Date: 2016-11-10
Type of information: discontinuation of development
phase: 3
Announcement: discontinuation of development
Company: OncoGenex Pharmaceuticals (USA - WA)
Product: custirsen (OGX-011)
Action
mechanism: antisense oligonucleotide. Custirsen is an experimental drug that is designed to block the production of the protein clusterin, which may play a fundamental role in cancer cell survival and treatment resistance. Clusterin is upregulated in tumor cells in response to treatment interventions such as chemotherapy, hormone ablation and radiation therapy and has been found to be overexpressed in a number of cancers, including prostate, lung, breast and bladder. Increased clusterin production has been linked to faster rates of cancer progression, treatment resistance and shorter survival duration. By inhibiting clusterin, custirsen is designed to alter tumor dynamics, slowing tumor growth and resistance to partner treatments, so that the benefits of therapy, including survival, may be extended.
Disease: prostate cancer
Therapeutic area: Cancer - Oncology
Country: Belgium, Canada, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Netherlands, Spain, UK, USA
Trial
details: The AFFINITY trial is a phase 3 study designed to confirm that adding custirsen to standard first-line docetaxel/prednisone treatment can slow tumor progression and enhance survival outcomes compared to standard first-line docetaxel/prednisone treatment alone. This will be a randomized, open-label, multicenter, international trial. Treatment will consist of docetaxel/prednisone/custirsen vs. docetaxel/prednisone. A total of at least 1000 patients will be randomized. Patients will be randomly assigned with equal probability to the two arms. (NCT01188187)
Latest
news: * On November 10, 2016, OncoGenex Pharmaceuticals announced its third quarter 2016 financial results. * On August 16, 2016, OncoGenex Pharmaceuticals announcedy results from the final analysis of AFFINITY, the Phase 3 trial of custirsen in men with metastatic castrate-resistant prostate cancer (CRPC) whose disease has progressed after treatment with docetaxel. The trial did not meet the primary endpoint of demonstrating a statistically significant improvement in overall survival for patients treated with custirsen in combination with cabazitaxel/prednisone compared to cabazitaxel/prednisone alone. The adverse events were consistent with those observed in previous trials of custirsen in metastatic CRPC. The final data will be submitted as a late-breaking abstract to the European Society for Medical Oncology (ESMO) Annual Congress 2016. As a result of these data and previous custirsen findings, OncoGenex plans to initiate discussions with the FDA to evaluate options related to an early analysis of the Phase 3 ENSPIRIT trial investigating custirsen in combination with docetaxel as second-line chemotherapy in patients with non-small cell lung cancer (NSCLC). OncoGenex has engaged MTS Health Partners, LP as its advisor to assist with the exploration of strategic alternatives. * On December 1, 2015, following an independent Data Monitoring Committee (DMC) meeting, OncoGenex Pharmaceuticals announced that its Phase 3 AFFINITY trial is continuing based on the pre-planned interim futility analysis of the intent-to-treat (ITT) population. In the final safety review, no new safety issues were identified by the DMC. Both the DMC and OncoGenex remain blinded to all analyses and final results are expected in the second half of 2016, depending on timing of the event-driven final analysis. The final AFFINITY efficacy analysis is designed to show a survival benefit with 85 percent power based on a hypothesized hazard ratio of 0.75. * On October 8, 2015, OncoGenex Pharmaceuticals announced that the European Medicines Agency (EMA) has completed its review of the proposed amendment to the company's Phase 3 AFFINITY protocol and statistical analysis plan. The amendment, which was agreed to by the FDA earlier this year, includes the addition of a co-primary endpoint designed to prospectively evaluate the survival benefit of custirsen in men who are at increased risk for poor outcomes when treated with cabazitaxel for metastatic castrate-resistant prostate cancer (mCRPC). The EMA supported plans for prospectively defining a poor prognostic subpopulation in the Phase 3 AFFINITY trial and suggested additional supportive analyses to show benefit for the poor prognostic subpopulation beyond the broader AFFINITY trial population. Following support from the FDA and EMA, the company is proceeding with its planned protocol amendment globally. * On May 30, 2015, OncoGenex Pharmaceuticals announced that results from a retrospective analysis of the Phase 3 SYNERGY trial showed a benefit with custirsen therapy in men with metastatic castrate-resistant prostate cancer (CRPC) who had a poor prognosis. The analysis, exploring the effect of clusterin inhibition in men at risk for poor outcomes, showed that over 40 percent of men in the trial had at least two of five common risk factors for poor prognosis. