Overview

This trial has been completed.

Conditions nonhematologic malignancies, lymphoma
Treatments ixazomib capsule b formulation, ixazomib capsule a formulation, ketoconazole, rifampin, drug: clarithromycin
Phase phase 1
Sponsor Millennium Pharmaceuticals, Inc.
Start date November 2011
End date April 2015
Trial size 125 participants
Trial identifier NCT01454076, C16009, U1111-1183-0218

Summary

This is an open-label, multicenter, sequential, 5-arm, phase 1 study of oral IXAZOMIB designed to assess drug-drug interaction with ketoconazole (Arm 1), the relative bioavailability of 2 capsule formulations of IXAZOMIB (Arm 2), food effect (Arm 3), drug-drug interaction with rifampin (Arm 4), and drug-drug interaction with clarithromycin (Arm 5) in patients with advanced nonhematologic malignancies or lymphoma.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Intervention model crossover assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
Patients receive a single 2.5-mg oral dose of IXAZOMIBCapsule B formulation on Day 1 and Day 15 during Cycle 1. Patients receive concomitant oral ketoconazole, a strong CYP3A inhibitor, at a dose of 400-mg once daily on Days 12 through 25 during Cycle 1.
ixazomib capsule b formulation
Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of IXAZOMIB Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
ketoconazole
(Experimental)
Patients receive a single oral dose of IXAZOMIB Capsule A or Capsule B formulation on Day 1, followed by a single dose of 4.0-mg of the alternate formulation (Capsule B formulation or A) on Day 15 of a 28-days pharmacokinetic cycle.
ixazomib capsule b formulation
Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of IXAZOMIB Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
ixazomib capsule a formulation
(Experimental)
Patients receive a single 4.0-mg oral dose of IXAZOMIB as Capsule B formulation with or without a standard high-fat breakfast on Day (D) 1 of Cycle (C) 1, followed by administration under the alternate food intake condition on D 15 of C 1. Fasted treatment: D 1 or 15 dose administered with ~ 8-oz of water following an overnight fast, including no medications, of ~10 hrs. Fed treatment: following an overnight fast, including no medications, of ~10 hrs, patients start breakfast 30 min prior to the administration of the D 1 or 15 dose. IXAZOMIB is administered 30 min after the start of the meal with ~8-oz of water. In both treatments, no food is allowed for at least 4 hrs postdose of the D 1 or 15 dose. Water is allowed except for 1 hr before and after drug administration.
ixazomib capsule b formulation
Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of IXAZOMIB Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
(Experimental)
Patients receive a single 4.0-mg oral dose of IXAZOMIB Capsule B formulation on Day 1 and Day 15 during Cycle 1, the 21-day PK cycle. Patients receive concomitant oral rifampin, a strong CYP3A inducer, at a dose of 600 mg once daily on Days 8 through 21 during Cycle 1.
ixazomib capsule b formulation
Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of IXAZOMIB Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
rifampin
(Experimental)
Patients receive a single 4.0-mg oral dose of IXAZOMIB Capsule B formulation on Day 6 during Cycle 1, the 21-day PK cycle. Patients receive concomitant oral clarithromycin, a strong CYP3A inhibitor, at a dose of 500 mg twice daily on Days 1 through 16 during Cycle 1.
ixazomib capsule b formulation
Applicable to all Arms: After completion of Cycle 1, patients receive a 4.0- mg dose of IXAZOMIB Capsule B formulation on Days 1, 8, and 15 of a 28-day schedule; however, starting with Cycle 4 and beyond patients will have the option of escalating to the 5.3-mg dose at the discretion of the investigator and the Millennium clinician. The maximum duration of treatment is 12 months after completion of Cycle 1 (13 months in total) unless it is determined that a patient would derive benefit from continued therapy beyond 12 cycles.
drug: clarithromycin

