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

NCT01454076 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: C16009U1111-1183-0218
• Study Type: interventional
• Target: 112
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (4)

• 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

  Baseline up to end of treatment (approximately 1.9 years)

Study Arms (5)

Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg

EXPERIMENTAL

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; Drug: Ixazomib 4 mg Capsule B; Drug: Ketoconazole

Arm 2: Ixazomib 4 mg Capsule A or B

EXPERIMENTAL

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 A; Drug: Ixazomib 4 mg Capsule B

Arm 3: Ixazomib 4 mg Fasted or Fed

EXPERIMENTAL

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

Arm 4: Ixazomib 4 mg + Rifampin 600 mg

EXPERIMENTAL

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: Rifampin; Drug: Ixazomib 4 mg Capsule B

Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg

EXPERIMENTAL

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; Drug: Ixazomib 4 mg Capsule B; Drug: Clarithromycin

Interventions

Ixazomib 2.5 mg DRUG

Ixazomib 2.5 mg Capsule B (Cycle 1 only)

Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg; Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg

Ixazomib 4 mg Capsule A DRUG

Ixazomib 4 mg Capsule A (Cycle 1 only)

Arm 2: Ixazomib 4 mg Capsule A or B

Ketoconazole DRUG

Ketoconazole 400 mg tablets (Cycle 1 only)

Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg

Rifampin DRUG

Rifampin 600 mg capsule (Cycle 1 only)

Arm 4: Ixazomib 4 mg + Rifampin 600 mg

Clarithromycin DRUG

Clarithromycin 500 mg tablets (Cycle 1 only)

Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg

Ixazomib 4 mg Capsule B DRUG

Ixazomib 4 mg Capsule B (Cycle 2 and beyond )

Arm 1: Ixazomib 2.5 mg + Ketoconazole 400 mg; Arm 5: Ixazomib 2.5 mg + Clarithromycin 500 mg

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 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Millennium Pharmaceuticals, Inc.: lead

Study Sites (1)

Unknown Facility

Dallas, Texas, United States

Location

Related Publications (3)

• 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.

  PMID: 28800141 DERIVED

• 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.

  PMID: 28783865 DERIVED

• 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.

  PMID: 26872892 DERIVED

MeSH Terms

Conditions

Lymphoma

Interventions

ixazomib; Ketoconazole; Rifampin; Clarithromycin

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Medical Director
• Organization: Takeda

trialdisclosures@takeda.com

+1-877-825-3327

Study Officials

• Medical Monitor

  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: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2011
• First Posted: October 18, 2011
• Study Start: November 10, 2011
• Primary Completion: April 1, 2015
• Study Completion: June 16, 2016
• Last Updated: November 1, 2017
• Results First Posted: November 1, 2017

Record last verified: 2017-06

Locations

US (1)