Clinical Trials

Date: 2016-10-13

Type of information: discontinuation of development

phase: 3

Announcement: discontinuation of development

Company: OncoGenex Pharmaceuticals (USA - WA)

Product: custirsen

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: non-small cell lung cancer (NSCLC)

Therapeutic area: Cancer - Oncology

Country: Australia, Germany, Hungary, Israel, Italy, Korea, Republic of, New Zealand, Poland, Russian Federation, Singapore, Singapore, Spain, Taiwan, Thailand, Ukraine, USA

Trial details:

• The Phase 3 ENSPIRIT trial is an international, randomized, open-label trial designed to evaluate a survival benefit for custirsen in the treatment of advanced or metastatic non-small cell lung cancer in 1,100 patients who have progressed after initial chemotherapy treatment. Patients are randomized to receive custirsen plus docetaxel or docetaxel alone. (NCT01630733)

Latest news:

• • On November 10, 2016, OncoGenex Pharmaceuticals announced its third quarter 2016 financial results. 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.
• • On October 13, 2016, OncoGenex Pharmaceuticals announced results from the final analysis of the Phase 3 ENSPIRIT trial of custirsen in patients whose non-small cell lung cancer (NSCLC) has progressed following initial treatments. 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 docetaxel compared to docetaxel alone. The median overall survival for the custirsen arm was 9.0 months versus 7.9 months for the control arm with a hazard ratio of 0.915 (one-sided p=0.178). Safety results were consistent with those observed in previous trials of custirsen in combination with chemotherapy. Previous custirsen trials have produced negative results. Oncogenex is now waiting for the results of apatorsen Phase 2 Borealis-2 bladder cancer trial  and is continuing to work with MTS Health Partners to explore strategic alternatives.
• • On April 30, 2015, OncoGenex Pharmaceuticals announced it has filed an amendment with the FDA, as well as initiated filing with regulatory agencies in other countries, to amend the statistical design and analysis plan of its pivotal, international Phase 3 ENSPIRIT trial evaluating custirsen in the treatment of non-small cell lung cancer (NSCLC). OncoGenex recently regained the rights to the investigational compound from Teva Pharmaceuticals Ltd. and is currently in the process of assuming sponsorship for all clinical development related to custirsen. The protocol amendment is designed to reduce the number of required patients enrolled in the trial and include an earlier, more rigorous second interim futility analysis. The protocol will now also include additional analyses, specifically an evaluation of overall survival (OS) by patient histology, as well as the effect of custirsen's efficacy among patients with poor prognostic risk factors. These changes do not affect the criteria for enrollment or conduct of the study, which continues to accrue patients. Enrollment is expected to be completed in the second half of 2016.
• Under the revised protocol, the following changes include:
• A reduced sample size: Changes to trial sample size were based on revising the hypothesized hazard ratio to 0.75 instead of 0.80, resulting in a sample size of 700 patients instead of 1,100. This change maintains a power of 90% while assessing for a more clinically meaningful difference.
• Revised timing of second survival futility analysis: The second analysis will now take place when 40% of events occur, instead of the original 50%. As previously reported, OncoGenex expects this to occur in mid-2015. An Independent Data Monitoring Committee recommended the ENSPIRIT trial continue based on the outcome of the first interim futility analysis in August 2014 . Trial results will remain blinded to the Independent Data Monitoring Committee and OncoGenex, as the sponsor, unless futility is observed.
• Additional analyses: An evaluation of OS by patient histology, and the effect of custirsen's efficacy among patients with varying risk factors and disease parameters, will now be conducted.
• • On August 21, 2014, OncoGenex Pharmaceuticals announced that the Phase 3 ENSPIRIT trial, evaluating custirsen in the treatment of non-small cell lung cancer (NSCLC), is continuing as planned per the recommendation of the Independent Data Monitoring Committee (IDMC) based upon completion of the first interim futility analysis. Patient enrollment to ENSPIRIT was initiated by Teva in September 2012. Two interim futility analyses are planned for stopping the trial. The first of these two futility analyses has now been completed which allows for acceleration of further enrollment. A second futility analysis will be conducted later in the trial. The FDA has granted Fast Track designation for the evaluation of custirsen in the ENSPIRIT trial.
• Custirsen is also being evaluated in the ongoing Phase 3 AFFINITY trial with second-line chemotherapy in men with metastatic castrate-resistant prostate cancer. The expected timing of AFFINITY results is based on a pre-specified number of death events, however the Company currently expect final results to be announced in late 2015 or early 2016.

Is general: Yes