Pharmacokinetics Study of Oral IXAZOMIB in Participants With Advanced Nonhematologic Malignancies or Lymphoma

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

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 participants with advanced nonhematologic malignancies or lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Nonhematologic Malignancies
• Intervention / Treatment: Drug: Ixazomib 2.5 mg; Drug: Ixazomib 4 mg Capsule B; Drug: Ketoconazole; Drug: Ixazomib 4 mg Capsule B; Drug: Ixazomib 4 mg Capsule A; Drug: Rifampin; Drug: Clarithromycin

• Study Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female participants 18 years or older.
• Participants 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.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Female participants 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 participants, 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 (that is, less than [< ] Grade 1 toxicity or participant's baseline status) from the reversible effects of prior anticancer therapy.

Exclusion Criteria:

• Peripheral neuropathy greater than (>) Grade 2 on clinical examination.
• Systemic treatment with strong inhibitors of cytochrome P450 (CYP) 1A2, 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.
• Participant has symptomatic brain metastasis. Participants 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 participants 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. Participants 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.
• Participants with gastric achlorhydria (Arm 1 only).
• Participants 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.
• Participants with known hypersensitivity to macrolide antibiotics (example, clarithromycin, erythromycin, azithromycin) or a history of jaundice/liver injury during prior exposure to clarithromycin (Arm 5 only).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg; Ixazomib 2.5 milligram (mg), capsule B, orally, once on Day 1 and 15 along with ketoconazole 400 mg, tablets, orally, once daily from Day 12 to 25 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.	Drug: Ixazomib 2.5 mg; Ixazomib 2.5 mg Capsule B (Cycle 1 only); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 2 and beyond ); Drug: Ketoconazole; Ketoconazole 400 mg tablets (Cycle 1 only); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 1 and beyond)
EXPERIMENTAL: Arm 2: Ixazomib 4 mg Capsule A or B; Ixazomib 4 mg, capsule A, orally, once on Day 1 followed by ixazomib 4 mg, capsule B once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, once on Day 1 followed by ixazomib 4 mg, capsule A once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.	Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 2 and beyond ); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 1 and beyond); Drug: Ixazomib 4 mg Capsule A; Ixazomib 4 mg Capsule A (Cycle 1 only)
EXPERIMENTAL: Arm 3: Ixazomib 4 mg Fasted or Fed; Ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fed state, once on Day 15 of Cycle 1 (28-day treatment cycle) or ixazomib 4 mg, capsule B, orally, under fed state, once on Day 1 followed by ixazomib 4 mg, capsule B, orally, under fasted state, once on Day 15 of Cycle 1 (28-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.	Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 2 and beyond ); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 1 and beyond)
EXPERIMENTAL: Arm 4: Ixazomib 4 mg + Rifampin 600 mg; Ixazomib, 4 mg, capsule B, orally, once on Day 8 along with rifampin 600 mg, capsule, orally, once daily from Day 1 to 14 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.	Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 2 and beyond ); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 1 and beyond); Drug: Rifampin; Rifampin 600 mg capsule (Cycle 1 only)
EXPERIMENTAL: Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg; Ixazomib, 2.5 mg, capsule B, orally, once on Day 6 along with clarithromycin, 500 mg, tablet, orally, twice daily from Day 1 to 16 of Cycle 1 (21-day treatment cycle). After Cycle 1, participants will receive ixazomib 4 mg, capsule B, orally, once daily on Days 1, 8 and 15 of each cycle (28-day treatment cycle) up to a maximum of 12 cycles, until disease progression or unacceptable toxicity.	Drug: Ixazomib 2.5 mg; Ixazomib 2.5 mg Capsule B (Cycle 1 only); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 2 and beyond ); Drug: Ixazomib 4 mg Capsule B; Ixazomib 4 mg Capsule B (Cycle 1 and beyond); Drug: Clarithromycin; Clarithromycin 500 mg tablets (Cycle 1 only)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Cmax: Maximum Observed Plasma Concentration for Ixazomib	Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hours[hrs])post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib	Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib	Arm 1:Days 1, 15 and Arm 5:Day 6 pre-dose and at multiple time points(up to 264 hrs)post-dose;Arm 2, 3:Days 1,15 pre-dose and at multiple time points(up to 216 hrs)post-dose;Arm 4:Day 8 pre-dose and at multiple time points(up to 168 hrs)post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)		Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45)
Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities		Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45
Number of Participants With Clinically Significant Vital Sign Abnormalities		Cycle 1 Day 1 up to 30 days after last dose of study drug (Arm 1 and 5: Cycle 19 Day 45; Arm 2: Cycle 7 Day 45; Arm 3: Cycle 22 Day 45; Arm 4: Cycle 25 Day 45
Percentage of Participants With Best Overall Response	Best overall response for a participant is best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1: Complete response (CR) was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (<) 10 millimeter [mm]). No new lesions. Partial response (PR) was defined as greater than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. Stable disease (SD) was defined as not qualifying for CR, PR, Progressive Disease (PD). An increase of >=20% from the nadir (or baseline, if it represents the point at which the sum of target disease was lowest) represents PD.	Baseline up to end of treatment (approximately 1.9 years)

