Advanced Solid Tumors
Conditions
Keywords
Drug Therapy
Brief summary
The primary purpose of this study is to assess the effect of multiple-dose administration of fluconazole on the single-dose intravenous (IV) pharmacokinetics (PK) of MLN4924; and to assess the effect of multiple-dose administration of itraconazole on the single-dose IV PK of MLN4924.
Detailed description
The drug being tested in this study is MLN4924. MLN4924 is being evaluated to assess drug-drug interactions (DDIs) with the moderate and strong CYP3A inhibitors, fluconazole and itraconazole, respectively, in participants with advanced solid tumors. This study will look at the blood concentrations of MLN4924 as it relates to treatment with fluconazole and itraconazole. The study will enroll approximately 52 participants. In Part A, participants will be administered MLN4924 via a 1-hour (+- 5 minutes) intravenous (IV) infusion in combination with either fluconazole or itraconazole administered orally. After participants complete Part A, they will have the opportunity to begin treatment in Part B. In Part B, participants will be administered MLN4924 via a 1-hour (+- 5 minutes) IV infusion in combination with either docetaxel or carboplatin + paclitaxel, the three of which would also be administered intravenously. This multi-center trial will be conducted in the United States. Participation in Part A of this study will include a screening visit and two weeks of treatment; participation in Part B of this study will include up to an 8-week drug washout period (from last dosing in Part A) and treatment until participants experience symptomatic deterioration, progressive disease, until treatment is discontinued for another reason, or until the study is stopped.
Interventions
DRUGMLN4924
MLN4924 intravenous solution.
DRUGFluconazole
Fluconazole tablets.
DRUGItraconazole
Itraconazole oral solution.
DRUGDocetaxel
Docetaxel intravenous solution.
DRUGCarboplatin
Carboplatin intravenous solution.
DRUGPaclitaxel
Paclitaxel intravenous solution.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female participants 18 years of age or older. 2. Must have a histologically or cytologically confirmed metastatic or locally advanced and incurable solid tumor that is deemed appropriate for treatment with 1 of the 2 chemotherapy regimens in Part B of this study, or have progressed despite standard therapy, or for whom conventional therapy is not considered effective. The tumor must be radiographically or clinically evaluable or measurable. 3. Recovered (that is, less than or equal to (\<=) Grade 1 toxicity) from the effects of prior antineoplastic therapy. 4. Suitable venous access for the study-required blood sampling for MLN4924 pharmacokinetic (PK) and pharmacodynamic assessments. 5. Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. 6. Clinical laboratory values as specified below within 3 days before the first dose of study drug: 1. Hemoglobin greater than or equal to (\>=) 9 gram per deciliter (g/dL) 2. Absolute neutrophil count \>=1,500 per cubic millimeter (/mm\^3), not supported by growth factor 3. Platelet count \>=100,000/mm\^3 4. Total bilirubin \<=upper limit of normal (ULN) 5. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) \<=1.5\*ULN 6. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) \<=2.5\*ULN • For participants to be treated with MLN4924 + docetaxel in Part B, AST and ALT must be \<=1.5\*ULN, and total bilirubin should be within the normal range. 7. Serum creatinine \<=1.2 mg/dL or calculated/measured creatinine clearance \>=50 mL/minute 7. Female participants who: 1. Are postmenopausal for at least 1 year before the screening visit, OR 2. Are surgically sterile, OR 3. If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through four months after the last dose of study drug, or 4. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal are not acceptable methods of contraception.) 5. Male participants, even if surgically sterilized (that is, status postvasectomy), who: 6. Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or 7. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[example, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal are not acceptable methods of contraception.) 8. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care. 9. Participants who are willing to refrain from donating blood for at least 90 days after their final dose of MLN4924 and (for male participants) willing to refrain from donating semen for at least 4 months after their final dose of MLN4924.