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone. These results were presented at the 51st Annual Meeting of the American Society of Clinical Oncology in Chicago. OncoGenex, in collaboration with study investigators, have defined a simple 5-criteria characterization for poor prognosis in prostate cancer based on the SYNERGY trial, which include: poor performance status, elevated prostate specific antigen (PSA), elevated lactate dehyrdogenase (LDH), decreased hemoglobin, and the presence of liver metastasis. The findings from the SYNERGY study show a preferential effect in patients who are more vulnerable to poor outcomes and may reveal the patient population most likely to benefit from clusterin inhibition in other studies. The Company will be meeting with the FDA in June to discuss a proposed amendment to the Phase 3 AFFINITY trial protocol and statistical analysis plan that would include a co-primary endpoint evaulating survival in men who are at increased risk for poor outcomes. In the AFFINITY trial, custirsen is being evaluated with second-line chemotherapy in men with metastatic CRPC. Results from this trial are expected later this year or in early 2016. A more simplified prognostic index score showed that over 40% of men in the trial had at least two of five common risk factors for poor prognosis. In these men, the analysis also showed a 27% lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone. The adverse events (AEs) observed in the SYNERGY trial were similar to custirsen's known AE profile. The most common serious AEs observed in 2 percent of patients treated with custirsen, beyond those observed in the control arm, included febrile neutropenia, pneumonia and fever. The most common grade 3 or higher adverse events in 3 percent of patients, whether classified as good or poor prognosis patients, were neutropenia, anemia, fatigue and febrile neutropenia. * On January 16, 2015, OncoGenex Pharmaceuticals announced that the AFFINITY trial is continuing as planned based upon completion of the interim futility analysis and the recommendation of the Independent Data Monitoring Committee (IDMC). The Phase 3 AFFINITY trial is designed to evaluate a survival benefit for custirsen in combination with second-line cabazitaxel chemotherapy in 635 men with metastatic castrate-resistant prostate cancer (CRPC). AFFINITY is being conducted at 95 global clinical trial sites and final survival results are expected to be announced in late 2015 or early 2016. OncoGenex recently announced that it has executed an initial agreement with Teva Pharmaceuticals Industries to regain rights to custirsen, which is being evaluated in Phase 3 clinical development as a treatment for prostate and lung cancers.
The company also announced it has discontinued the development of its custirsen program after the AFFINITY and ENSPIRIT Phase 3 clinical trials failed to meet their primary endpoints.
Separately, an analysis of a prospectively defined subpopulation of men in the AFFINITY trial who had multiple poor prognostic risk factors revealed that the combination of custirsen and cabazitaxel did not meet the rigorous criteria required to demonstrate an improvement in overall survival (hypothesized hazard ratio ?0.69, one-sided p value ?0.015). This subpopulation was identified and evaluated based on a retrospective analysis of a previous Phase 3 trial of men with similar clinical features who experienced a reduced risk of death when custirsen was added to chemotherapy. In addition, OncoGenex pursued the evaluation of this subpopulation, independent of the ITT, in order to obtain an expedited approval for these patients with more aggressive disease.
As part of the Phase 3 development program for custirsen, OncoGenex continues with its ENSPIRIT clinical trial in patients with non-small cell lung cancer (NSCLC). The trial is evaluating the ability of custirsen, in combination with docetaxel treatment as second-line chemotherapy, to extend survival in patients with NSCLC. Based on current enrollment projections, ENSPIRIT results could be available in the second half of 2016.
OncoGenex, in collaboration with study investigators, has defined a simple five-criteria characterization for poor prognostic patients with prostate cancer to be treated with custirsen based on the Phase 3 SYNERGY trial, which includes: 1) poor performance status, 2) elevated prostate specific antigen (PSA), 3) elevated lactate dehyrdogenase (LDH), 4) decreased hemoglobin and 5) the presence of liver metastasis. AFFINITY patients with poor prognosis will be identified as having two or more of these five well-recognized high-risk criteria. The proposed change for AFFINITY is also consistent with custirsen's mechanism of action, as custirsen was designed to address treatment resistance which may be more prevalent in this subpopulation.
In the revised statistical analysis plan for the AFFINITY trial, the hypothesized hazard ratio (HR) for the poor prognosis subpopulation is specified to be 0.69 with the critical HR ? 0.778. The hypothesized HR for intent-to-treat patients (ITT population) remains unchanged as 0.75 with the critical HR ? 0.820.
Timing for the final analysis of the poor prognosis subpopulation is projected to occur by the end of 2015, while the final analysis of the ITT population is projected to occur in the second half of 2016. An interim analysis of the ITT population will coincide with the final analysis of the poor prognosis subpopulation. This interim analysis will have both futility and early efficacy criteria defined for the ITT population. If the final analysis of the poor prognostic subpopulation shows a survival benefit for custirsen, OncoGenex may initiate a regulatory submission.
