 kilogram (kg) STANDARD_DEVIATION 5.036 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 1 / 3 | 0 / 3 | 0 / 3 | 0 / 7 | 0 / 4 | 1 / 20 | 0 / 12 | 0 / 6 | 0 / 2 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 4 / 4 | 20 / 20 | 12 / 12 | 6 / 6 | 2 / 2 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 2 / 3 | 2 / 3 | 0 / 3 | 5 / 7 | 3 / 4 | 14 / 20 | 6 / 12 | 3 / 6 | 2 / 2 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Ixazomib
MTD was highest dose of Ixazomib, at which \<=1 of 6 participants experienced dose-limiting toxicity (DLT) during Cycle 1 of Phase 1. DLT was defined as any of following considered possibly related to therapy: 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 (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 millisecond \[msec\]);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.
Time frame: Cycle 1 (21 days)
Population: DLT-evaluable population was defined as all participants who received all Cycle 1 doses of ixazomib and completed Cycle 1 or who experienced DLT in Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Maximum Tolerated Dose (MTD) of Ixazomib | 2 mg/m^2 |
Primary
Number of Participants With a TEAE of Peripheral Neuropathy
Neurotoxicity was assessed as the number of participants with the TEAE of peripheral neuropathy.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Population: Safety population included all participants who received at least 1 dose of ixazomib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 1 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 1 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 1 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 1 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 3 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 3 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 1 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Neuropathy Peripheral | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With a TEAE of Peripheral Neuropathy | Peripheral Sensory Neuropathy | 0 Participants |
Primary
Number of Participants With Clinically Significant Abnormalities Reported as TEAEs
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.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Population: Safety population included all participants who received at least 1 dose of ixazomib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 1 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 1 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 1 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 1 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 1 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 1 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 1 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 1 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 1 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 1 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 1 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 2 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 1 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 1 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 1 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 1 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 2 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 1 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 1 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Platelet Count Decreased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haemoglobin Decreased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Urea Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | White Blood Cell Count Decreased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Neutrophil Count Decreased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Alanine Aminotransferase Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Liver Function Test Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Calcium Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Blood Creatinine Increased | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Abnormalities Reported as TEAEs | Haematocrit Decreased | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs
The number of participants with any clinically significant changes in vital signs collected throughout the study that were reported as TEAEs. Measurement of vital signs, included oral temperature, blood pressure, and heart rate.
Time frame: From first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Population: Safety population included all participants who received at least 1 dose of ixazomib.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 1 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With Clinically Significant Changes in Vital Signs Reported as TEAEs | 0 Participants |
Primary
Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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 first dose of the study drug through 30 days after the last dose of study drug or start of subsequent antineoplastic therapy (Up to 81.1 months)
Population: Safety population included all participants who received at least 1 dose of ixazomib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 5 Participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 7 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 4 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 20 Participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 14 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 12 Participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 6 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | AEs | 2 Participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Number of Participants With One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 2 Participants |
Primary
Recommended Phase 2 Dose (RP2D) of Ixazomib
The RP2D of Ixazomib was determined in Part 1 (dose escalation) on the basis of the totality of safety, tolerability, pharmacokinetics (PK) and pharmacodynamic data observed in Cycle 1 and beyond.
