dm+d

Unassigned

New Medicines

DCVax-LNewly diagnosed glioblastoma multiforme - following standard of care

Information

DCVax-L
New molecular entity
Northwest Biotherapeutics
Northwest Biotherapeutics

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Phase III Clinical Trials
Yes
Aug 22Northwest Bio announce that the MHRA has approved their Paediatric Investigation Plan (PIP), a pre-requisite for applying for approval of DCVax®-L for use in adults [33].
Feb 22Northwest Biotherapeutics announce commencement of production of its first dendritic cell cancer vaccine for a compassionate use patient at its recently licensed production facility in Sawston, UK. The Company anticipates that Phase 1A of the Sawston facility will have the capacity to produce cancer vaccines for 450-500 patients per year. [31]
Oct 21Company announces they have been issued a HTA licence in the UK and the MHRA inspection has been conducted at Sawston. It awaits an official MHRA inspection report to know if any responsive actions may be required, and anticipates that this process will be completed before year-end [30].
May 21Northwest Biotherapeutics submits an application to the MHRA requesting certification of the Sawston facility to produce GMP clinical grade medical products. The company is hopeful that an initial licence will be issued and production of GMP DCVax-L products in the Sawston facility may begin by around the end of Q3 2021 [28].
Jun 20NW BIO is also developing new and expanded facilities for manufacturing in Sawston for the UK and the European market [27].
Apr 19Northwest Bio are in the process of finalising agreements with Advent BioServices for manufacturing of DCVax products in the UK, with the intention to manufacture DCVax products for the whole European region. Northwest Bio has yet to apply for fast track status in the US [25].
Apr 16Northwest Bio plans to apply for fast track status in the US [19].
Apr 16In their 2015 annual report, Northwest Bio highlight that it will be necessary to greatly scale up the volume of manufacturing if DCvax-L is approved, far above the level needed for the trials. To their knowledge, no such products have successfully completed the necessary scale-up for commercialisation without material difficulties. For example, Dendreon Corporation encountered substantial difficulties trying to scale up the manufacturing of its Provenge® product for commercialization [18].
Apr 16Northwest Bio has entered into an agreement with King’s College London to manufacture DCVax for their clinical trial and compassionate use cases. Cognate BioServices will manage and supervise the processing [18].
Apr 16PIII study is still ongoing but no new patients are being recruited. Northwest Bio states that it is having ongoing dialog with regulators, and is providing further information [18].
Aug 15Northwest Bio suspend screening of new patient candidates for a PIII trial of DCVax-L for newly diagnosed glioblastoma multiforme (GBM) while it submits certain information from the trial for regulatory review [18].
Sep 14The PIM designation covers treatment of malignant gliomas, including the most severe form Glioblastoma multiforme, as well as newly diagnosed and recurrent cases [15].
Sep 14UK MHRA awards DCVax-L the first ever ´Promising Innovative Medicine´ (PIM) designation, marking the first step in the Early Access to Medicines Scheme (EAMS), the UK’s new fast-track access programme [15].
Apr 13Northwest Biotherapeutics announce that the PIII trials for Glioblastoma multiforme have been "adopted" as a national priority trial in the UK, under the "adoption" program managed by the National Institute for Health Research (NIHR) [12].
Jan 11Northwest Biotherapeutics will be able to petition the FDA for accelerated approval if the PII glioblastoma multiforme trial generates results consistent to those obtained from previous trials [8].
Dec 07An MAA was filed with Swissmedic in Switzerland. The company believes it has fulfilled its commitments & as of Jun 10, review of the MAA was ongoing. No development reported elsewhere in Europe [8].
Jul 07Company plans to file for approval in both the US and EU in early 2009, based upon the results of a pivotal PII trial of 141 US pts, planned to conclude in Dec 08 (1).
Jul 07DCVax-Brain authorised for use in selected Swiss cancer clinics for glioblastoma by the Swiss Institute of Public Health (1).
Jul 07DCVax-Brain granted orphan drug status in EU (1).

Category

Autologous somatic cell therapy, produced using patient tumour cells (TCs), and precursor dendritic cells (DCs) collected from their blood by leukapheresis. DCs are exposed ex vivo to TCs, learn to recognise them, and then are re-infused regularly.
In England and Wales, about 1,860 gliomas are diagnosed each year (2), of which 740 to 840 are GBM (grade 4 glioma) (3). Median survival is 11 mths (4).
Newly diagnosed glioblastoma multiforme - following standard of care
Intradermal