Exclusion criteria
1. Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel, and carboplatin is allowed. 2. Treatment with any systemic antineoplastic therapy or investigational products within 21 days before the first dose of study treatment. 3. Radiotherapy within 14 days before the first dose of study treatment. 4. Prior treatment with radiation therapy involving \>= 25 percent (%) of hematopoietically active bone marrow. 5. Known hypersensitivity or history of severe intolerance or toxicity to study-assigned chemotherapy. Note: History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based formulations) for participants to be treated with MLN4924 + docetaxel; history of hypersensitivity to carboplatin for participants to be treated with MLN4924 + carboplatin + paclitaxel; or history of severe hypersensitivity to paclitaxel (Cremophor-based formulations) for participants to be treated with MLN4924 + carboplatin + paclitaxel in Part B. 6. Known hypersensitivity/allergy to fluconazole or itraconazole or their respective excipients. 7. Systemic treatment with moderate and strong cytochrome P450 (CYP) CYP3A inhibitors or inducers must be discontinued at least 14 days before the first dose of MLN4924. Moderate and strong CYP3A inhibitors and CYP3A inducers are not permitted during the study. Participants must have no history of amiodarone use in the 6 months before the first dose of MLN4924. 8. Any life-threatening or serious medical or psychiatric illness unrelated to cancer that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. 9. Major surgery within 14 days before the first dose of study treatment. 10. Active uncontrolled infection or severe infectious disease, such as pneumonia, meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection. 11. Clinically significant central nervous system disease defined as untreated, progressive, or requiring steroids for control of symptoms. 12. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of fluconazole or itraconazole including difficulty swallowing capsules. 13. Persistent diarrhea (\>= Grade 2) lasting greater than (\>) 3 days within 2 weeks before the first dose of study treatment. 14. Known hepatic cirrhosis, hepatitis B surface antigen-positive status, or suspected active hepatitis C infection. Note: Participants who have isolated positive hepatitis B core antibody (that is, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. 15. Known human immunodeficiency virus (HIV) positive status. 16. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of study drug. 17. Uncontrolled high blood pressure (that is, systolic blood pressure \>180 millimeter of mercury \[mmHg\], diastolic blood pressure \>95 mmHg). 18. Left ventricular ejection fraction \< 50% as assessed by echocardiogram or radionuclide angiography. 19. Congestive heart failure New York Heart Association Class III or IV, or Class II with a recent decompensation requiring hospitalization within 4 weeks before screening. 20. Cardiomyopathy or history of ischemic heart disease. o Participants with ischemic heart disease who have had acute coronary syndrome (ACS), myocardial infarction (MI), or revascularization (example, coronary artery bypass graft, stent) in the past 6 months are excluded. However, participants with ischemic heart disease who have had ACS, MI, or revascularization greater than 6 months before screening and who are without cardiac symptoms may enroll. 21. Arrhythmia (example, history of polymorphic ventricular fibrillation or torsade de pointes). However, participants with \< Grade 3 atrial fibrillation for a period of at least 6 months may enroll. Grade 3 atrial fibrillation is defined as symptomatic and incompletely controlled medically, or controlled with device (example, pacemaker) or ablation, and is excluded. Participants with paroxysmal atrial fibrillation are permitted to enroll. 22. Prolonged rate corrected QT interval (QTc) \>=500 millisecond (msec), calculated according to institutional guidelines. 23. Implantable cardioverter defibrillator. 24. Participants with a cardiac pacer whose heart rate is set at a fixed rate and participants on concomitant medication that may limit increase in heart rate in response to hypotension (example, high-dose beta blocker). 25. Moderate to severe aortic or mitral stenosis or other valvulopathy (ongoing). 26. Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary fibrosis, and pulmonary arterial hypotension.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Fluconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Fluconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
| Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Plasma Clearance (CLp) for MLN4924 | Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A | — |
| Part A Tmax: Time to Reach the Cmax for MLN4924 | Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A | — |
| Part A: Volume of Distribution (Vz) for MLN4924 | Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A | — |
| Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A | — |
| Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | Day 1 up to 24 hours post infusion | — |
| Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | Baseline up to 30 days after the last dose of study drug (Day 40 for Part A; approximately Cycle 29 for Part B) | — |
| Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29 Day 35 | — |
| Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29 Day 35 | — |
| Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29 | — |
| Part B: Percentage of Participants With Objective Response | Baseline up to symptomatic deterioration, progressive disease (PD), treatment discontinuation, or until the study is stopped (approximately Cycle 29) | Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as complete disappearance of all target lesions. All pathological lymph nodes, both target and non-target, must decrease to normal (short axis less than \[\<\]10 millimeter \[mm\]). PR was defined as at least 30% decrease under baseline of the sum of diameters of all target lesions. |
| Part B: Duration of Response | Time from the date of first documentation of a response and PD (approximately up Cycle 29) | The duration of response was defined in participants with disease response (CR or PR) as the time between the first documentation of response and progressive disease (PD). Responders without PD will be censored at the last clinical assessment of response. CR was defined as complete disappearance of all target lesions. All pathological lymph nodes, both target and non-target, must decrease to normal (short axis \<10 mm). PR was defined as at least 30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative site in the United States from 01 April 2014 to 05 June 2017.
