Lymphoma, Nonhematologic Malignancies
Conditions
Keywords
Cmax: maximum plasma concentration, AUC0-tlast: area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration
Brief summary
This is an open-label, multicenter, sequential, 5-arm, phase 1 study of oral IXAZOMIB designed to assess drug-drug interaction with ketoconazole (Arm 1), the relative bioavailability of 2 capsule formulations of IXAZOMIB (Arm 2), food effect (Arm 3), drug-drug interaction with rifampin (Arm 4), and drug-drug interaction with clarithromycin (Arm 5) in participants with advanced nonhematologic malignancies or lymphoma.
Interventions
DRUGIxazomib 2.5 mg
Ixazomib 2.5 mg Capsule B (Cycle 1 only)
DRUGIxazomib 4 mg Capsule A
Ixazomib 4 mg Capsule A (Cycle 1 only)
DRUGIxazomib 4 mg Capsule B
Ixazomib 4 mg Capsule B (Cycle 2 and beyond )
DRUGKetoconazole
Ketoconazole 400 mg tablets (Cycle 1 only)
DRUGRifampin
Rifampin 600 mg capsule (Cycle 1 only)
DRUGClarithromycin
Clarithromycin 500 mg tablets (Cycle 1 only)
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female participants 18 years or older. * Participants must have a diagnosis of histologically or cytologically confirmed metastatic and/or advanced solid tumor malignancy or lymphoma for which no effective standard treatment is available. * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. * Female participants who are postmenopausal at least 1 year, or surgically sterile, or if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time from the time of signing the consent form through 90 days after the last dose of study drug, or agree to practice true abstinence. * Male participants, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug or agree to practice true abstinence. * Voluntary written informed consent. * Clinical laboratory values as specified in protocol. * Suitable venous access. * Recovered (that is, less than \[\< \] Grade 1 toxicity or participant's baseline status) from the reversible effects of prior anticancer therapy.
Exclusion criteria
* Peripheral neuropathy greater than (\>) Grade 2 on clinical examination. * Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2, strong inhibitors of CYP3A, or strong CYP3A inducers or use of ginkgo biloba or St. John's wort within 14 days before the first dose of IXAZOMIB. * Participant has symptomatic brain metastasis. Participants with brain metastases must: have stable neurologic status following surgery or radiation for at least 2 weeks after completion of the definitive therapy; and be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Female participants who are pregnant or lactating. * Serious illness that could interfere with protocol completion. * Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time. * Prior treatment with rituximab or other unconjugated any antibody treatment within 42 days (21 days if there is clear evidence of progressive disease or immediate treatment is mandated). * Ongoing treatment with corticosteroids. * Radiotherapy within 21 days before the first dose of study drug. * Major surgery within 14 days before the first dose of study drug. * Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to first dose of study drug. * Life-threatening illness unrelated to cancer. * Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive, or suspected hepatitis C infection. * Diagnosis or treatment of another malignancy within 2 years preceding first dose, or previously diagnosed with another malignancy and have any evidence of residual disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. * Evidence of uncontrolled cardiovascular conditions. * QTc \> 500 milliseconds on a 12-lead electrocardiogram (ECG). * Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of IXAZOMIB including difficulty swallowing capsules; diarrhea \> Grade 1 despite supportive therapy. * Participants with gastric achlorhydria (Arm 1 only). * Participants who have used any nicotine containing products within 14 days before the first dose of study drug (Arm 1, Arm 4, and Arm 5). * Treatment with any investigational products or systemic antineoplastic therapies within 21 days before the first dose of IXAZOMIB. * Participants with known hypersensitivity to macrolide antibiotics (example, clarithromycin, erythromycin, azithromycin) or a history of jaundice/liver injury during prior exposure to clarithromycin (Arm 5 only).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cmax: Maximum Observed Plasma Concentration for Ixazomib | Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hours[hrs])post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45) | — |
| Percentage of Participants With Best Overall Response | Baseline up to end of treatment (approximately 1.9 years) | Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1: Complete response (CR) was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (\<) 10 millimeter \[mm\]). No new lesions. Partial response (PR) was defined as greater than or equal to (\>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease (SD) was defined as not qualifying for CR, PR, Progressive Disease (PD). An increase of \>=20% from the nadir (or baseline, if it represents the point at which the sum of target disease was lowest) represents PD. |
| Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45 | — |
| Number of Participants With Clinically Significant Vital Sign Abnormalities | Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States from 10 November 2011 to 16 June 2016. An additional 1 center was activated but did not screen or enroll any participants.