Further information

Yes

Trial or other data

May 22Results of the double blind, randomized, placebo controlled PIII trial released (n=331). The original primary endpoint, when the trial was designed in 2007, was progression-free survival (PFS); while the trial was underway, pseudo-progression (PsPD) became recognized as major issue -- difficulty distinguishing real vs. PsPD. So, the statistical analysis plan focused on overall survival (OS), and specified OS as the primary endpoint before unblinding. OS endpoints could not be within-study comparisons of DCVax-L patients vs. placebo patients, because placebo patients received DCVax-L following crossover. So, the OS endpoints compared DCVax-L patients with external controls (taken from 5 newly diagnosed GBM trials & 10 recurrent GBM trials). The primary endpoint, in newly diagnosed patients, was met with median OS 19.3 months from randomisation (22.4 months from surgery) vs. 16.5 months from randomisation in controls. mMGMT OS was 30.2 months from randomisation (33 months from surgery) vs. 21.3 months from randomisation in controls. Survival tail showed 13% OS with DCVax-L vs 5.7% with controls at 5 years. In recurrent GBM, OS was 13.2 months vs. 7.8 months from recurrence in controls. Survival tail showed 20.7% vs. 9.6% at 24 months after recurrence, and 11.1% vs. 5.1% at 30 months after recurrence [32].
Oct 20NW BIO announces that the database for the PIII trial of DCVax®-L for gliobastoma has been locked, allowing independent statisticians to have access to the unblinded raw data. The statisticians will proceed as quickly as possible with analyses of the raw data and prepare summaries of the trial results for review by the Company, the Principal Investigator, the Steering Committee of the Trial, the Scientific Advisory Board, and a panel of independent brain cancer experts, who will analyse the data with the statisticians in preparation for public announcement and scientific publication [26].
Nov 18Updated blinded interim data from a PIII trial (NCT00045968 ) of 100 patients showed the median overall survival from surgery of 40.4 months (95% Cl: 35.5-46.5) in 2017 and 58.4 months (95% Cl: 45.9-94.5) in 2018. In ITT population of 331 patients, a median survival of 23.1 months from surgery was reported for both 2018 and 2017 data. Updated 2018 data showed that the survival rate at first, second and third year were 89.3%, 46.4% and 28.2%, respectively. In 131 patients with methylated MGMT gene status, median survival was 35.1 months from surgery and 19.8 months for patients with unmethylated MGMT gene status. The survival rate at first, second and third year were 94.6%, 66.6% and 49.1% in patients with methylated MGMT gene status. In patients with unmethylated MGMT gene status, the survival rate was 56.4%, 32.6% and 14.3% for the first, second and third year, respectively. The corresponding standard-of-care (SOC) median survival value was 15-17 months. In 131 patients with methylated MGMT gene status, median survival was 34.7 months from surgery, while standard of care value showed a median survival of 21.7 months. In 162 patients with methylated MGMT gene status, median survival was 19.8 months from surgery, while standard of care value showed a median survival of 12.7 months. Overall, a particularly extended median survival of 40.5 months post-surgery was displayed by the top 100 patients (30%) of the total 331 patients. This extended survival was not fully explained by known prognostic factors including age younger than 50 years, methylated MGMT gene status and complete resection (surgical removal) of the tumour. Only 8% of these 100 patients had a favourable status on all three of the prognostic factors. At the time of analysis, out of 223 patients who crossed 30 months following surgery, 67 (30%) lived 30 months and displayed Kaplan-Meier (KM)-derived median survival estimate of 46.5 months. Also out of 182 patients who crossed 36 months following surgery, 44 (24.2%) lived 36 months and displayed KM-derived median survival estimate of 88.2 months [24].
May 18Preliminary data from NCT00045968 suggests it is feasible and safe, and may extend survival [23].
Dec 17Company completed a $US12 million financing to fund operations and to expand support the ongoing PIII trial in newly diagnosed Glioblastoma multiforme [22].
Feb 17FDA lifts the partial clinical hold on PIII trial. With Northwest Bio having decided to close enrollment 17 subjects short of its target, the lifting of the partial clinical hold will not trigger renewed recruitment in the trial. But the FDA action clears a regulatory concern for Northwest Bio. The study has passed its threshold of 248 disease-progression events—the primary endpoint—and is nearing the 233 patient deaths that need to occur before it starts analyzing the overall survival secondary endpoint. Northwest Bio thinks it will take several months for the trial to reach the overall survival threshold, and that the routine checks and cleaning that are performed before the database is closed will be a multi-month process. As such, it is unclear when Northwest Bio will present data from the trial [21].
Dec 16Northwest Biotherapeutics announces that 331 of the planned 348 patients have been enrolled in the PIII trial, and that data “events” have been accumulating towards the endpoints of the trial. The company had estimated that the numbers of “events” to reach the main endpoints of the trial may be reached in Nov 16. Since the summer of 2015, the trial has been subject to a partial clinical hold, only on recruitment. As a result of the partial hold, the trial has not enrolled the last 17 of the total 348 patients. To date, the regulators have not agreed to remove the partial hold, but have allowed all of the patients in the trial to continue being treated in accordance with the protocol. The company is pursuing ongoing dialog with regulators. The company is no longer seeking to enrol the last 17 of the 348 patients and instead focus on accumulation of “events” necessary for the trial endpoints. When sufficient events have accumulated, the process of moving toward data lock and analysis of the data will begin [20].