Time frame: Cycle 1 through Cycle 39 (Up to 28.3 months)
Population: Safety population included all participants who received at least 1 dose of ixazomib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Recommended Phase 2 Dose (RP2D) of Ixazomib | 2 mg/m^2 |
Secondary
AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 72 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 56.53 hr*ng/mL | Standard Deviation 15.509 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 177.67 hr*ng/mL | Standard Deviation 115.682 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 109.00 hr*ng/mL | Standard Deviation 41.012 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 458.00 hr*ng/mL | Standard Deviation 42.426 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 605.00 hr*ng/mL | — |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 159.05 hr*ng/mL | Standard Deviation 91.853 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 251.00 hr*ng/mL | Standard Deviation 62.506 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 808.50 hr*ng/mL | Standard Deviation 212.839 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 1435.60 hr*ng/mL | Standard Deviation 1027.388 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 449.00 hr*ng/mL | Standard Deviation 185.952 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 416.50 hr*ng/mL | Standard Deviation 47.376 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 1915.00 hr*ng/mL | Standard Deviation 148.492 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 903.85 hr*ng/mL | Standard Deviation 382.903 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 451.64 hr*ng/mL | Standard Deviation 194.522 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 351.00 hr*ng/mL | Standard Deviation 141.434 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 937.86 hr*ng/mL | Standard Deviation 334.208 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 410.00 hr*ng/mL | Standard Deviation 138.773 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 2297.20 hr*ng/mL | Standard Deviation 1137.822 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 11 | 1010.00 hr*ng/mL | — |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-72): Area Under the Plasma Concentration-Time Curve From Time 0 to 72 Hours Postdose for Ixazomib | Day 1 | 509.00 hr*ng/mL | — |
Secondary
AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 3.383 hr*ng/mL | Standard Deviation 1.721 |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 56.533 hr*ng/mL | Standard Deviation 15.5095 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 20.700 hr*ng/mL | Standard Deviation 4.5255 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 177.667 hr*ng/mL | Standard Deviation 115.682 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 109.000 hr*ng/mL | Standard Deviation 41.0122 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 458.000 hr*ng/mL | Standard Deviation 42.4264 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 159.050 hr*ng/mL | Standard Deviation 91.8532 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 605.000 hr*ng/mL | — |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 251.000 hr*ng/mL | Standard Deviation 62.506 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 808.500 hr*ng/mL | Standard Deviation 212.8391 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 1435.600 hr*ng/mL | Standard Deviation 1027.3881 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 449.000 hr*ng/mL | Standard Deviation 185.9516 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 1915.000 hr*ng/mL | Standard Deviation 148.4924 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 416.500 hr*ng/mL | Standard Deviation 47.3762 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 418.175 hr*ng/mL | Standard Deviation 218.7115 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 903.846 hr*ng/mL | Standard Deviation 382.9033 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 351.000 hr*ng/mL | Standard Deviation 141.4337 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 937.857 hr*ng/mL | Standard Deviation 334.2082 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 410.000 hr*ng/mL | Standard Deviation 138.7732 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 2297.200 hr*ng/mL | Standard Deviation 1137.8221 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 1 | 509.000 hr*ng/mL | — |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Day 11 | 1010.000 hr*ng/mL | — |
Secondary
CL/F: Blood Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Ixazomib
CL/F is apparent clearance of the drug from the plasma.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Population: CL/F was not reported as this PK parameter could not be calculated.
Secondary
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (up to 264 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 2.120 ng/mL | Standard Deviation 0.3974 |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 2.837 ng/mL | Standard Deviation 1.5051 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 10.190 ng/mL | Standard Deviation 2.5597 |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 8.857 ng/mL | Standard Deviation 5.5598 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 22.200 ng/mL | Standard Deviation 11.3137 |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 31.650 ng/mL | Standard Deviation 15.2028 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 29.000 ng/mL | Standard Deviation 24.1831 |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 56.500 ng/mL | Standard Deviation 14.1421 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 21.100 ng/mL | Standard Deviation 10.1237 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 101.100 ng/mL | Standard Deviation 71.3597 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 85.420 ng/mL | Standard Deviation 30.7632 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 68.167 ng/mL | Standard Deviation 34.7876 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 105.450 ng/mL | Standard Deviation 41.79 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 117.933 ng/mL | Standard Deviation 67.1924 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 58.900 ng/mL | Standard Deviation 36.1337 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 59.871 ng/mL | Standard Deviation 32.5851 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 59.343 ng/mL | Standard Deviation 41.9853 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 61.800 ng/mL | Standard Deviation 24.878 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 85.600 ng/mL | Standard Deviation 58.8496 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 109.660 ng/mL | Standard Deviation 27.5668 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 1 | 26.600 ng/mL | — |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Ixazomib | Day 11 | 27.200 ng/mL | — |
Secondary
Emax: Maximum Observed Effect for Ixazomib
Emax was determined to characterize the whole blood 20S proteasome inhibition parameters.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Population: No data is reported due to concerns about the third-party laboratory's performance of the 20S assay that precluded the ability to confirm the accuracy of the data generated. The data was not considered reliable.
