Date: 2016-09-29
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, being held from September 25th through September 28th in New York City.
Company: Northwest Biotherapeutics (USA - MD)
Product: DCVax®-Direct
Action
mechanism: immunotherapy product/cell therapy. DCVax® is comprised of activated, educated dendritic cells, that mobilize or help the entire immune system. Instead of aiming at a single target, DCVax is designed at to target the full set of biomarkers on a patient’s cancer. The DCVax technology is expected to be applicable to most cancers, and is embodied in several distinct product lines. One of the product lines (DCVax®-L) is designed to cover all solid tumor cancers in which the tumors can be surgically removed. Another product line (DCVax®-Direct) is designed for all solid tumor cancers which are considered inoperable and cannot be surgically removed. We believe the broad applicability of DCVax to many cancers provides multiple opportunities for commercialization and partnering. DCVax-Direct is administered by direct injection into a patient’s tumors. It can be injected into any number of tumors, enabling patients with locally advanced disease or with metastases to be treated. DCVax-Direct can also be injected into tumors in virtually any location in the body: not only tissues at or near the surface of the body but also, with ultra-sound guidance, into interior tissues.
Disease: solid tumors
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: The study comprises a Phase I component during which the optimal dose of DCVax-Direct for the treatment of solid tissue tumors will be identified, followed by a Phase II component to determine if the injection of DCVax-Direct into selected solid tissue tumors has the ability to reduce tumor growth. (NCT01882946 )
Latest
news: * On September 29, 2016, Northwest Biotherapeutics announced that Dr. Marnix Bosch, Chief Technical Officer of NW Bio, presented additional information relating to the DCVax®-Direct Phase I Trial in a poster presentation at the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival, being held from September 25th through September 28th in New York City. As explained in Dr. Bosch’s poster presentation, under the Wheler methodology individual life expectancy is determined through measurements of 5 key risk factors: serum albumin, serum LDH, number of metastases, GI tumor, and ECOG (Eastern Cooperative Oncology Group) performance status. The expected survival is 24.0, 15.2, 8.4, 6.2 or 4.1 months for patients with 0, 1, 2, 3 or 4-5 of the above risk factors, respectively. Dr. Bosch’s New York and London presentations applied the Wheler system to determine estimated individual-patient life expectancies, and compare those to the actual clinical results in each patient in the top 30% of patients in the DCVax-Direct Phase I Trial. Dr. Bosch’s poster will be available on the Company’s website starting today. The top 20% of the patients in the DCVax-Direct Phase I Trial have each exceeded 2 years of survival so far, and are still alive. The longest survivor to date has reached nearly 3 years. The top 30% of the patients in the DCVax-Direct Phase I Trial (including pancreatic, melanoma, lung, ovarian, sarcoma and other cancers) have average actual individual survival to date of 26.7 months, compared with average expected individual survival of 12.3 months. The Wheler system for assessing individual patient life expectancies can be found at Wheler, et al.; Survival of 1,181 Patients in a Phase I Clinic: The MD Anderson Clinical Center for Targeted Therapy Experience. Clin. Cancer Res. 2012 May 15; 18(10): 2922–2929. Dr. Bosch’s presentation also included assessments of dendritic cell quality and their relationship with patient outcomes, such as stabilization of disease and overall survival. The encouraging survival results correlate with underlying mechanisms of action and cellular and immune profiles, including phenotype analyses, and relative production of a wide range of cytokines by the dendritic cells. Additional positive observations include T-cell infiltration, and PD-L1 expression, with 64% of the patients evaluable for PD-L1 checkpoint expression (14 of 22) showing either de novo or significantly increased expression of PD-L1 following DCVax-Direct treatment, indicating potential for combination of DCVax-Direct and checkpoint inhibitors. Such information will also be helpful in shaping later stage trials. * On May 2, 2016, Northwest Biotherapeutics announced an operations update in regard to its Phase I and II Trials, Scientific Advisory Board and Nasdaq compliance. The Company has received updated data from the ongoing follow-up of patients in the Phase I portion of the DCVax-Direct trial. To date, 20 of the 40 patients have exceeded 12 months overall survival, 13 of the 40 patients exceed 18 months OS, at least 10 of those 13 patients (with 2 of the 13 currently unknown) are still alive at OS times up to 29 months to date, with the majority having exceeded 20 months. The Company has undertaken extensive analyses of data from the Phase I portion of the Phase I/II trial of DCVax-Direct for all types of inoperable solid tumors. The Phase I portion of the study involved 3 different dose levels, 2 different product formulations, 13 different cancers, several modes of image guidance for treatment administration and multiple measures related to immune system activation. Analyses of this data have found some novel, unexpected and encouraging results that are of significance