Pre-assignment details
Participants with advanced nonhematologic malignancies or lymphoma were enrolled in this 5 arm study to receive one of the following treatments in Cycle 1: ixazomib + ketoconazole; ixazomib Capsule A or B formulation; ixazomib in fasted or fed state; ixazomib + rifampin; ixazomib + clarithromycin; Cycle 2 up to Cycle 12: ixazomib alone in all arms.
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg Ixazomib 2.5 milligram (mg), capsule B, orally, once on Day 1 and 15 along with ketoconazole 400 mg, tablets, orally, once daily from Day 12 to 25 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants received ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity. | 29 |
| Arm 2: Ixazomib 4 mg Capsule A or B Ixazomib 4 mg, capsule A, orally, once on Day 1 followed by ixazomib 4 mg, capsule B once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, once on Day 1 followed by ixazomib 4 mg, capsule A once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants received ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity. | 20 |
| Arm 3: Ixazomib 4 mg Fasted or Fed Ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fed state, once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, under fed state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants received ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity. | 24 |
| Arm 4: Ixazomib 4 mg + Rifampin 600 mg Ixazomib, 4 mg, capsule B, orally, once on Day 8 along with rifampin 600 mg, capsule, orally, once daily from Day 1 to 14 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants received ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity. | 18 |
| Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg Ixazomib, 2.5 mg, capsule B, orally, once on Day 6 along with clarithromycin, 500 mg, tablet, orally, twice daily from Day 1 to 16 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants received ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity. | 21 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 8 | 2 | 7 | 0 | 2 |
| Overall Study | Other | 2 | 0 | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 3 | 4 | 2 | 1 | 2 |
Baseline characteristics
| Characteristic | Arm 2: Ixazomib 4 mg Capsule A or B | Arm 3: Ixazomib 4 mg Fasted or Fed | Arm 4: Ixazomib 4 mg + Rifampin 600 mg | Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg | Total | Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 60.5 years STANDARD_DEVIATION 13.33 | 62.3 years STANDARD_DEVIATION 11.86 | 61.6 years STANDARD_DEVIATION 11.33 | 60.0 years STANDARD_DEVIATION 11.04 | 61.3 years STANDARD_DEVIATION 11.01 | 61.8 years STANDARD_DEVIATION 8.71 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 3 Participants | 1 Participants | 4 Participants | 16 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 21 Participants | 17 Participants | 17 Participants | 96 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 166.4 centimeter (cm) STANDARD_DEVIATION 9.64 | 170.2 centimeter (cm) STANDARD_DEVIATION 9.76 | 169.2 centimeter (cm) STANDARD_DEVIATION 10.03 | 172.6 centimeter (cm) STANDARD_DEVIATION 11.11 | 168.9 centimeter (cm) STANDARD_DEVIATION 10 | 166.6 centimeter (cm) STANDARD_DEVIATION 9.26 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 0 Participants | 0 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) White | 15 Participants | 18 Participants | 17 Participants | 19 Participants | 91 Participants | 22 Participants |
| Region of Enrollment United States | 20 participants | 24 participants | 18 participants | 21 participants | 112 participants | 29 participants |
| Sex: Female, Male Female | 11 Participants | 11 Participants | 8 Participants | 6 Participants | 53 Participants | 17 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 10 Participants | 15 Participants | 59 Participants | 12 Participants |
| Weight | 69.78 kilogram (kg) STANDARD_DEVIATION 13.057 | 74.09 kilogram (kg) STANDARD_DEVIATION 16.358 | 80.22 kilogram (kg) STANDARD_DEVIATION 17.183 | 81.93 kilogram (kg) STANDARD_DEVIATION 20.973 | 76.64 kilogram (kg) STANDARD_DEVIATION 18.083 | 77.44 kilogram (kg) STANDARD_DEVIATION 19.956 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 28 / 29 | 20 / 20 | 23 / 24 | 18 / 18 | 20 / 21 |
| serious Total, serious adverse events | 12 / 29 | 5 / 20 | 12 / 24 | 3 / 18 | 10 / 21 |
Outcome results
Primary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
Time frame: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
Population: The PK-evaluable population included all participants who received protocol-specified dose in Cycle 1 without dose reductions/interruptions, did not receive any excluded concomitant medication during PK sampling, and had sufficient concentration-time data to permit estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 551.985 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 191.449 |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 1148.778 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 581.4376 |