A retrospective analysis of data from the Phase 3 SYNERGY trial presented earlier this year showed a benefit with custirsen therapy when added to first-line docetaxel chemotherapy in men with mCRPC who had a poor prognosis. The analysis showed that over 40 percent of men in the SYNERGY trial had at least two of the five common risk factors for poor prognosis as stated above. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone.
In addition, exploratory SYNERGY data analyses recently presented at the 2015 European Cancer Congress (ECC 2015) demonstrated that custirsen treatment significantly lowered serum clusterin (sCLU) levels from baseline in men with mCRPC. In addition, these data showed that sCLU reductions after custirsen treatment resulted in higher two-year survival rates in patients who were at increased risk for poor outcomes. Of those patients with lower sCLU levels, the data also showed a correlation to an overall survival benefit for custirsen-treated patients who were at increased risk for poor outcomes.
* On June 10, 2015, OncoGenex Pharmaceuticals announced that the FD has agreed to the Company's proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan. The amendment includes the addition of a co-primary endpoint designed to prospectively evaluate the survival benefit of custirsen in men who are at increased risk for poor outcomes when treated with cabazitaxel for metastatic castrate-resistant prostate cancer (CRPC). The FDA is in agreement with plans for prospectively defining a poor prognostic subpopulation in the Phase 3 AFFINITY trial. OncoGenex, in collaboration with study investigators, has defined a simple 5-criteria characterization for poor prognosis in prostate cancer based on the Phase 3 SYNERGY trial, which includes: poor performance status, elevated prostate specific antigen (PSA), elevated lactate dehyrdogenase (LDH), decreased hemoglobin, and the presence of liver metastasis. Patients with poor prognosis will be identified as having 2 or more of these 5 well-recognized high-risk criteria. The proposed change for AFFINITY is also consistent with custirsen's mechanism of action, since custirsen was designed to address treatment resistance which may be more prevalent in this subpopulation.
In the revised statistical analysis plan for the AFFINITY trial, the hypothesized hazard ratio (HR) for the poor prognosis subpopulation is specified to be 0.69 with the critical HR ? 0.778. The hypothesized HR for the intent-to-treat patients (ITT population) remains unchanged as 0.75 with the critical HR ? 0.820.
Timing for the final analysis of the poor prognosis subpopulation is projected to occur by the end of 2015, while the final analysis for the ITT population is projected to occur in the second half of 2016. FDA and OncoGenex have further agreed that an interim analysis will occur for the ITT population when the final analysis for the poor prognosis subpopulation occurs. This interim analysis will have both futility and early efficacy criteria defined for the ITT population. If the earlier final analysis on the poor prognostic subpopulation shows a survival benefit for custirsen, OncoGenex could initiate a regulatory submission. The entire trial could also be stopped early due to efficacy based on the interim assessment for the ITT population by the Independent Data Monitoring Committee (IDMC).
OncoGenex has also initiated a review with the European Medicines Agency (EMA) for the proposed amendment to the Phase 3 AFFINITY protocol and statistical analysis plan, and expects to have this completed in the second half of 2015.
A retrospective analysis of data from the Phase 3 SYNERGY trial recently presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) showed a benefit with custirsen therapy when added to first-line docetaxel chemotherapy in men with metastatic CRPC who had a poor prognosis. The analysis showed that over 40 percent of men in the trial had at least 2 of the 5 common risk factors for poor prognosis as stated above. In these men, the analysis found a 27 percent lower risk of death when custirsen was used in combination with first-line docetaxel compared to docetaxel alone (See below).
AFFINITY is being conducted at 95 global clinical trial sites and earlier this year, the IDMC recommended the trial continue following the completion of an interim futility analysis. The trial is fully accrued, and the protocol amendment does not affect the conduct of the study.
The SYNERGY trial evaluated custirsen plus docetaxel/prednisone compared with docetaxel/prednisone alone in men with metastatic CRPC (n=1,022). Following 509 deaths, median overall survival (OS) was 23.4 months (m) vs. 22.2 m for custirsen and control arms, respectively (hazard ratio [HR] 0.93; P = 0.42). In retrospective analyses, a prognostic scoring system was developed in the control arm using multiple variable modeling and was used to dichotomize patients into good and poor prognosis. The analysis included 984 patients with complete data. Median survival for the poor and good prognosis groups in the control arm was 14.0 m and 30.4 m, respectively (HR = 3.66). The custirsen HR effect differed between poor and good prognosis groups (interaction P = 0.069). The HR estimate for custirsen survival benefit for those in the poor prognosis group was 0.73 (95% CI: 0.59 to 0.90) and 1.02 (95% CI: 0.76 to 1.37) for those in the good prognosis. When analyzed separately (n=492), the median OS in the poor prognostic group was 17.0 m in the custirsen arm vs. 14.0 m in the control arm (HR=0.73, 95%CI: 0.59 to 0.90, P = 0.004).
