Phase 1 study of ixazomib, an investigational proteasome inhibitor, in advanced non-hematologic malignancies.

Abstract

PURPOSE:

Ixazomib is an investigational proteasome inhibitor with demonstrated antitumor activity in xenograft models of multiple myeloma (MM), lymphoma, and solid tumors. This open-label, phase 1 study investigated intravenous (IV) ixazomib, in adult patients with advanced non-hematologic malignancies.

METHODS:

Patients received IV ixazomib twice-weekly for up to twelve 21-day cycles. The 0.125 mg/m(2) starting dose was doubled (one patient/dose) until 1.0 mg/m(2) based on dose-limiting toxicities (DLTs) in cycle 1. This was followed by 3 + 3 dose-escalation and expansion at the maximum tolerated dose (MTD). Primary objectives included safety and MTD assessment. Secondary objectives included assessment of pharmacokinetics, pharmacodynamics, and disease response.

RESULTS:

Ixazomib was escalated from 0.125 to 2.34 mg/m(2) to determine the MTD (n = 23); patients were then enrolled to MTD expansion (n = 73) and pharmacodynamic (n = 20) cohorts. Five patients experienced DLTs (1.0 and 1.76 mg/m(2): grade 3 pruritic rash; 2.34 mg/m(2): grade 3 and 4 thrombocytopenia, and grade 3 acute renal failure); thus, the MTD was 1.76 mg/m(2). Drug-related grade ≥3 adverse events (AEs) included thrombocytopenia (23 %), skin and subcutaneous (SC) tissue disorders (16 %), and fatigue (9 %). Among 92 evaluable patients, one (head and neck cancer) had a partial response and 30 had stable disease. Ixazomib terminal half-life was 3.8-7.2 days; plasma exposures increased dose-proportionally and drug was distributed to tumors. Inhibition of whole-blood 20S proteasome activity and upregulation of ATF-3 in tumor biopsies demonstrated target engagement.

CONCLUSIONS:

In patients with solid tumors, ixazomib was associated with a manageable safety profile, limited antitumor activity, and evidence of downstream proteasome inhibition effects.

• Authors: David C Smith, Thea Kalebic, Jeffrey R Infante, Lillian L Siu, Daniel Sullivan, Gordana Vlahovic, John S Kauh, Feng Gao, Allison J Berger, Stephen Tirrell, Neeraj Gupta, Alessandra Di Bacco, Deborah Berg, Guohui Liu, Jianchang Lin, Ai-Min Hui, John A Thompson
• Journal: Investigational new drugs (Invest New Drugs) Vol. 33 Issue 3 Pg. 652-63 (Jun 2015) ISSN: 1573-0646 [Electronic] United States
• PMID: 25777468 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Activating Transcription Factor 3
• Boron Compounds
• Proteasome Inhibitors
• ixazomib
• Glycine

Topics

• Activating Transcription Factor 3 (metabolism)
• Adult
• Aged
• Boron Compounds (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Cohort Studies
• Dose-Response Relationship, Drug
• Female
• Glycine (adverse effects, analogs & derivatives, pharmacokinetics, pharmacology, therapeutic use)
• Hematologic Neoplasms (pathology)
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Proteasome Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Treatment Outcome