| Arm 2: Ixazomib 4 mg Capsule A | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 1284.079 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 941.4838 |
| Arm 2: Ixazomib 4 mg Capsule B | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 1334.659 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 1244.0951 |
| Arm 3: Ixazomib 4 mg Fasted | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 1465.979 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 812.0514 |
| Arm 3: Ixazomib 4 mg Fed | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 998.698 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 1019.1868 |
| Arm 4: Ixazomib 4 mg + Rifampin 600 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 231.527 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 134.972 |
| Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib | 613.112 nanogram*hour per milliliter (ng*hr/mL)] | Standard Deviation 375.0216 |
Primary
Cmax: Maximum Observed Plasma Concentration for Ixazomib
Time frame: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hours[hrs])post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
Population: The pharmacokinetic (PK)-evaluable population included all participants who received protocol-specified dose in Cycle 1 without dose reductions/interruptions, did not receive any excluded concomitant medication during PK sampling, and had sufficient concentration-time data to permit estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 38.975 nanogram per milliliter (ng/mL) | Standard Deviation 21.3727 |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 39.250 nanogram per milliliter (ng/mL) | Standard Deviation 27.3318 |
| Arm 2: Ixazomib 4 mg Capsule A | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 61.866 nanogram per milliliter (ng/mL) | Standard Deviation 48.3909 |
| Arm 2: Ixazomib 4 mg Capsule B | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 71.949 nanogram per milliliter (ng/mL) | Standard Deviation 46.2132 |
| Arm 3: Ixazomib 4 mg Fasted | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 77.001 nanogram per milliliter (ng/mL) | Standard Deviation 53.5905 |
| Arm 3: Ixazomib 4 mg Fed | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 22.752 nanogram per milliliter (ng/mL) | Standard Deviation 15.0506 |
| Arm 4: Ixazomib 4 mg + Rifampin 600 mg | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 25.706 nanogram per milliliter (ng/mL) | Standard Deviation 15.1435 |
| Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg | Cmax: Maximum Observed Plasma Concentration for Ixazomib | 37.245 nanogram per milliliter (ng/mL) | Standard Deviation 21.4416 |
Primary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
Time frame: Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
Population: The PK-evaluable population included all participants who received protocol-specified dose in Cycle 1 without dose reductions/interruptions, did not receive any excluded concomitant medication during PK sampling, and had sufficient concentration-time data to permit estimation of PK parameters by noncompartmental analysis methods.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.090 hours |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.500 hours |
| Arm 2: Ixazomib 4 mg Capsule A | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.290 hours |
| Arm 2: Ixazomib 4 mg Capsule B | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.250 hours |
| Arm 3: Ixazomib 4 mg Fasted | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.020 hours |
| Arm 3: Ixazomib 4 mg Fed | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 4.000 hours |
| Arm 4: Ixazomib 4 mg + Rifampin 600 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1.450 hours |
| Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib | 1 hours |
Secondary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45)
Population: The safety population included all participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 29 participants |
| Arm 1: Ixazomib 2.5 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 12 participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 20 participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 5 participants |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 24 participants |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 12 participants |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 18 participants |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 21 participants |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 10 participants |
Secondary
Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities
Time frame: Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45
Population: The safety population included all participants who received at least one dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Blood and lymphatic system disorders | 11 participants |
| Arm 1: Ixazomib 2.5 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Metabolism and nutrition disorders | 22 participants |
