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

NCT ID: NCT01454076

Last Updated: 2017-11-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-11-10
• Study Completion Date: 2016-06-16

Brief 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 participants with advanced nonhematologic malignancies or lymphoma.

Conditions

Nonhematologic Malignancies; Lymphoma

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Ixazomib 2.5 mg

Intervention Type: DRUG

Ixazomib 2.5 mg Capsule B (Cycle 1 only)

Ixazomib 4 mg Capsule B

Intervention Type: DRUG

Ixazomib 4 mg Capsule B (Cycle 2 and beyond )

Ketoconazole

Intervention Type: DRUG

Ketoconazole 400 mg tablets (Cycle 1 only)

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.

Group Type: EXPERIMENTAL

Ixazomib 4 mg Capsule A

Intervention Type: DRUG

Ixazomib 4 mg Capsule A (Cycle 1 only)

Ixazomib 4 mg Capsule B

Intervention Type: DRUG

Ixazomib 4 mg Capsule B (Cycle 1 and beyond)

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.

Group Type: EXPERIMENTAL

Ixazomib 4 mg Capsule B

Intervention Type: DRUG

Ixazomib 4 mg Capsule B (Cycle 1 and beyond)

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.

Group Type: EXPERIMENTAL

Rifampin

Intervention Type: DRUG

Rifampin 600 mg capsule (Cycle 1 only)

Ixazomib 4 mg Capsule B

Intervention Type: DRUG

Ixazomib 4 mg Capsule B (Cycle 1 and beyond)

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.

Group Type: EXPERIMENTAL

Ixazomib 2.5 mg

Intervention Type: DRUG

Ixazomib 2.5 mg Capsule B (Cycle 1 only)

Ixazomib 4 mg Capsule B

Intervention Type: DRUG

Ixazomib 4 mg Capsule B (Cycle 2 and beyond )

Clarithromycin

Intervention Type: DRUG

Clarithromycin 500 mg tablets (Cycle 1 only)

Interventions

Ixazomib 2.5 mg

Ixazomib 2.5 mg Capsule B (Cycle 1 only)

Intervention Type: DRUG

Ixazomib 4 mg Capsule A

Ixazomib 4 mg Capsule A (Cycle 1 only)

Intervention Type: DRUG

Ixazomib 4 mg Capsule B

Ixazomib 4 mg Capsule B (Cycle 2 and beyond )

Intervention Type: DRUG

Ketoconazole

Ketoconazole 400 mg tablets (Cycle 1 only)

Intervention Type: DRUG

Rifampin

Rifampin 600 mg capsule (Cycle 1 only)

Intervention Type: DRUG

Clarithromycin

Clarithromycin 500 mg tablets (Cycle 1 only)

Intervention Type: DRUG

Ixazomib 4 mg Capsule B

Ixazomib 4 mg Capsule B (Cycle 1 and beyond)

Intervention Type: DRUG

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Millennium Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Millennium Pharmaceuticals, Inc.

Locations

Dallas, Texas, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 28800141 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28783865 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26872892 (View on PubMed)

Other Identifiers

U1111-1183-0218

Identifier Type: REGISTRY

Identifier Source: secondary_id

C16009

Identifier Type: -

Identifier Source: org_study_id