Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 1 Study to Evaluate the Effects of Fluconazole and Itraconazole CYP3A-Mediated Inhibition on the Pharmacokinetics, Safety, and Tolerability of MLN4924 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: MLN4924
* Drug: Fluconazole
* Drug: Itraconazole
* Drug: Docetaxel
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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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 (<=) Grade 1 toxicity) from the effects of prior antineoplastic therapy. Suitable venous access for the study-required blood sampling for MLN4924 pharmacokinetic (PK) and pharmacodynamic assessments. Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Clinical laboratory values as specified below within 3 days before the first dose of study drug: Hemoglobin greater 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 <=upper limit of normal (ULN) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) <=1.5*ULN 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. Serum creatinine <=1.2 mg/dL or calculated/measured creatinine clearance >=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 completion of treatment according to this protocol. Major surgery within 14 days before the first dose of study treatment. Active uncontrolled infection or severe infectious disease, such as pneumonia, meningitis, septicemia, or methicillin-resistant Staphylococcus aureus infection. Clinically significant central nervous system disease defined as untreated, progressive, or requiring steroids for control of symptoms. Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of fluconazole or itraconazole including difficulty swallowing capsules. Persistent diarrhea (>= Grade 2) lasting greater than (>) 3 days within 2 weeks before the first dose of study treatment. 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. Known human immunodeficiency virus (HIV) positive status. 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. Uncontrolled high blood pressure (that is, systolic blood pressure >180 millimeter of mercury [mmHg], diastolic blood pressure >95 mmHg). Left ventricular ejection fraction < 50% as assessed by echocardiogram or radionuclide angiography. 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. 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. 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. Prolonged rate corrected QT interval (QTc) >=500 millisecond (msec), calculated according to institutional guidelines. Implantable cardioverter defibrillator. 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). Moderate to severe aortic or mitral stenosis or other valvulopathy (ongoing). Known moderate to severe chronic obstructive pulmonary disease (COPD), interstitial lung disease, pulmonary fibrosis, and pulmonary arterial hypotension.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN4924 + Fluconazole<br>Part A: MLN4924, 8 milligram per square meter (mg/m^2), intravenously, once on Days 1 and 8; and fluconazole, 400 milligram (mg), tablets, orally, once on Day 4, and 200 mg, once daily on Days 5-10. Part B: MLN4924, at a dose previously deemed tolerable, given on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, Clinicaltrials.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle. | Drug: MLN4924<br>* MLN4924 intravenous solution.<br>Drug: Fluconazole<br>* Fluconazole tablets.<br>Drug: Docetaxel<br>* Docetaxel intravenous solution.<br>Drug: Carboplatin<br>* Carboplatin intravenous solution.<br>Drug: Paclitaxel<br>* Paclitaxel intravenous solution.<br>|
| Experimental: MLN4924 + Itraconazole<br>Part A: MLN4924, 8-mg/m^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part A (safety lead-in step): MLN4924, 15mg/m^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part A: MLN4924, 20mg/m^2, intravenously, once on Days 1 and 8; and itraconazole, 200 mg, oral solution, once daily on Days 4-10. Part B: MLN4924, at a dose previously deemed tolerable given, on Days 1, 3, and 5 of each 21-day Cycle (Study C15010, ClinicalTrails.gov Identifier # NCT01862328) in combination with docetaxel or carboplatin + paclitaxel at standard dose regimen on Day 1 of each 21-day Cycle. | Drug: MLN4924<br>* MLN4924 intravenous solution.<br>Drug: Itraconazole<br>* Itraconazole oral solution.<br>Drug: Docetaxel<br>* Docetaxel intravenous solution.<br>Drug: Carboplatin<br>* Carboplatin intravenous solution.<br>Drug: Paclitaxel<br>* Paclitaxel intravenous solution.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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. | Baseline up to symptomatic deterioration, progressive disease (PD), treatment discontinuation, or until the study is stopped (approximately Cycle 29) | 
| 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 from the date of first documentation of a response and PD (approximately up Cycle 29) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug Therapy