Pre-assignment details
Participants with advanced solid tumors were enrolled in this study to receive MLN4924. This study included 2 parts: Part A (drug-drug interaction)- participants received MLN4924 with fluconazole or itraconazole and in Part B (standard of care)- participants received MLN4924 in combination with docetaxel or carboplatin and paclitaxel.
Participants by arm
| Arm | Count |
|---|---|
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg MLN4924 8 milligram per square meter (mg/m\^2), infusion, intravenously, once on Days 1 and 8 along with fluconazole, 400 milligram (mg), tablets, orally, once on Day 4, and 200 mg, once daily on Days 5-10. | 13 |
| Part A: MLN4924 8 mg/m^2 + Itraconazole 200 mg MLN4924 8 mg/m\^2, infusion, intravenously, once on Days 1 and 8 along with itraconazole, 200 mg, solution, orally, once daily on Days 4-10. | 13 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg MLN4924 15 mg/m\^2, infusion, intravenously, once on Days 1 and 8 along with itraconazole, 200 mg, solution, orally, once daily on Days 4-10. | 6 |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg MLN4924 20 mg/m\^2, infusion, intravenously, once on Days 1 and 8 along with itraconazole, 200 mg, solution, orally, once daily on Days 4-10. | 19 |
| Total | 51 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part A: Drug-drug Interaction 2 | Adverse Event | 3 | 0 | 1 | 2 | 0 | 0 |
| Part A: Drug-drug Interaction 2 | Other | 0 | 0 | 1 | 0 | 0 | 0 |
| Part A: Drug-drug Interaction 2 | Symptomatic Deterioration | 1 | 5 | 0 | 1 | 0 | 0 |
| Part A: Drug-drug Interaction 2 | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Part B: Standard of Care | Adverse Event | 0 | 0 | 0 | 0 | 4 | 1 |
| Part B: Standard of Care | Other | 0 | 0 | 0 | 0 | 0 | 2 |
| Part B: Standard of Care | Progressive Disease | 0 | 0 | 0 | 0 | 10 | 8 |
| Part B: Standard of Care | Symptomatic Deterioration | 0 | 0 | 0 | 0 | 5 | 0 |
| Part B: Standard of Care | Withdrawal by Subject | 0 | 0 | 0 | 0 | 4 | 2 |
Baseline characteristics
| Characteristic | Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: MLN4924 8 mg/m^2 + Itraconazole 200 mg | Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 7 Participants | 5 Participants | 8 Participants | 25 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 1 Participants | 11 Participants | 26 Participants |
| Body Mass Index (BMI) | 1.792 square meter (m^2) STANDARD_DEVIATION 0.3405 | 1.712 square meter (m^2) STANDARD_DEVIATION 0.2384 | 1.883 square meter (m^2) STANDARD_DEVIATION 0.2297 | 2.021 square meter (m^2) STANDARD_DEVIATION 0.3736 | 1.868 square meter (m^2) STANDARD_DEVIATION 0.3372 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 10 Participants | 6 Participants | 14 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 3 Participants | 0 Participants | 5 Participants | 8 Participants |
| Height | 165.82 centimeter (cm) STANDARD_DEVIATION 12.142 | 166.49 centimeter (cm) STANDARD_DEVIATION 10.023 | 167.93 centimeter (cm) STANDARD_DEVIATION 6.998 | 171.46 centimeter (cm) STANDARD_DEVIATION 9.399 | 168.34 centimeter (cm) STANDARD_DEVIATION 10.122 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 10 Participants | 4 Participants | 16 Participants | 41 Participants |
| Region of Enrollment United States | 13 Participants | 13 Participants | 6 Participants | 19 Participants | 51 Participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 4 Participants | 8 Participants | 27 Participants |
| Sex: Female, Male Male | 6 Participants | 5 Participants | 2 Participants | 11 Participants | 24 Participants |
| Weight | 71.22 kilogram (kg) STANDARD_DEVIATION 24.051 | 64.21 kilogram (kg) STANDARD_DEVIATION 16.536 | 76.58 kilogram (kg) STANDARD_DEVIATION 16.616 | 87.55 kilogram (kg) STANDARD_DEVIATION 32.311 | 76.15 kilogram (kg) STANDARD_DEVIATION 26.471 |
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 |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 13 | 3 / 13 | 1 / 6 | 2 / 19 | 6 / 23 | 1 / 13 |
| other Total, other adverse events | 13 / 13 | 13 / 13 | 6 / 6 | 18 / 19 | 23 / 23 | 13 / 13 |
| serious Total, serious adverse events | 3 / 13 | 3 / 13 | 2 / 6 | 5 / 19 | 14 / 23 | 6 / 13 |
Outcome results
Primary
Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Fluconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: The PK evaluable population included all enrolled participants who received all protocol-specified dose regimens within each period during Part A, did not received any excluded medications throughout the completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Fluconazole | 450 h*ng/mL | Geometric Coefficient of Variation 16.8 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Fluconazole | 498 h*ng/mL | Geometric Coefficient of Variation 15.9 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [102.53, 119.43]
Primary
Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 465 h*ng/mL | Geometric Coefficient of Variation 25.1 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 585 h*ng/mL | Geometric Coefficient of Variation 23.9 |
| Part A: MLN4924 15 mg/m^2 | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 798 h*ng/mL | Geometric Coefficient of Variation 18.1 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 1060 h*ng/mL | Geometric Coefficient of Variation 16.1 |
