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

NCT02122770 | Completed Phase 1 Results DMC

• 2 other identifiers: C15011U1111-1155-6191
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 4

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.

Conditions

Advanced Solid Tumors

Keywords

Drug Therapy

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (11)

• 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

Study Arms (2)

MLN4924 + Fluconazole

EXPERIMENTAL

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; Drug: Fluconazole; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel

MLN4924 + Itraconazole

EXPERIMENTAL

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; Drug: Itraconazole; Drug: Docetaxel; Drug: Carboplatin; Drug: Paclitaxel

Interventions

MLN4924 DRUG

MLN4924 intravenous solution.

MLN4924 + Fluconazole; MLN4924 + Itraconazole

Fluconazole DRUG

Fluconazole tablets.

MLN4924 + Fluconazole

Itraconazole DRUG

Itraconazole oral solution.

MLN4924 + Itraconazole

Docetaxel DRUG

Docetaxel intravenous solution.

MLN4924 + Fluconazole; MLN4924 + Itraconazole

Carboplatin DRUG

Carboplatin intravenous solution.

MLN4924 + Fluconazole; MLN4924 + Itraconazole

Paclitaxel DRUG

Paclitaxel intravenous solution.

MLN4924 + Fluconazole; MLN4924 + Itraconazole

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (4)

Winship Cancer Institute at Emory University

Atlanta, Georgia, 30322, United States

Location

Siteman Cancer Center - South County

St Louis, Missouri, 63110, United States

Location

Sarah Cannon Cancer Center

Nashville, Tennessee, 37203, United States

Location

Mary Crowley Medical Research Center

Dallas, Texas, 75230, United States

Location

MeSH Terms

Interventions

pevonedistat; Fluconazole; Itraconazole; Docetaxel; Carboplatin; Paclitaxel

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperazines; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Director Clinical Science

  Millennium Pharmaceuticals, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 23, 2014
• First Posted: April 25, 2014
• Study Start: April 1, 2014
• Primary Completion: June 5, 2017
• Study Completion: June 5, 2017
• Last Updated: January 7, 2019
• Results First Posted: January 7, 2019

Record last verified: 2018-06

Locations

US (4)