Phase I trial of OGX-427, a 2'methoxyethyl antisense oligonucleotide (ASO), against heat shock protein 27 (Hsp27): Final results.

Abstract

3077 Background: Hsp27 is a chaperone protein that affects multiple pathways implicated in cancer progression and treatment resistance. OGX-427 is a 2nd generation ASO that inhibits Hsp27 expression resulting in cell growth inhibition, apoptosis, and enhanced chemotherapy efficacy. The purpose of this study was to determine the safety profile and Phase 2 dose of OGX-427 alone and in combination with docetaxel (D). Methods: Eligible patients (pts) had metastatic castrate resistant prostate cancer (CRPC), breast, non-small cell lung (NSCLC), or ovarian cancer. OGX-427 was administered IV weekly on a 21-day schedule after 3 loading doses. OGX-427 was escalated over 5 planned dose levels (DL) (200-1,000 mg) and OGX-427+D (75mg/m2) over 2 DL (800 and 1,000 mg) with 6 pts/DL. Results: 36 pts were treated with OGX-427 and 12 with OGX-427+D. Median age was 62 (33-86) yrs ; 27 pts had CRPC, 11 breast, 5 ovary and 5 NSCLC ; median prior chemotherapy regimens was 3 (0-6). 1 pt had dose-limiting toxicity with a grade 3 cerebral bleed into a metastasis. Of 556 infusions, 1 dose needed modification for toxicity. Infusion reactions (rigors, pruritus, flushing, back pain, dyspnea) were seen at DL ≥600 mg (interruption 14 pts, discontinuation 5 pts). PTT transiently increased to ≥ twice pretherapy levels at Cmax in 71% pts at DL≥ 800mg. The most common serious adverse events were dyspnea (5) and hydronephrosis/high creatinine (2). In pts with measurable disease, 4/30 given OGX-427 had a confirmed minor response or stable disease (SD) as best response and, of 7 pts with CRPC given OGX-427+D, 2 had a partial response and 1 SD for 7 months. PSA declines of ≥30% were seen in 3/16 (OGX-427) and 5/9 (OGX-427+D) evaluable pts. Of 41 pts with total or Hsp27+ circulating tumor cell (CTC) counts >5 at baseline, 10/32 (OGX-427) and 5/9 (OGX-427+D) pts decreased to ≤5. Conclusions: OGX-427 at the maximum doses tested of 1,000 mg was well tolerated and combination with D was feasible. Toxicity consisted mainly of infusion reactions and transient PTT changes. Changes in tumor markers, measurable disease, and CTC suggested single-agent activity. Further study of OGX-427 alone and in combination with D is planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncogenex Technologies Oncogenex Technologies Oncogenex Technologies