History  - CV247 as developed by Dr John Carter MRCVS MB AcA (Veterinary Surgeon). Its formulation was based on over thirty years experience in treating cancer in Cats and  Dogs, Dr Carter has demonstrated some interesting anecdotal responses. Each animal was treated at his veterinary surgery in Harrow, Middlesex. 

Animals given CV247 were monitored by the named Veterinary Surgeon of the Imperial Cancer Research Fund and the chief Veterinary surgeon of the Ludwig Institute of Cancer research, Andor Sebesteny BVSc Dip BACT MRCVS. In this uncontrolled setting there appeared to be some tumour regression with no reported toxicity. 

Dr Carter approached Professor Beverly at the Middlesex hospital to perform a controlled experiment in 50 mice with implanted tumours. In this controlled experiment, tumour regression was also seen. 

These encouraging anecdotal results prompted Dr Carter to supply the formulation to human patients with terminal malignancy on a compassionate basis. Patients came to him by word of mouth and were seen in his own practice. Again in this prospective but uncontrolled setting there appeared to be some tumour regression or stabilization without any reported toxicity.

IVY medical chemicals, the registered owner of CV247 sponsored clinical trials at Bedford Hospital starting in 2001 and two human trials have been completed so far:-

Trial one  - Does CV247  influence quality of life & malignant progression ?

Introduction: This study evaluated oral CV247 utilising types 1&2 cycloxegenase inhibition properties of salicylic acid and the anti-oxidant properties of copper gluconate, manganese gluconate and ascorbic acid combined with a diet rich in fresh fruit, vegetables, low in saturated fats, salt and artificial colour and preservatives. 

Methods: 37 patients had progressive malignancy at trial entry (>2 consecutive increases in tumour markers >10% or radiological progression), had either extensive pre-treated or had diseases in which the benefits of starting conventional treatment were not certain (14 had prostate cancer, 2 ovary, 12 colorectal, 2 breast, 7 miscellaneous).

Results: CV247 was well tolerated.  A bladder cancer patient with haematuria was withdrawn. 6 patients complained of grade I abdominal discomfort (3 requiring complete reversal with ranitidine), 6 had poor appetite, 4 bad taste, 2 haematuria, 4 lethargy, 2 joint pains, 1 weight loss and 1 dry skin. Serum copper & manganese levels remained normal. The 2 ovarian carcinoma patients (progressing pre-trial on MRI with rapidly rising CA-125), had stable disease for 8 months and 14 months (continuing).  A further 5 ovary cancer patients will be recruited into this study. 52% of 28 heavily pre-treated patients (all tumour types) had stabilisation for 3.5 months.  No further trials are planned in this group. 6 (86%) of the 7 early prostate patients (no metastasis or hormone therapy, pre-trial increasing PSA, 5 post-radiotherapy) had mean stabilisation of 8.3 months (peaked between 2-3 months).  5 patients continue on improved quality of life and symptoms. 

Conclusion: These interesting results justified a randomised double-blind trial comparing CV247 & diet versus salicylates alone, in this group of prostate cancer patients.    

Publications: 

Preliminary phase II results of the salicylate rich formula CV247 in patients with malignant disease.  Robert James Thomas, Sara Godward, Madeleine M. Williams, Wassif F. Wassif. Abstract Book of the 27^th ESMO Congress, Sup5, Pg 30.  

Preliminary phase II results of the salicylate rich formula CV247 in patients with malignant disease. Thomas R, Godward S, Williams M, Wassif W. BOA Annual Scientific Meeting in association with BASO, Cambridge . September 2002.

Trial 2 - A randomised double blind phase II study of CV247 versus sodium Salicylate in patients with early prostate cancer. 

