CVac

Treatment method

CVac is an ex vivo dendritic cell priming technology involving MFP, or mannan fusion protein, where a fusion protein of MUC1 and Glutathione S-transferase is coupled to oxidized polymannose. The dendritic cells are the orchestrators of the immune system. ‘Priming’ dendritic cells involves exposing those cells to disease antigens in order to get the immune system to properly recognise the antigen and mount an appropriate response. With CVac this takes place outside the body of the patient (ex vivo), with dendritic cells obtained by leukapheresis. The antigen in this case is MUC1, known to be overexpressed on a variety of cancer cells and in CVac MUC1 is conjugated to the carbohydrate mannan to facilitate uptake by the dendritic cells. CVAc can be administered subcutaneously, whereas Provenge is intravenous.

Early development in Melbourne

CVac originated in the mid-1990s at the Austin Research Institute, a medical research facility then associated with Melbourne's Austin Hospital (and that merged with the Burnet Institute in 2006). The original version of the product was developed in the laboratory of the Austin Professor Ian McKenzie in 1993. CVac therapy was originally intended to be in vivo but the Austin researchers started getting better results in ex vivo therapy.

Development by Prima BioMed

Prima BioMed was formed around 2001 to commercialise a number of Austin Research Institute projects including CVac. The company was taken public in July 2001 on the ASX in a reverse takeover of a defunct mineral explorer called Prima Resources. CVac ultimately ended up as Prima BioMed's core project until Prima's acquisition of the French biotechnology company Immutep SA in 2014.

CAN-001 Phase Ib study, 2001-2003

CVac's original clinical study was a Phase Ib trial in ten patients which started in July 2001. In July 2003 PRR announced that two patients - one with kidney cancer and the other with ovarian cancer - had reached the two year mark without any further progression in their tumours. The results of the trial were published in February 2006 in the journal Clinical Cancer Research

CAN-002 Phase IIa study, 2004-2007

In April 2004 a Phase IIa trial of CVac in 20 ovarian cancer patients obtained ethics approval. Recruitment for the trial, to be undertaken in Melbourne, commenced in around June 2004 and completed in 2006 with favourable data being reported in March 2007. Prima BioMed chose ovarian cancer because it was one of the two cancers that seemed to have the best response in the Phase I trial, and also because ovarian cancer has traditionally been associated with poorer outcomes than other cancers. In this study CVac showed stabilization of disease in four of the 21 patients, based on stabilization or reduction in the tumour marker CA-125. These results were published in the Journal for ImmunoTherapy of Cancer in June 2014.

CAN-003 Phase IIb study, 2010-2015

CVac (a "MUC1 Dendritic Cell Vaccine") was taken into the Phase II 'CAN-003' study in epithelial ovarian cancer in July 2010. This study recruited 63 patients in either their first or second remission after previous therapies. The first seven patients were not randomised, with Prima using those patients to establish batch-to-batch manufacturing comparability for the product. The remaining 56 randomised 1:1 to either CVac or placebo.

In September 2013 Prima reported top-line interim data from this trial which showed no observed difference between treatment and control group in terms of Progression-free survival (PFS). For patients in the trial in their first remission the control (43 patients) median PFS favoured the control group. However, for patients in their second remission the advantage was to CVac, with PFS of 7.69 months versus 5.14 months for controls. This result was not statistically significant (p=0.09) but had a trend towards significance

In May 2014, when Prima reported final PFS data from CAN-003, it was able to show median PFS for CVac patients in second remission of 12.91 months versus 4.94 months for the control group. This result had statistical significance (p=0.04)

In November 2014 Prima reported that the median for Overall Survival (OS) in the second remission patients had not been reached after 36 months, which compared favourably with an estimated OS for standard-of-care patients of 25.5 months. This analysis had a p value of 0.07. Prima reported final Overall Survival numbers for CAN-003 in May 2015. In this analysis the median survival number for CVac patients had still not been reached at 42 months and the p value remained 0.07.

CAN-004 study, 2012-2015

Prima had originally intended that CAN-003 would be a lead-in to a Phase III study that was initially called CANVAS (Cancer Vaccine Study) and then CAN-004.This study was going to recruit 800 patients in remission across 150 centers in 22 countries in Europe, Australasia and the US with a primary endpoint of PFS. The study had started recruiting in February 2012 (ClinicalTrials.gov identifier NCT01521143). In November 2013, having considered the favorable trend data on second remission patients, announced that it was altering the protocol for CAN-004 in order to enrich it for second remission patients. The new protocol switched CAN-004 to a 210-patient Phase II randomised and controlled study for second remission patients, with a primary endpoint of Overall Survival. The amended protocols started gaining approval in January 2014 and patients started enrolling in April 2014. However, in February 2015 Prima announced that it was no longer recruiting into its CVac studies.

CAN-301 study in pancreatic cancer

In December 2014 Prima started recruitment for a new Phase I/II study in pancreatic cancer that would recruit up to 40 patients in a single-arm study as a proof of concept that CVac could work in cancers other than ovarian (ClinicalTrials.gov identifier NCT02310971). The patients would enter the study after resection of their tumor. However this study was canceled in February 2015 along with CAN-004.

Approvals

CVac was approved for use by the Dubai Health City Authority in May 2011.

In November 2013 Prima was able to attract Neopharm, an Israeli pharma company, as the licensing partner for Israel and the Palestinian Territories. This deal will see Neopharm buying the product from Prima and the two companies sharing profits.

Manufacturing

CVac was manufactured in Germany by Fraunhofer IZI (Das Fraunhofer-Institut für Zelltherapie und Immunologie), an institute of the Fraunhofer Society in Leipzig, Saxony The Fraunhofer IZI was authorized to manufacture the treatment in Europe in late 2011 after meeting criteria laid down by the German Arzneimittelgesetz (Drug Law). Prima intended that its product would be manufactured at this one central location, with patient blood being flown to Leipzig and primed dendritic cells being shipped back to the relevant trial site.

Software platform

In late May 2015 Prima BioMed announced a collaboration with Database Integrations Inc (DBI), from Alpharetta, Georgia. DBI designed and built the iCAN software platform that managed electronic records and electronic signatures for CVac. Under the collaboration Prima and DBI will market the platform to other developers of cellular therapy worldwide.