| Part A: MLN4924 20 mg/m^2 | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 1120 h*ng/mL | Geometric Coefficient of Variation 30.4 |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole | 1130 h*ng/mL | Geometric Coefficient of Variation 23.5 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [112.13, 134.82]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference90% CI: [106.99, 158.35]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [91.14, 111.68]
Primary
Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Fluconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: The PK evaluable population included all enrolled participants who received all protocol-specified dose regimens within each period during Part A, did not received any excluded medications throughout the completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Fluconazole | 445 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 16.7 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Fluconazole | 491 hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 15.5 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [102.34, 118.69]
Primary
Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 459 h*ng/mL | Geometric Coefficient of Variation 24.7 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 571 h*ng/mL | Geometric Coefficient of Variation 23.5 |
| Part A: MLN4924 15 mg/m^2 | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 793 h*ng/mL | Geometric Coefficient of Variation 18.2 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 1030 h*ng/mL | Geometric Coefficient of Variation 17.3 |
| Part A: MLN4924 20 mg/m^2 | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 1110 h*ng/mL | Geometric Coefficient of Variation 30.2 |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Part A AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN4924 and MLN4924 + Itraconazole | 1140 h*ng/mL | Geometric Coefficient of Variation 22.7 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [110.92, 133.24]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference90% CI: [106.99, 158.35]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [90.72, 113.23]
Primary
Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Fluconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: The pharmacokinetic (PK) evaluable population included all enrolled participants who received all protocol-specified dose regimens within each period during Part A, did not received any excluded medications throughout the completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole | 51.6 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 52.3 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole | 51.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 30.8 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric least square (LS) means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [82.6, 118.05]
Primary
Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole
Time frame: Day 1 (MLN4924) and Day 8 (MLN4924 + Itraconazole): pre-dose and at multiple time points (up to 72 hours) post-dose
Population: The PK evaluable population included all enrolled participants who received all protocol-specified dose regimens within each period during Part A, did not received any excluded medications throughout the completion of PK sampling, and had sufficient MLN4924 plasma concentration-time data to estimate PK parameters.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 59.1 ng/mL | Geometric Coefficient of Variation 52.4 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 66.8 ng/mL | Geometric Coefficient of Variation 53.7 |
| Part A: MLN4924 15 mg/m^2 | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 121 ng/mL | Geometric Coefficient of Variation 61 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 193 ng/mL | Geometric Coefficient of Variation 46.9 |
| Part A: MLN4924 20 mg/m^2 | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 178 ng/mL | Geometric Coefficient of Variation 76.3 |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole | 137 ng/mL | Geometric Coefficient of Variation 29.9 |
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [85.35, 149.74]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference90% CI: [89.97, 282.96]
Comparison: Natural-log transformed pharmacokinetic parameters were fit using a mixed effects model with study day as a fixed effect and participant as a random effect. Geometric LS means and geometric LS mean ratio were back-transformed least squares mean and treatment mean difference.90% CI: [55.19, 108.17]
Secondary
Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE)
Time frame: Baseline up to 30 days after the last dose of study drug (Day 40 for Part A; approximately Cycle 29 for Part B)
Population: The safety population for Part A included all enrolled participants who received at least 1 dose of MLN4924 during Part A and safety population for Part B included all participants who continued to Part B and received at least 1 dose of study drugs during Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 13 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 3 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 13 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 3 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 6 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 2 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 18 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 5 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 23 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 14 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | TEAE | 13 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) | SAE | 6 Participants |