In this group there is significant debate as to the best treatment, and as less than 5% of the patients with indolent tumours will die of their disease, the vast majority are being over treated with therapies which carry significant toxicities, namely radiotherapy, brachytherapy or surgery. For indolent prostate cancer many physicians recommend a watch and wait strategy. This strategy is often interpreted as “no treatment” and is often unacceptable to the patients once they received the very emotive label of cancer. Furthermore, there is also considerable debate and very little confirmed randomised data for the optional management for relapsing patients, post radical treatment. The general consensus from NICE and WACN guidelines is to adopt a watch and wait policy. This trial, therefore, is open to patients in both these categories.

One mechanism of action of CV247 is blocking the over expression of the COX genes which are integrally involved in the fundamentals of cancer progression, namely; reduced apoptosis (immortality), adjacent organ invasion, development of new blood vessel formation (angiogenesis) and spread to other areas of the body (metastases).  Over expression of COX-2 is also associated with other markers of malignancy namely increased activation of tyrosine kinase signalling (e.g. EDF, PDGF SRC & ras). Inhibitors of tyrosine kinase have also been shown to reduce COX-2 expression. Direct inhibition of COX expression is now, understandably, the subject of intensive pre-clinical and clinical research. 

CV247 also has antioxidant properties of Vitamin C and trace mineral essential for the formation of Superoxide Dimutase (SOD).  

Trial Objectives  

1. To investigate the effectiveness and tolerability of CV247 in patients with indolent or relapsing prostate cancer.

2. To compare the effectiveness and tolerability of CV247 with sodium salicylate.

Trial design  - This is a randomised, double blind, phase II study in men with progressive indolent prostate cancer. It is firstly testing the tumour static properties of sodium salicylate and secondly testing whether the addition of the dietary supplements manganese, copper gluconates and ascorbic acid (CV247) improve its effectiveness. As it would be very difficult to control for diet, both groups are given general dietary advice. Although a placebo has been included in prostate cancer trials such as the Stampede study, they are taken in addition to other therapies or in the adjuvant setting.  

All patient were required to have progressive disease measured by their PSA doubling time and can either have had no previous radical therapy or be relapsing post radical therapy. For the former group the definition of PSA progression is based on at least two PSA’s calculating a doubling time of less than 4 years; for patients post radical therapy the ASTRO definition is adopted (two consecutive increases in PSA from three consecutive analysis > 1.5 ug/dl) .

Trial end points  

[1] Unsatisfactory therapeutic response - This trial is unusual because the patient and physician may define a satisfactory response as a reduction in PSA or a prolongation of the doubling time. In this latter scenario, a decision to withdraw is based on the preferences and individual circumstances of each patient and clinician, who are both blind to the treatment arms. For example, one patient may have a high threshold for stopping the trial and starting hormone therapy, so a small prolongation in doubling time is acceptable. Another patient may only be comfortable if his PSA has stabilised or dropped. A Kaplan-Meyer survival curve will be plotted for each group. To calculate PSADT for PSA_a to PSA_b between time (t):  

PSA_a                x      t

                        PSA_b - PSA_a

[2] Prolongation in PSA doubling time (PSADT) - An average PSA doubling time will be calculated at trial entry and after study medication. The baseline PSA is defined as the highest at either day zero or day 28. The change in PSADT, for each group will be statistically compared using paired parametric analysis.

[3] Toxicity and prostate volume - All patients with an abnormal digital rectal examination post radical treatment and all with who have not received radical therapy will have a transrectal ultrasound at trial entry and six monthly. If there is significant prostatic growth (>50%), even if the PSA has stabilised they should be withdrawn from the study. Patients experiencing significant toxicity will be withdrawn. A full list of toxicity will be tabulated and compared for each group.

Current status; Recruiting for this trial finished in Jan 2007. Statistical analysis is underway. No patients are treated with CV247 off trial and no trials are currentlyopen.

Trial contact To find out more about these and other trials contact Madeleine Williams at the Primrose Research Unit, Bedford Hospital. MK42 9DJ.
Email madeline.williams@bedhos.anglox.nhs.uk

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