Phase 1
Completed N=51
Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors
Source: ClinicalTrials.gov NCT02122770 ↗Enrolled (actual)
51
Serious AEs
37.9%
Results posted
Jan 2019
Primary outcomePrimary: Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole — 51.6; 51.0 nanogram per milliliter (ng/mL)
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Fluconazole |
51.6; 51.0 | — |
| 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 |
445; 491 | — |
| PRIMARY Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Fluconazole |
450; 498 | — |
| PRIMARY Part A Cmax: Maximum Observed Plasma Concentration for MLN4924 and MLN4924 + Itraconazole |
59.1; 66.8; 121; 193; 178; 137 | — |
| 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 |
459; 571; 793; 1030; 1110; 1140 | — |
| PRIMARY Part A AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN4924 and MLN4924 + Itraconazole |
465; 585; 798; 1060; 1120; 1130 | — |
| SECONDARY Part A: Plasma Clearance (CLp) for MLN4924 |
31.7; 29.2; 35.2; 35.8; 28.6; 23.2 | — |
| SECONDARY Part A Tmax: Time to Reach the Cmax for MLN4924 |
1.04; 1.02; 1.24; 1.05; 1.21; 1.50 | — |
| SECONDARY Part A: Volume of Distribution (Vz) for MLN4924 |
503; 445; 494; 511; 477; 445 | — |
| SECONDARY Part A: Terminal Phase Elimination Half-life (T1/2) for MLN4924 |
11.0; 10.6; 9.74; 9.88; 11.6; 13.3 | — |
| SECONDARY Part A: Blood to Plasma (B/P) Concentration Ratio for MLN4924 |
51.1; 43.7; 55.2; 35.1; 69.2; 54.7 | — |
| SECONDARY Number of Participants Who Experience at Least 1 Treatment-emergent Adverse Event (TEAE) and Serious Adverse Event (SAE) |
13; 13; 6; 18; 23; 13 | — |
| SECONDARY Number of Participants With TEAEs Related to Clinically Significant Laboratory Evaluation Findings |
1; 2; 0; 0; 4; 2 | — |
| SECONDARY Number of Participants With TEAEs Related to Clinically Significant Vital Sign Findings |
0; 2; 0; 0; 5; 3 | — |
| SECONDARY Number of Participants With Clinically Significant Change From Baseline in Body Weight Measurements |
0; 0; 0; 1; 1; 1 | — |
| SECONDARY Part B: Percentage of Participants With Objective Response |
10.5; 22.2 | — |
| SECONDARY Part B: Duration of Response |
4.07; 8.46 | — |
Eligibility Criteria
Inclusion Criteria
- Male or female participants 18 years of age or older.
- 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.
- Recovered (that is, less than or equal to ( =) 9 gram per deciliter (g/dL)
- Absolute neutrophil count >=1, 500 per cubic millimeter (/mm^3), not supported by growth factor
- Platelet count >=100,000/mm^3
- Total bilirubin =50 mL/minute
- Female participants who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- 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
- 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.)
- Male participants, even if surgically sterilized (that is, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
- 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.)
- 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.
- 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
- Prior treatment with MLN4924; however, prior treatment with docetaxel, paclitaxel, and carboplatin is allowed.
- Treatment with any systemic antineoplastic therapy or investigational products within 21 days before the first dose of study treatment.
- Radiotherapy within 14 days before the first dose of study treatment.
- Prior treatment with radiation therapy involving >= 25 percent (%) of hematopoietically active bone marrow.
- 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.
- Known hypersensitivity/allergy to fluconazole or itraconazole or their respective excipients.
- 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.
- Any life-threatening or serious medical or psychiatric illness unrelated to cancer that could, in the investigator's opinion, potentially interfere with the completio
Data sourced from ClinicalTrials.gov (NCT02122770). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.