Secondary
Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements
Time frame: Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29
Population: The safety population for Part A included all enrolled participants who received at least 1 dose of MLN4924 during Part A and safety population for Part B included all participants who continued to Part B and received at least 1 dose of study drugs during Part B.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 0 participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 0 participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 0 participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 0 participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 0 participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 0 participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 1 participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 1 participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 1 participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 0 participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 2 AE: 10 - <20% decrease from baseline | 0 participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 1 AE: 5 < 10% decrease from baseline | 1 participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements | Grade 3 AE: >=20% decrease from baseline | 0 participants |
Secondary
Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings
Time frame: Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29 Day 35
Population: The safety population for Part A included all enrolled participants who received at least 1 dose of MLN4924 during Part A and safety population for Part B included all participants who continued to Part B and received at least 1 dose of study drugs during Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 1 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 1 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 1 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 1 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 1 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 1 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 2 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 1 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 1 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 1 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 1 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 1 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 1 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 2 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 1 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 2 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 1 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 2 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 3 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 7 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 4 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 2 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 2 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 3 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 1 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 3 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutrophil count decreased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyponatraemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Aspartate aminotransferase increased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Pancytopenia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Platelet count decreased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood urea increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood bilirubin increased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypokalaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Liver function test increased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypomagnesaemia | 2 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Gamma-glutamyltransferase increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Blood creatinine increased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Leukopenia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Thrombocytopenia | 2 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperuricaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hyperbilirubinaemia | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | White blood cell count decreased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypoalbuminaemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Hypophosphataemia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Anaemia | 2 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Alanine aminotransferase increased | 1 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Lymphocyte count decreased | 0 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings | Neutropenia | 2 Participants |
Secondary
Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings
Time frame: Part A: Baseline up to Day 40; Part B: Baseline up to approximately Cycle 29 Day 35