for further trials. Also, the Company and physician advisors have completed clinical analyses and preparations for injection of multiple tumors in multiple different tissue locations (going well beyond what any other known trial has undertaken), as well as a greater number of treatment cycles, for the upcoming Phase II portion of the trial. In addition, the Company and its manufacturer, Cognate BioServices, Inc. (“Cognate”) have completed a lengthy program of development work to further optimize the DCVax-Direct investigational product. * On June 1, 2015, Northwest Biotherapeutics announced new data on their Phase I trial of DCVax-Direct for direct injection into all types of inoperable solid tumors. The patients enrolled in the trial had late stage cancers, with an average of three inoperable tumors. The patients had failed multiple prior therapies and had a poor prognosis. The trial enrolled 40 patients, and 39 were evaluable. A conservative treatment regimen was used. Although the patients had multiple inoperable tumors, only 1 tumor was injected with DCVax-Direct. The treatments included only 3 injections in the first 2 weeks (Day 0, 7 and 14), and up to 3 additional injections spaced months apart thereafter (Weeks 8, 16 and 32), over a total period of 8 months. Patients typically received their first injection about 1-1/2 months after recruitment. Four patients are still in the process of completing the study visits, and data collection is ongoing on all of the patients. The trial tested three different dose levels of DCVax-Direct, two different methods of activating the dendritic cells that comprise DCVax-Direct, and a dozen different cancers. Findings to date include encouraging survival data and substantial induction of immune checkpoint expression (PD-L1). Findings to date include the following: 27 of 39 patients are still alive at up to 18 months after first injection. Findings to date relating to immunological responses include the following: Induction of PDL-1 immune checkpoint expression was seen in 64% of evaluable patients (14 of 22) following DCVax-Direct treatment. This suggests that the tumors are putting up defenses against the immune responses induced by DCVax-Direct, and marks these patients as potential candidates for treatment with checkpoint inhibitor therapies. Based on the findings from the Phase I trial, the Company plans to enhance its Phase II trials in several ways, including by using only the preferred activation method of the DCVax dendritic cells and injecting multiple inoperable tumors at each treatment visit, not just one. Northwest Biotherapeutics plans to pursue Phase II trials in non-small cell lung cancer and sarcoma, as well as a Phase II trial for multiple diverse types of cancers similar to the Phase I study. The Company also plans to expand the trial sites to include countries beyond the U.S.
Dr. Bosch’s New York presentation, as well as his presentation at a cancer vaccines conference in London last week, included information about estimated life expectancies for individual patients (not for types of cancers or medians of groups of patients) based on a system developed and published by Dr. Jennifer Wheler at MD Anderson Cancer Center. The Wheler system was based upon clinical experience with 1,181 patients with diverse cancers at the MD Anderson Phase I Cancer Clinic (where most of the DCVax-Direct Trial was conducted). Wheler validated and enhanced (with additional risk factors) a system for prediction of individual-patient life expectancies previously developed by the Royal Marsden Hospital in the UK and well established in the field. A fundamental purpose of early stage exploratory trials, such as the DCVax-Direct Phase I trial, is to evaluate both product characteristics and patient characteristics – and especially to identify which patients show the best responses to the experimental product. Such evaluations enable later stage trials to be designed with more precision, to focus on the patients who are the best fit for the experimental product and to potentially best demonstrate the performance of the experimental product. The DCVax-Direct Phase I Trial included more than a dozen different types of cancers, as well as sub-types (e.g., several different types of sarcoma), patients with varying numbers of inoperable and locally advanced or metastatic tumors, and varying numbers and types of prior treatment regimens that had all failed. This diversity enabled demonstration, in a wide range of settings, of the safety and feasibility of DCVax-Direct (including feasibility of the novel intra-tumoral injections) as well as an initial signal or indication of potential results.
Patient survival correlates with the method of dendritic cell activation used. With the preferred method, 18 of 21 patients are still alive.
Treatment effects have been observed in diverse cancers, including lung, breast, colorectal, pancreatic, sarcoma, melanoma, neuro-endocrine and other cancers.
Patient survival correlates with the number of DCVax-Direct injections.
Patient survival also correlates with stabilization of disease at Week 8 (4th injection visit). Among patients treated with the preferred method of dendritic cell activation, 16 of 19 achieved stable disease (i.e., less than 25% increase in tumor size from baseline) at Week 8.
An increase in T-cell infiltration into tumors, by functionally active T-cells, was seen following DCVax-Direct treatment.
Both local effects (in the injected tumor) and systemic effects were observed.
