Clinical trial NCT00830869: A Phase 1 Study of IXAZOMIB in Adult Patients With Advanced Nonhematologic Malignancies
Official title: An Open-Label, Dose Escalation, Phase 1 Study of IXAZOMIB (MLN9708), a Second-Generation Proteasome Inhibitor, in Adult Patients With Advanced Nonhematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Non-hematologic Malignancies
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2009-01-28
Enrollment: 116
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label, multicenter, phase 1, dose escalation study of IXAZOMIB. The primary purpose of this study is to determine the safety profile, establish the maximum tolerated dose, and inform the phase 2 dose of IXAZOMIB administered intravenously in participants with nonhematologic malignancies.


Eligibility criteria: Inclusion Criteria:

Each participant must meet all of the following inclusion criteria to be enrolled in the study:

1. Male or female participants 18 years or older.
2. Eastern Cooperative Oncology Group performance status 0-2.
3. A diagnosis of a nonhematologic malignancy for which standard treatment is no longer effective. In the expanded cohort, enrollment will be limited to participants with a diagnosis of NSCLC, H\&N cancer (squamous cell cancer), STS, or PC.
4. Suitable venous access for pharmacokinetic (PK) and pharmacodynamic evaluations.
5. Female participants who are post menopausal, surgically sterile, or agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.

   Male participants who agree to practice 2 effective methods of contraception or abstain from heterosexual intercourse.
6. Voluntary written consent must be obtained.
7. Adequate clinical laboratory values during the screening period.
8. In the escalation portion of the study, radiographically or clinically evaluable tumor was required, but measurable disease as defined by response evaluation criteria in solid tumors (RECIST) criteria was not required. In the MTD disease expansion cohorts and the TPEC, clinically measurable disease as defined by RECIST criteria was required for evaluation of NSCLC, H\&N cancer, and STS. Prostate specific antigen (PSA) alone was acceptable for evaluation of PC.
9. For participants in the TPEC, tumor tissue that, in the opinion of the investigator, could have been safely biopsied using a core needle.

Exclusion Criteria:

Participants meeting any of the following exclusion criteria are not to be enrolled in the study:

1. Peripheral neuropathy greater than or equal to (\>=) Grade 2.
2. Female participants who are lactating or have a positive serum pregnancy test during the screening period.
3. Major surgery within 14 days before the first dose of treatment.
4. Infection requiring systemic antibiotic therapy or other serious infection within 14 days before the first dose of study treatment.
5. Life-threatening illness unrelated to cancer.
6. Diarrhea greater than (\>) Grade 1 based on the National Cancer Institute Common Terminology .Criteria for Adverse Events (NCI CTCAE) categorization.
7. Systemic antineoplastic therapy / or radiotherapy within 21 days before the first dose of study treatment.
8. Systemic treatment with prohibited medications.
9. Participant has symptomatic brain metastasis.
10. Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or myocardial infarction within the past 6 months.
11. QTc \>470 milliseconds (msec) on a 12-lead electrocardiogram (ECG) obtained during the screening period.
12. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C positive.
13. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
14. Treatment with any investigational products within 28 days before the first dose of study treatment.
15. For participants in the TPEC and participants in the MTD disease expansion cohorts who gave informed consent to undergo tumor biopsy, ongoing anticoagulant therapy (example, aspirin, clopidogrel \[Plavix ®\], warfarin, or heparin) that cannot be held to permit tumor biopsy .
16. Known allergy to boron or excipients.

Primary outcomes:
measure: Part 1: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: Part 1: Cycle 1 Day 1 up to Cycle 1 Day 21
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Event (SAEs)
timeFrame: Part 1: Cycle 1 Day 1 up to Cycle 10 Day 41; Part 2: Cycle 1 Day 1 up to Cycle 12 Day 41
measure: Number of Participants With Clinically Significant TEAEs Related to Laboratory Abnormalities
timeFrame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: Day 1 up to 30 days after last dose of study drug (Cycle 12 Day 41)
Secondary outcomes:
measure: Part 1: AUC (0-72): Area Under the Plasma Concentration-time Curve From Time 0 to 72 Hours Post-dose for Ixazomib
timeFrame: Part 1: Cycle 1 Days 1 and 11: pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part 1: C0: Initial Plasma Concentration After Bolus Intravenous Administration
timeFrame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
measure: Part 1: Rac: Accumulation Ratio for Ixazomib
timeFrame: Cycle 1 Day 11 pre-dose and at multiple time points (up to 72 hours) post-dose
measure: Part 1: Terminal Phase Elimination Half-life (T1/2) for Ixazomib
timeFrame: Part 1: Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
measure: Part 1: E Max: Maximum Observed Effect for Ixazomib
timeFrame: Part 1: Cycle 1 Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
measure: Part 1: TEmax: Time to Maximum Observed Effect (Emax) for Ixazomib
timeFrame: Part 1: Cycle 1 Days 1 and 11 pre-dose and at multiple time points (up to 72 hours) post-dose; Cycle 1 Day 11 pre-dose and at multiple time points (up to 264 hours) post-dose
measure: Number of Participants With Best Overall Response
timeFrame: Day 18 up to Day 21 of each cycle (Part 1: up to Cycle 10; Part 2: up to Cycle 12)
measure: Part 2: Ixazomib Concentration in Postdose Clinical Tumor Samples in Ixazomib 1.76 mg/m^2-TPEC
timeFrame: Cycle 1 Days 1 and 4: Predose and (from 4-20 hours) post-dose
measure: 20S Proteasome Activity of Ixazomib in the Tumor Tissue
timeFrame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose
measure: Expression of Biomarker (ATF-3) in Tumor Tissue
timeFrame: Cycle 1 Days 1 and 4 pre-dose and at multiple time points (up to 2 hours of tumor biopsy) post-dose
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Seattle
country: United States
facility: University of Washington- Seattle Cancer Care
state: Washington
city: Toronto
country: Canada
facility: Princess Margaret Hospital
state: Ontario
Study officials:
affiliation: Millennium Pharmaceuticals, Inc.
name: Medical Monitor
role: STUDY_DIRECTOR
References: