Clinical trial NCT01454076: Pharmacokinetics Study of Oral IXAZOMIB in Participants With Advanced Nonhematologic Malignancies or Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
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
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2011-10-18
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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).

Primary outcomes:
measure: Cmax: Maximum Observed Plasma Concentration for Ixazomib
timeFrame: 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
measure: AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Ixazomib
timeFrame: 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
measure: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Ixazomib
timeFrame: 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:
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities
timeFrame: 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
measure: Number of Participants With Clinically Significant Vital Sign Abnormalities
timeFrame: 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
measure: Percentage of Participants With Best Overall Response
timeFrame: Baseline up to end of treatment (approximately 1.9 years)
Other outcomes:
Locations:
city: Dallas
country: United States
state: Texas
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.