| Arm 1: Ixazomib 2.5 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Investigations | 10 participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Investigations | 5 participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Blood and lymphatic system disorders | 7 participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Metabolism and nutrition disorders | 12 participants |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Investigations | 11 participants |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Blood and lymphatic system disorders | 9 participants |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Metabolism and nutrition disorders | 13 participants |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Blood and lymphatic system disorders | 2 participants |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Metabolism and nutrition disorders | 6 participants |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Investigations | 4 participants |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Investigations | 5 participants |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Blood and lymphatic system disorders | 1 participants |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities | Metabolism and nutrition disorders | 6 participants |
Secondary
Number of Participants With Clinically Significant Vital Sign Abnormalities
Time frame: Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45
Population: The safety population included all participants who received at least one dose of any study drug.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 participants | 0.324 |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 participants | — |
| Arm 2: Ixazomib 4 mg Capsule A | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 participants | — |
| Arm 2: Ixazomib 4 mg Capsule B | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 participants | — |
| Arm 3: Ixazomib 4 mg Fasted | Number of Participants With Clinically Significant Vital Sign Abnormalities | 0 participants | — |
Secondary
Percentage of Participants With Best Overall Response
Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1: Complete response (CR) was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (\<) 10 millimeter \[mm\]). No new lesions. Partial response (PR) was defined as greater than or equal to (\>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease (SD) was defined as not qualifying for CR, PR, Progressive Disease (PD). An increase of \>=20% from the nadir (or baseline, if it represents the point at which the sum of target disease was lowest) represents PD.
Time frame: Baseline up to end of treatment (approximately 1.9 years)
Population: The response-evaluable population included participants who had measurable disease at baseline, received at least 1 dose of any study drug, and had at least 1 postbaseline response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1: Ixazomib 2.5 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Arm 1: Ixazomib 2.5 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Arm 1: Ixazomib 2.5 mg | Percentage of Participants With Best Overall Response | SD | 63 percentage of participants |
| Arm 1: Ixazomib 2.5 mg | Percentage of Participants With Best Overall Response | PD | 38 percentage of participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Percentage of Participants With Best Overall Response | PD | 50 percentage of participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg | Percentage of Participants With Best Overall Response | SD | 50 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule A | Percentage of Participants With Best Overall Response | PD | 59 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule A | Percentage of Participants With Best Overall Response | PR | 6 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule A | Percentage of Participants With Best Overall Response | SD | 35 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule A | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule B | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule B | Percentage of Participants With Best Overall Response | PR | 0 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule B | Percentage of Participants With Best Overall Response | PD | 47 percentage of participants |
| Arm 2: Ixazomib 4 mg Capsule B | Percentage of Participants With Best Overall Response | SD | 53 percentage of participants |
| Arm 3: Ixazomib 4 mg Fasted | Percentage of Participants With Best Overall Response | PD | 47 percentage of participants |
| Arm 3: Ixazomib 4 mg Fasted | Percentage of Participants With Best Overall Response | SD | 53 percentage of participants |
| Arm 3: Ixazomib 4 mg Fasted | Percentage of Participants With Best Overall Response | PR | 1 percentage of participants |
| Arm 3: Ixazomib 4 mg Fasted | Percentage of Participants With Best Overall Response | CR | 0 percentage of participants |