Secondary
Overall Response Rate (ORR)
ORR is defined as percentage of participants with complete response (CR) or partial response (PR) or minimal response (MR) as assessed by the investigator using International Myeloma Working Group Uniform Response criteria. CR=Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. PR=≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to \<200 mg /24 h. MR=25-49% reduction in the serum monoclonal paraprotein maintained for a minimum of 6 weeks; 50-89% reduction in 24-h urinary light chain excretion, which still exceeds 200 mg/24 h, maintained for a minimum of 6 weeks; for participants with non-secretory myeloma only, 25-49% reduction in plasma cells in a bone marrow aspirate and on trephine biopsy, if biopsy is performed, maintained for a minimum of 6 weeks; 25-49% reduction in the size of soft tissue plasmacytomas; no increase in the size or number of lytic bone lesions.
Time frame: Cycle 1 through Cycle 115 (Up to 80.1 months)
Population: Response-evaluable population included participants who received at least 1 dose of study drug, had measurable disease at baseline, and at least 1 post baseline disease assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 33 percentage of participants |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 33 percentage of participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 50 percentage of participants |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 50 percentage of participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 5 percentage of participants |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 10 percentage of participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 9 percentage of participants |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 18 percentage of participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 33 percentage of participants |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 33 percentage of participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR+MR | 0 percentage of participants |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Overall Response Rate (ORR) | CR+PR | 0 percentage of participants |
Secondary
T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib
Time frame: Cycle 1, Day 11: predose and at multiple time points (up to 264 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 135.00 hr | — |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 126.50 hr | Standard Deviation 2.121 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 129.33 hr | Standard Deviation 25.658 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 105.88 hr | Standard Deviation 21.071 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 92.70 hr | Standard Deviation 8.485 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 115.85 hr | Standard Deviation 26.368 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 123.06 hr | Standard Deviation 33.877 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 124.93 hr | Standard Deviation 41.33 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | T1/2: Terminal Disposition Phase Elimination Half-life for Ixazomib | 134.00 hr | — |
Secondary
TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
TEmax was determined to characterize the whole blood 20S proteasome inhibition parameters.
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Population: No data is reported due to concerns about the third-party laboratory's performance of the 20S assay that precluded the ability to confirm the accuracy of the data generated. The data was not considered reliable.
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Cycle 1, Days 1 and 11: Predose and at multiple time points (Up to 264 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Dose Escalation Cohort 1: Ixazomib 0.24 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.100 hours |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.000 hours |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 0.775 hours |
| Dose Escalation Cohort 3: Ixazomib 0.8 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.275 hours |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 0.775 hours |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 0.500 hours |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.000 hours |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 0.667 hours |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 0.832 hours |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.010 hours |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 0.617 hours |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 0.583 hours |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 0.525 hours |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.500 hours |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 1 | 1.000 hours |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Day 11 | 1.500 hours |
Secondary
λz: Terminal Disposition Phase Rate Constant for Ixazomib
Time frame: Cycle 1, Day 11: predose and at multiple time points (Up to 264 hours) postdose
Population: PK population was defined as all participants who had sufficient dosing data and ixazomib concentration-time data to permit calculation of ixazomib PK parameters. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Cohort 2: Ixazomib 0.48 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.005 1/hr | — |
| Dose Escalation Cohort 4: Ixazomib 1.2 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.005 1/hr | Standard Deviation 0.0001 |
| Dose Escalation Cohort 5: Ixazomib 1.68 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.006 1/hr | Standard Deviation 0.0012 |
| Dose Escalation Cohort 6: Ixazomib 2.0 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.007 1/hr | Standard Deviation 0.0012 |
| Dose Escalation Cohort 7: Ixazomib 2.23 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.008 1/hr | Standard Deviation 0.0007 |
| Relapsed and Refractory Expansion Cohort: Ixazomib 2.0 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.006 1/hr | Standard Deviation 0.0015 |
| Velcade-Relapsed (VR) Expansion Cohort: Ixazomib 2.0 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.006 1/hr | Standard Deviation 0.0018 |
| Proteasome Inhibitor-Naive Expansion Cohort: Ixazomib 2 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.006 1/hr | Standard Deviation 0.002 |
| Carfilzomib Expansion Cohort: Ixazomib 2.0 mg/m^2 | λz: Terminal Disposition Phase Rate Constant for Ixazomib | 0.005 1/hr | — |