The PACIFIC trial, an investigator-sponsored, randomized Phase II study, will will be conducted to evaluate OGX-427 (OncoGenex) in men with metastatic castrate-resistant prostate cancer (CRPC) who are experiencing a rising Prostate-Specific Antigen or PSA while receiving abiraterone acetate (Zytiga?;Janssen Biotech, Inc/Johnson & Johnson). The aim of the study is to determine if adding OGX-427 to a treatment with abiraterone acetate can reverse or delay treatment resistance.
OGX-427 is designed to inhibit the production of Heat Shock Protein 27 (Hsp27 also known as heat shock protein beta-1 or HSPB1), a cell-survival protein found at elevated levels in many human cancers including prostate, bladder, breast and non-small cell lung cancer.
Complex system
The main function of Hsp27 is to provide thermotolerance in vivo, cytoprotection, and support of cell survival under stress conditions. Hsp27 acts In vitro as an ATP-independent chaperone by inhibiting protein aggregation and by stabilizing partially denatured proteins, which ensures refolding by the Hsp70-complex. Hsp27 is also involved in the apoptotic signalling pathway. It interacts with the outer mitochondrial membranes and interferes with the activation of 
cytochrome c/Apaf-1/dATP complex and therefore inhibits the activation of procaspase-9. [1] The phosphorylated form of Hsp27 inhibits Daxx apoptotic protein and prevents the association of Daxx with Fas and Ask1.[2]
Overexpression of Hsp27 is thought to be an important factor leading to the development of treatment resistance and is associated with negative clinical outcomes in patients with various tumor types.
Trial
Approximately 80 men who are being treated with abiraterone acetate and have evidence of a rising PSA without evidence symptomatic or radiographic progression, will be randomized to either continue treatment with abiraterone acetate and prednisone alone, or have OGX-427 added to the abiraterone acetate and prednisone treatment.
In this new trial, patients will be stratified based on whether they have received prior chemotherapy and will continue on study until symptomatic, radiographic or other documented disease progression occurs. The primary objective will be to compare the two treatment groups for delaying further disease progression while on Zytiga by assessing the progression-free survival (PFS) rate at 60 days after adding OGX-427. Secondary objectives for this trial include comparing the treatment arms for PSA responses, objective responses, time to progression, circulating tumor cells (CTCs) and other biomarkers.
Adaptive pathways
“The rationale for PACIFIC is based on the idea that resistance to treatment is caused by cancer cells using adaptive pathways to escape and proliferate,” said Scott Cormack, President and CEO of OncoGenex Pharmaceuticals. “OGX-427 and abiraterone acetate are potentially synergistic because they disrupt androgen receptor signaling in different ways. We believe that by adding OGX-427 to abiraterone acetate in patients who are experiencing a rising PSA we may be able to reverse treatment resistance and extend the benefits of abiraterone acetate.”
Other trials
OGX-427 has been evaluated in a phase I trial in patients with bladder, breast, prostate, ovarian, or NSCLC who have failed potentially curative treatments or for which a curative treatment does not exist. Final results of this phase I trial were presented during an oral presentation at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting.
The phase I trial evaluated 36 patients treated with OGX-427 as a single agent and 12 patients with OGX-427 in combination with docetaxel who had failed up to six prior chemotherapy treatments. OGX-427 as a single agent administered weekly was evaluated at doses from 200 mg up to 1000 mg in five cohorts of approximately six patients in each cohort. Two further cohorts tested OGX-427 at the 800 and 1000 mg doses combined with docetaxel. Patients could receive up to ten 21-day cycles.
Mono- and combination therapy
OGX-427 was well tolerated both as a monotherapy and in combination with docetaxel. Most adverse events were mild (grade 1 or 2) and mainly occurred during the three ?loading doses? given over nine days prior to weekly dosing. The majority of adverse events potentially related to OGX-427 consisted of grade 1 or 2 fever, chills, itching, or flushing (associated with the infusion of OGX-427) and fatigue. Despite evaluating OGX-427 at very high doses, a maximum tolerated dose for OGX-427 was not reached in this trial.
One of the notable results in this trial was the decrease at all doses and in all diseases evaluated in the trial for both total circulating tumor cells (CTCs), and CTCs which were positive for Hsp27, Hsp27(+) CTCs. Recent studies have shown that the presence of CTCs in peripheral blood may be of prognostic significance for patients with solid tumors and patients with values of ? 5 CTCs are generally considered to have a more favorable prognosis.
References
[1] Sarto C, Binz PA, Mocarelli P (April 2000). Heat shock proteins in human cancer. Electrophoresis 21 (6): 1218?26. doi:10.1002/(SICI)1522-2683(20000401)21:6<1218::AID-ELPS1218>3.0.CO;2-H.
[2] Charette SJ, Lavoie JN, Lambert H, Landry J (October 2000). .Mol. Cell. Biol. 20 (20): 7602?12. doi:10.1128/MCB.20.20.7602-7612.2000. .
For more information:
Hotte SJ, Yu EY, Hirte HW, Higano CS, Gleave ME, Chi KN. Phase I trial of OGX-427, a 2’methoxyethyl antisense oligonucleotide (ASO), against heat shock protein 27 (Hsp27): Final results. J Clin Oncol28:15s, 2010 (suppl; abstr 3077)
Understanding Circulating Tumor Cells May Help Improve Cancer Diagnosis and Prognosis-Onco’Zine – The International Cancer Network; December 12, 2012
High CTC Levels Predicted Poor Outcome in Metastatic Breast Cancer Independent of Serum Tumor Markers –Onco’Zine – The International Cancer Network; December 10, 2010
Clinical trials
– NCT01454089 – A Phase 2 Study Comparing Chemotherapy in Combination With OGX-427 or Placebo in Patients With Bladder Cancer
– NCT01120470 – OGX-427 in Castration Resistant Prostate Cancer Patients
– NCT00487786 – Safety Study of an Antisense Product in Prostate, Ovarian, NSCL, Breast or Bladder Cancer
– NCT00959868 – A Study for Treatment of Superficial Bladder Cancer Using OGX-427
– NCT01681433 – OGX-427 in Metastatic Castrate-Resistant Prostate Cancer With Prostate-Specific Antigen Progression While Receiving Abiraterone
Photo credit: OncoGenex Pharmaceuticals Inc.
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