Abstract 4502 is a preclinical study combining custirsen (OGX-011) in a prostate cancer model.
Abstract 4592 presents interim safety data for a phase 2 trial (run by partner $LLY) of an ISIS antisense drug against survivin in combination with docetaxel for castrate resistant prostate cancer. Two interim safety and futility analyses were conducted and were acceptable, and the study continued to enroll a total of 150 pts. PFS endpoint data will be available in 2011.
Abstract 4573 is a preclinical study combining custirsen (OGX-011) and HSP90 inhibitors in prostate cancer models.
Abstract TPS180 describes the ongoing phase 3 SYNERGY trial for custersin (OGX-011) in prostate cancer. No data presented, but it does say that enrollment (800 pts) is expected to be complete within 2 years, ie by September 2012 (OGXI management has not provided any guidance on how long the trial would take to enroll)
Saturday June 4th: Oral Presentation 2:15 PM - 2:30 PM Abstract #4502
"An evaluation of clusterin antisense inhibitor OGX-011 in combination with the second-generation antiandrogen MDV3100 in a castrate-resistant prostate cancer model."
Hiroaki Matsumoto, MD
Background: Experimental evidence strongly implicate the AR and intra-tumoral androgen synthesis in promoting tumor cell survival and development of castrate resistant prostate cancer (CRPC). The new second generation AR antagonist, MDV3100, has shown activity in preclinical and clinical studies. Our previous studies link androgen ablation therapy with clusterin upregulation and castrate resistance, and we developed the antisense inhibitor, OGX-011, that synergistically enhances both castration and chemotherapies in prostate cancer (CaP) models. In this study, we tested whether OGX-011 sensitized MDV3100 and delayed progression in castrate-resistant LNCaP model.
Methods: Effects of single vs combination MDV3100 and OGX-011 regimens on AR-positive LNCaP cell growth rates, protein, and gene expression were analyzed using crystal violet assay, flow cytometry, western blotting and RT-PCR, respectively. AR transcriptional activity was measured by PSA-luciferase reporter assay, while AR degradation was assessed by cycloheximide chase assay. The effects combination treatment on castrate-resistant LNCaP tumor growth was assessed in castrated male athymic mice.
Results: Combination OGX-011 + MDV3100 showed synergistic effect and more potently suppressed LNCaP cell growth rates in a dose and time dependent manner compared to OGX-011 or MDV3100 monotherapy. As negative controls, no synergism was seen in AR negative PC3 cells. PARP cleavage, sub G0/G1 apoptotic fraction and repressed AKT phosphorylation was most enhanced with combined therapy. Interestingly, OGX-011 accelerated AR degradation and repressed AR transcriptional activity in combination with MDV3100. In vivo, combined OGX-011 + MDV3100 significantly delayed castration-resistant LNCaP tumor progression and PSA progression compared to scramble oligonucleotide + MDV3100 (p<0.05 and p<0.05 at 12weeks, respectively).
Conclusions: OGX-011 combined with MDV3100 down-regulated AR levels and activity and suppressed castrate resistant LNCaP cell growth in vitro and in vivo, providing pre-clinical proof-of-principle as a promising approach for AR targeting therapy in CRPC
Sunday June 5th: Poster Presentation. Abstract #4592
"Interim results of a randomized phase II study with window-design to evaluate antitumor activity of the survivin antisense oligonucleotide (ASO) LY2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC)."
Pawel J. Wiechno, MD, PhD
Background: Survivin is a member of the inhibitor of apoptosis proteins (IAP). Its expression in prostate cancer is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination.
Methods: 150 patients were randomized to standard docetaxel/prednisone every 21 days (Arm A) or LY2181308 as a 3-hour IV loading dose on three consecutive days followed by weekly 3-hr IV maintenance doses (Arm B). The experimental arm also included a window of monotherapy of LY2181308 equivalent to a 21-day cycle of docetaxel prior to starting combined treatment. There were two planned interim analyses, after 20 and 60 patients respectively, to assess safety and futility. The primary endpoint is progression-free-survival (PFS).
Results: The addition of LY2181308 to standard first-line treatment in CRPC showed no significant increase in toxicity compared to docetaxel treatment alone. Neutropenia grade 3/4 was observed in 11/40 (23%) in Arm B versus 2/20 (10%) in Arm A. There was no febrile neutropenia, grade 3/4 anemia or thrombocytopenia in either arm. The only important difference for Arm B was grade 1/2 thrombocytopenia (17/40; 43%) and anemia (13/40; 33%), which was not present in Arm A. Toxicity of LY2181308 in the window period was mild (nonhematologic grade 1/2 toxicities) as previously described. These toxicities were manageable, and did not increase with addition of docetaxel. The PK profile for both docetaxel and LY2181308 was as previously described.
Conclusions: The manageable toxicity profile of the combination of LY2181308 and docetaxel justified continuation of the phase II study. Enrollment of 150 patients has been completed and PFS data are expected in 2011.