Collaborators and Investigators

• Sponsor: Millennium Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Gupta N, Hanley MJ, Venkatakrishnan K, Bessudo A, Rasco DW, Sharma S, O'Neil BH, Wang B, Liu G, Ke A, Patel C, Rowland Yeo K, Xia C, Zhang X, Esseltine DL, Nemunaitis J. Effects of Strong CYP3A Inhibition and Induction on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor: Results of Drug-Drug Interaction Studies in Patients With Advanced Solid Tumors or Lymphoma and a Physiologically Based Pharmacokinetic Analysis. J Clin Pharmacol. 2018 Feb;58(2):180-192. doi: 10.1002/jcph.988. Epub 2017 Aug 11.
• Hanley MJ, Gupta N, Venkatakrishnan K, Bessudo A, Sharma S, O'Neil BH, Wang B, van de Velde H, Nemunaitis J. A Phase 1 Study to Assess the Relative Bioavailability of Two Capsule Formulations of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma. J Clin Pharmacol. 2018 Jan;58(1):114-121. doi: 10.1002/jcph.987. Epub 2017 Aug 7.
• Gupta N, Hanley MJ, Venkatakrishnan K, Wang B, Sharma S, Bessudo A, Hui AM, Nemunaitis J. The Effect of a High-Fat Meal on the Pharmacokinetics of Ixazomib, an Oral Proteasome Inhibitor, in Patients With Advanced Solid Tumors or Lymphoma. J Clin Pharmacol. 2016 Oct;56(10):1288-95. doi: 10.1002/jcph.719. Epub 2016 Mar 17.

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 10, 2011
• Primary Completion (ACTUAL): April 1, 2015
• Study Completion (ACTUAL): June 16, 2016

Study Registration Dates

• First Submitted: October 13, 2011
• First Submitted That Met QC Criteria: October 17, 2011
• First Posted (ESTIMATE): October 18, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 1, 2017
• Last Update Submitted That Met QC Criteria: June 16, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Cmax: maximum plasma concentration; AUC0-tlast: area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms; Lymphoma; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Anti-Bacterial Agents; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Leprostatic Agents; Protein Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inducers; Antifungal Agents; Steroid Synthesis Inhibitors; Cytochrome P-450 CYP3A Inducers; Antitubercular Agents; 14-alpha Demethylase Inhibitors; Antibiotics, Antitubercular; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C8 Inducers; Cytochrome P-450 CYP2C19 Inducers; Cytochrome P-450 CYP2C9 Inducers; Glycine Agents; Ixazomib; Ketoconazole; Rifampin; Clarithromycin; Glycine
• Other Study ID Numbers: C16009; U1111-1183-0218 (REGISTRY: WHO)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No