Primary Outcomes

Measure
Arm 1: Ratio of geometric mean Cmax and AUC0-tlast of IXAZOMIB administered as Capsule B formulation with ketoconazole versus when administered as a single agent and 90% confidence intervals (CI)
time frame: Cycle 1: Days 1-28
Arm 2: Ratio of geometric mean Cmax and AUC0-tlast of Capsule B formulation versus Capsule A formulation and 90% CI
time frame: Cycle 1: Days 1-28
Arm 3: Capsule B formulation ratio of geometric mean Cmax and AUC0-tlast of IXAZOMIB administered as Capsule B formulation with food versus without food and 90% CI
time frame: Cycle 1: Days 1-28
Arm 4: Ratio of geometric mean Cmax and AUC0-tlast of IXAZOMIB administered as Capsule B with rifampin versus when administered as a single agent and 90% confidence intervals (CI)
time frame: Cycle 1: Days 1-21
• Arm 5: Ratio of geometric mean Cmax and AUC0-tlast of IXAZOMIB administered as Capsule B with clarithromycin versus when administered as a single agent and 90% confidence intervals (CI)
time frame: Cycle 1: Days 1-21

Secondary Outcomes

Measure
Adverse events, serious adverse events, assessments of clinical laboratory values, and vital sign measurements
time frame: From the time informed consent is signed through 30 days after the last dose of study drug, approximately 13 months
Measures of disease response according to standard criteria
time frame: Q2 cycles for first 4 cycles, then Q3 cycles, approximately 13 months

Eligibility Criteria

Male or female participants at least 18 years old.

Inclusion Criteria: - Male or female patients 18 years or older - Patients must have a diagnosis of histologically or cytologically confirmed metastatic and/or advanced solid tumor malignancy or lymphoma for which no effective standard treatment is available - Female patients who are postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time from the time of signing the consent form through 90 days after the last dose of study drug, or agree to practice true abstinence - Male patients, even if surgically sterilized, agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug OR agree to practice true abstinence - Voluntary written informed consent - Clinical laboratory values as specified in protocol - Suitable venous access - Recovered (ie, < Grade 1 toxicity or patient's baseline status) from the reversible effects of prior anticancer therapy Exclusion Criteria: - Peripheral neuropathy > Grade 2 on clinical examination - Systemic treatment with strong inhibitors of CYP1A2, strong inhibitors of CYP3A, or strong CYP3A inducers or use of ginkgo biloba or St. John's wort within 14 days before the first dose of IXAZOMIB - Patient has symptomatic brain metastasis. Patients with brain metastases must: have stable neurologic status following surgery or radiation for at least 2 weeks after completion of the definitive therapy; AND be without neurologic dysfunction that would confound the evaluation of neurologic and other adverse events - Female patients who are pregnant or lactating - Serious illness that could interfere with protocol completion - Autologous stem cell transplant within 6 months before Day 1 of Cycle 1, or prior allogeneic stem cell transplant at any time - Prior treatment with rituximab or other unconjugated any antibody treatment within 42 days (21 days if there is clear evidence of progressive disease or immediate treatment is mandated) - Ongoing treatment with corticosteroids - Radiotherapy within 21 days before the first dose of study drug - Major surgery within 14 days before the first dose of study drug - Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to first dose of study drug - Life-threatening illness unrelated to cancer - Known human immunodeficiency virus (HIV) positive, hepatitis B surface antigen-positive, or suspected hepatitis C infection - Diagnosis or treatment of another malignancy within 2 years preceding first dose, OR previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection - Evidence of uncontrolled cardiovascular conditions - QTc > 500 milliseconds on a 12-lead electrocardiogram (ECG) - Known gastrointestinal disease or procedure that could interfere with the oral absorption or tolerance of IXAZOMIB including difficulty swallowing capsules; diarrhea > Grade 1 despite supportive therapy - Patients with gastric achlorhydria - Patients who have used any nicotine containing products within 14 days before the first dose of study drug (Arm 1, Arm 4, and Arm 5) - Treatment with any investigational products or systemic antineoplastic therapies within 21 days before the first dose of IXAZOMIB

Additional Information

Official title A Phase 1 Study of Oral IXAZOMIB (MLN9708) to Assess Relative Bioavailability, Food Effect, Drug-Drug Interaction With Ketoconazole, Clarithromycin or Rifampin; and Safety and Tolerability in Patients With Advanced Nonhematologic Malignancies or Lymphoma
Trial information was received from ClinicalTrials.gov and was last updated in November 2016.
Information provided to ClinicalTrials.gov by Takeda.