Population: The safety population for Part A included all enrolled participants who received at least 1 dose of MLN4924 during Part A and safety population for Part B included all participants who continued to Part B and received at least 1 dose of study drugs during Part B.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 0 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 2 Participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 1 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 0 Participants |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 1 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 0 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 5 Participants |
| Part A: MLN4924 20 mg/m^2 | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 7 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Tachycardia | 3 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Hypotension | 3 Participants |
| Part A: MLN4924 20 mg/m^2 + Itraconazole 200 mg | Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings | Sinus tachycardia | 0 Participants |
Secondary
Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924
Time frame: Day 1 up to 24 hours post infusion
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | End of infusion | 51.1 Ratio | Geometric Coefficient of Variation 64.1 |
| Part A: MLN4924 8 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 2 hours post infusion | 69.2 Ratio | Geometric Coefficient of Variation 16.2 |
| Part A: MLN4924 8 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 8 hours post infusion | 71.1 Ratio | Geometric Coefficient of Variation 20.5 |
| Part A: MLN4924 8 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 24 hours post infusion | 71.9 Ratio | Geometric Coefficient of Variation 25.5 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 2 hours post infusion | 54.7 Ratio | Geometric Coefficient of Variation 34.7 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 8 hours post infusion | 73.7 Ratio | Geometric Coefficient of Variation 27.5 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 24 hours post infusion | 67.6 Ratio | Geometric Coefficient of Variation 31.3 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | End of infusion | 43.7 Ratio | Geometric Coefficient of Variation 56.9 |
| Part A: MLN4924 15 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 8 hours post infusion | 70.7 Ratio | Geometric Coefficient of Variation 38.4 |
| Part A: MLN4924 15 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 2 hours post infusion | 66.5 Ratio | Geometric Coefficient of Variation 30.2 |
| Part A: MLN4924 15 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 24 hours post infusion | 66.3 Ratio | Geometric Coefficient of Variation 17.7 |
| Part A: MLN4924 15 mg/m^2 | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | End of infusion | 55.2 Ratio | Geometric Coefficient of Variation 30.4 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 24 hours post infusion | 58.0 Ratio | Geometric Coefficient of Variation 23.1 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 2 hours post infusion | 48.8 Ratio | Geometric Coefficient of Variation 28.2 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | End of infusion | 35.1 Ratio | Geometric Coefficient of Variation 74.7 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 | 8 hours post infusion | 56.7 Ratio | Geometric Coefficient of Variation 14.6 |
Secondary
Part A: Plasma Clearance (CLp) for MLN4924
Time frame: Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A: Plasma Clearance (CLp) for MLN4924 | Day 1 | 31.7 liter per hour (L/h) | Geometric Coefficient of Variation 24.9 |
| Part A: MLN4924 8 mg/m^2 | Part A: Plasma Clearance (CLp) for MLN4924 | Day 8 | 28.6 liter per hour (L/h) | Geometric Coefficient of Variation 30.2 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Plasma Clearance (CLp) for MLN4924 | Day 8 | 23.2 liter per hour (L/h) | Geometric Coefficient of Variation 32.5 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Plasma Clearance (CLp) for MLN4924 | Day 1 | 29.2 liter per hour (L/h) | Geometric Coefficient of Variation 27.5 |
| Part A: MLN4924 15 mg/m^2 | Part A: Plasma Clearance (CLp) for MLN4924 | Day 1 | 35.2 liter per hour (L/h) | Geometric Coefficient of Variation 16.3 |
| Part A: MLN4924 15 mg/m^2 | Part A: Plasma Clearance (CLp) for MLN4924 | Day 8 | 26.5 liter per hour (L/h) | Geometric Coefficient of Variation 18.6 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Plasma Clearance (CLp) for MLN4924 | Day 1 | 35.8 liter per hour (L/h) | Geometric Coefficient of Variation 41.6 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Plasma Clearance (CLp) for MLN4924 | Day 8 | 35.5 liter per hour (L/h) | Geometric Coefficient of Variation 33.6 |
Secondary
Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924
Time frame: Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 1 | 11.0 hour | Geometric Coefficient of Variation 15.7 |
| Part A: MLN4924 8 mg/m^2 | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 8 | 11.6 hour | Geometric Coefficient of Variation 14.2 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 8 | 13.3 hour | Geometric Coefficient of Variation 17.8 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 1 | 10.6 hour | Geometric Coefficient of Variation 20.6 |
| Part A: MLN4924 15 mg/m^2 | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 1 | 9.74 hour | Geometric Coefficient of Variation 7.4 |