Sunday June 5th: Poster Presentation. Abstract #4573
"CLU inhibition using OGX-011 as an adjuvant therapeutic strategy for HSP90 inhibition in prostate cancer."
Francois Lamoureux, PhD
Background: Prostate cancer (PCa) responds initially to anti-androgen therapies, however, progression to castration resistant disease (CRPC) frequently occurs. Several small molecule inhibitors of HSP90 show promise in CRPC and other cancers. However, most HSP90 inhibitors (17-AAG or PF-04928473 and its prodrug PF-04929113) trigger the elevation of HSPs (HSP90, 70, 27 and clusterin), which lead to tumor cell survival and treatment resistance. We hypothesized that targeting clusterin (CLU) using siRNA or the antisense drug, OGX-011, may enhance HSP90 inhibitors-induced cell death in PCa.
Methods: Inducible and constitutive CLU and other HSP mRNA and protein levels were measured by real-time RT-PCR and immunoblot assays. The combination of OGX-011 with PF-04928473 or 17-AAG was evaluated in vitro on LNCaP and PC3 cells growth and apoptosis. The HSP90 inhibitor PF-04929113 was evaluated in combination with OGX-011 in vivo in athymic mice bearing castration resistant LNCaP xenografts, while the combination of OGX-011 with 17-AAG was evaluated in PC3 xenografts.
Results: In prostate tumor cell lines, PF-04928473 and 17-AAG induced expression of HSPs in a dose and time dependent manner, and especially CLU at RNA and protein level, by increasing HSF-1 nuclear translocation and transcription activity. In vitro, OGX-011 synergistically enhanced the activity of HSP90 inhibitors on cell growth and apoptosis with increased sub-G1 fraction and PARP cleavage. These biologic events were accompanied by decreased expression of HSPs, Akt, AR and PSA, and HSF-1 transcriptional activity. In vivo, OGX-011, administered 3 times a week (IP, 15mg/kg), potentiated the effect of orally administered HSP90 inhibitors (PF-04929113: 25mg/kg; 17-AAG: 50mg/kg), significantly inhibiting tumor growth by 80% and prolonging survival in PC3 and castrate resistant LNCaP xenograft model compared to the HSP90 inhibitors alone.
Conclusions: These results indicate that HSP90 inhibitor-mediated induction of CLU expression can be attenuated by OGX-011, with synergistic effects on delaying progression of CRPC. This work was supported by the Canadian Institutes of Health Research fellowship.
Monday June 6, 8:00 AM to 12:00 PM Abstract No: TPS180
SYNERGY: A randomized phase III study comparing first-line docetaxel/prednisone to docetaxel/prednisone plus custirsen in metastatic castrate-resistant prostate cancer (mCRPC).
Author(s): K. N. Chi, J. S. De Bono, C. S. Higano; British Columbia Cancer Agency, Vancouver, BC, Canada; The Institute for Cancer Research and Royal Marsden Hospital, Sutton, United Kingdom; Fred Hutchinson Cancer Research Center, Seattle, W
Background: Custirsen (OGX-011) is a second generation antisense oligonucleotide (ASO) with a prolonged tissue half-life, greater potency and less toxicity than first-generation ASOs (CCR, 2008; 14(3): 833-839). Custirsen inhibits the expression of clusterin, a stress-induced, cytoprotective chaperone protein that is up-regulated in various cancers. In prostate cancer, clusterin expression is increased after androgen ablation or chemotherapy and contributes to treatment resistance. In vitro and in vivo studies show that the targeted knockdown of clusterin by custirsen results in increased sensitivity to cancer therapies (CCR, 2010; 16(4):1088-93). In a phase I neoadjuvant study, custirsen concentrations achieved in prostate tissue at the 640 mg dose level resulted in >94% decreases in clusterin expression and increased apoptosis (JNCI, 2005; 97(17): 1287-1296). Phase II studies have been completed in mCRPC, breast and lung cancer. In one phase II study, 82 patients with mCRPC randomized to receive docetaxel/prednisone (DOC/P) alone or DOC/P plus custirsen (640 mg IV weekly), median overall survival (OS) was 16.9 and 23.8 months in the two groups respectively, at a median follow-up of 35 months (JCO, 2010, 28:4247-4254). The phase III study, SYNERGY, will confirm whether adding custirsen to standard 1st line DOC/P treatment slows tumor progression and enhances survival beyond DOC/P alone.
Methods: SYNERGY is a randomized, open-label, multi-center, international trial that is planned to enroll 800 patients with mCRPC. Chemotherapy-naïve patients will receive either DOC/P q 21d or DOC/P plus custirsen (640 mg IV weekly) until disease progression or unacceptable toxicity. The primary outcome measure is OS. Additional analyses include progression-free survival at Day 140 and Day 225, safety of custirsen combined with DOC/P, PSA measurements, and the association of efficacy measures with reduction of serum clusterin levels. All randomized patients will be included in the primary and secondary analyses (intent-to-treat analysis). The study was initiated in Sept, 2010 with an expected full accrual within 2 years. NCT01188187.