Apr 16Northwest Bio does not know what will happen with the partial hold of its PIII trial, whether it will be released from the screening hold and complete planned enrollment. There is also some possibility that changes requested by the FDA and/or other regulators could complicate the application process for product approval [18].
Mar 16PIII trial is on partial clinical hold for screening of new patients for further enrolment; however, over 300 of the planned 348 patients had been enrolled in the trial as of December 31, 2015, and the patients already in the trial have continued to be treated in accordance with the trial protocol, without interruption [18].
Jan 16Estimated completion date for the PIII NCT00045968 study is Sep 16 [17].
Mar 15Encouraging survival data on 51 GMB cancer patients treated with DCVax®-L. The data showed substantially longer than expected survival in patients with apparent early progression (recurrence) of their cancer, including those with such aggressive cancer that the tumor was already re-growing by the end of 6 weeks of daily radiotherapy and chemotherapy after surgical removal of the original tumor. Median OS of the 51 Information Arm patients as a whole was 18.3 months; about 30% lived beyond 2 years, and most of these patients (12 of the 15) remain alive. These 51 GBM patients were treated in an Information Arm outside the Company´s PIII l trial asthey were not eligible for the trial, due to evidence of early tumor re-growth following 6 weeks of daily radiotherapy and chemotherapy which are standard of care. [16]
Jun 14PIII NCT00045968 study is currently recruiting pts. Collection of primary outcome data should be completed in Sep 14 [14].
Mar 14The Data Safety Monitoring Board (DSMB) has made an unblinded review of the safety data for the ongoing international PIII GBM Trial, and has recommended that the trial continue as planned. [13]
Mar 13Northwest Biotherapeutics anticipates completing enrollment of its PIII trial by Q1 or early Q2 of next year, and expects to reach its first interim analysis for efficacy by approximately Q3 of this year [11].
Aug 12Northwest Biotherapeutics has received approval from the MHRA for the Company´s PIII trial of DCVax-L to proceed in the UK. The trial is already underway at 40+ sites in the US. The trial has been approved by the UK National Research Ethics Committee. The study (NCT00045968) is enrolling 300 patients with newly diagnosed GBM for whom surgery is indicated. Patients must enter screening at a participating site prior to surgical resection of the tumour. They will receive the standard of care, including radiation and temozolomide therapy and two out of three will additionally receive DCVax-L, with the remaining one third receiving a placebo. Patients randomized to the placebo arm will have the option to receive DCVax-L in a crossover arm on documented disease progression. The primary endpoint is progression free survival. Overall survival is a secondary endpoint. Historically patients with newly diagnosed GBM show a median time to progression of about 8-9 months with median survival of 15-16 months. Immunization starts following primary therapy and will be given at weeks 0, 2 and 4 and at months 2, 4, 8 and 12, 18, 24 and 30.
The study started in Dec 2006 and primary outcome data are expected by Jun 13 [9,10].
Jan 11Company announced that it is resuming enrollment into its ongoing 240-patient, double blind, randomized, placebo controlled PII trial for Glioblastoma multiforme. 33 patients had already been enrolled and continue to be treated with the vaccine. The trials stalled due to financial pressures [7].
Aug 10Further long-term follow-up data from PI and I/II trials reported. The data to July 1, 2010, show that no patients died during the 9-month period since the last update (Sep 09). Median survival is 3 years with 33% of patients reaching 4-year survival, and 27% reaching or exceeding 6-year survival (up from 22% who had reached or exceeded 6-year survival as of the last update). The longest surviving patient has now exceeded 10 years[6].
Oct 09The company has announced further long-term follow-up data, for the period from January through September 2009, from its prior PI and PI/II trials. During the update period, only 1 of the 20 patients died, and that patient had survived for 80.5 months. The median survival time in the DCVax-Brain trials is 36.4 months vs 14.6 months in historical controls. 22% of the patients treated with DCVax-Brain have survived for 5-years; with standard care, <5% of patients are alive at 5 years [5].
Jul 09It is intended that DCVax-Brain is used as an adjuvant to primary surgery, carmustine or temozolamide (3).
Jul 09The 10-day manufacturing process produces several yrs of personalized vaccine for the pt. DCVax-Brain is administered as an intradermal injection in the arm or thigh (1).
Feb 09Long-term data from PI/II trials showed that none of the 20 pts with GBM treated with standard of care plus DCVax-Brain died. To date, 68% of pts have lived >2 yrs, 63% have lived >2.5 yrs, 53% have lived >3 yrs, 35% have lived >4 yrs and 25% have lived >5 yrs. In contrast, pts who received full standard of care (surgery, radiation & chemotherapy) without DCVax-Brain have a median survival of 14.6 mths, and <5% are typically alive at 5 yrs. Two of the 20 pts who received the vaccine experienced progression (recurrence) of their brain cancer. Results showed that 95% of DCVax-Brain treated pts have lived longer than the median survival of 14.6 mths with existing standard of care treatment. Likewise, 95% of DCVax-Brain treated pts have been free of disease progression (recurrence) for longer than the median progression free survival of 6.9 mths with existing standard of care treatment (1).

Evidence based evaluations