| Part A: MLN4924 15 mg/m^2 | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 8 | 11.0 hour | Geometric Coefficient of Variation 8 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 1 | 9.88 hour | Geometric Coefficient of Variation 13.8 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 | Day 8 | 10.7 hour | Geometric Coefficient of Variation 9.7 |
Secondary
Part A Tmax: Time to Reach the Cmax for MLN4924
Time frame: Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 1 | 1.04 hour |
| Part A: MLN4924 8 mg/m^2 | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 8 | 1.21 hour |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 8 | 1.50 hour |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 1 | 1.02 hour |
| Part A: MLN4924 15 mg/m^2 | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 1 | 1.24 hour |
| Part A: MLN4924 15 mg/m^2 | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 8 | 1.03 hour |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 1 | 1.05 hour |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A Tmax: Time to Reach the Cmax for MLN4924 | Day 8 | 1.13 hour |
Secondary
Part A: Volume of Distribution (Vz) for MLN4924
Time frame: Days 1 and 8: predose and at multiple time-points (up to 72 hours) postdose for Part A
Population: PK population:enrolled participants who received all protocol-specified dose regimens within each period in Part A,did not receive any excluded medications throughout completion of PK sampling, had sufficient MLN4924 plasma concentration-time data to estimate PK parameters. PK analysis population where data at specified time points were available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part A: Volume of Distribution (Vz) for MLN4924 | Day 1 | 503 Liter (L) | Geometric Coefficient of Variation 29.2 |
| Part A: MLN4924 8 mg/m^2 | Part A: Volume of Distribution (Vz) for MLN4924 | Day 8 | 477 Liter (L) | Geometric Coefficient of Variation 30.8 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Volume of Distribution (Vz) for MLN4924 | Day 8 | 445 Liter (L) | Geometric Coefficient of Variation 37.9 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part A: Volume of Distribution (Vz) for MLN4924 | Day 1 | 445 Liter (L) | Geometric Coefficient of Variation 34.3 |
| Part A: MLN4924 15 mg/m^2 | Part A: Volume of Distribution (Vz) for MLN4924 | Day 1 | 494 Liter (L) | Geometric Coefficient of Variation 22 |
| Part A: MLN4924 15 mg/m^2 | Part A: Volume of Distribution (Vz) for MLN4924 | Day 8 | 421 Liter (L) | Geometric Coefficient of Variation 22 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Volume of Distribution (Vz) for MLN4924 | Day 1 | 511 Liter (L) | Geometric Coefficient of Variation 42.6 |
| Part A: MLN4924 15 mg/m^2 + Itraconazole 200 mg | Part A: Volume of Distribution (Vz) for MLN4924 | Day 8 | 550 Liter (L) | Geometric Coefficient of Variation 27.3 |
Secondary
Part B: Duration of Response
The duration of response was defined in participants with disease response (CR or PR) as the time between the first documentation of response and progressive disease (PD). Responders without PD will be censored at the last clinical assessment of response. CR was defined as complete disappearance of all target lesions. All pathological lymph nodes, both target and non-target, must decrease to normal (short axis \<10 mm). PR was defined as at least 30% decrease under baseline of the sum of diameters of all target lesions. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: Time from the date of first documentation of a response and PD (approximately up Cycle 29)
Population: The response-evaluable population included all participants who received at least 1 dose of study drug in Part B, had measurable disease as entry criteria for Part B, and had at least 1 postbaseline disease assessment. The response-evaluable population where data at specified time points were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part B: Duration of Response | 4.07 months | Standard Deviation 1.44 |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part B: Duration of Response | 8.46 months | Standard Deviation 1.464 |
Secondary
Part B: Percentage of Participants With Objective Response
Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR was defined as complete disappearance of all target lesions. All pathological lymph nodes, both target and non-target, must decrease to normal (short axis less than \[\<\]10 millimeter \[mm\]). PR was defined as at least 30% decrease under baseline of the sum of diameters of all target lesions.
Time frame: Baseline up to symptomatic deterioration, progressive disease (PD), treatment discontinuation, or until the study is stopped (approximately Cycle 29)
Population: The response-evaluable population included all participants who received at least 1 dose of study drug in Part B, had measurable disease as entry criteria for Part B, and had at least 1 postbaseline disease assessment. The response-evaluable population where data at specified time points were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: MLN4924 8 mg/m^2 | Part B: Percentage of Participants With Objective Response | 10.5 percentage of participants |
| Part A: MLN4924 8 mg/m^2 + Fluconazole 400 mg | Part B: Percentage of Participants With Objective Response | 22.2 percentage of participants |