Prostate Cancer and Clinical Trial Results

Disease and current treatment

Prostate cancer affects a large number of patients with around 220,000 new diagnoses/year in the USA.  The management of prostate cancer is stratified into different risk groups based on the risk of suffering morbidity or mortality as a result of prostate cancer itself, balanced with the risk of morbidities associated with the various treatments.  Although many patients with prostate cancer die of other causes before death from the cancer, the disease and especially its recurrence have serious and life-threatening consequences. The goal of available prostate cancer therapies is to prolong disease free survival.  The goal of ProstAtak™ is to make the disease free survival period longer than the patients’ overall life expectancy.

Risk categories are based on pre-treatment prostate specific antigen (PSA) levels, tumor pathology grade (Gleason score) and tumor stage (TNM staging system).  According to the American Cancer Society, 86% of newly diagnosed prostate cancers are localized. Treatment options for local disease include radiation therapy (RT) and radical prostatectomy (RP).  Overall use for either modality is about 50% with regional differences depending on treatment center and availability to the population.  Both approaches have a 30-50% rate of disease recurrence.  After recurrence, the patients have a choice of physical castration (orchiectomy) or androgen deprivation therapy (ADT), a form of medical castration, to delay progression and for palliation of symptoms.  However, castrate hormone levels have many side effects that significantly decrease quality of life, so the choices are not easily accepted. Quality of life issues are becoming an even greater issue as men are diagnosed with prostate cancer at younger ages, where the impact of these toxicities is greater.  Advantagene’s ProstAtak™ is designed to delay and decrease the rate of recurrence. 

Several Phase I trials in cancer patients have been run with AdV-tk, the active agent in ProstAtak™ (See Table 2 below). These studies demonstrated anti-tumor activity in recurrent prostate cancer and established the safety and biodistribution of AdV-tk after injection into the prostate and other sites. After obtaining positive results in many preclinical and Phase I AdV-tk monotherapy studies, a Phase II trial combining AdV-tk with radiation (TKR™) to look for efficacy in the target prostate population was undertaken through an Advantagene sponsored IND.

Encouraging Phase I results have also been reported by other investigators in various tumor types, including brain cancer, ovarian cancer, colorectal liver metastases and mesothelioma.  Unprecedentedly, in the mesothelioma study, two of three patients are still alive without progression 5 years after treatment (S Albelda, U. Penn.). A Finish group conducted a small controlled clinical study in malignant gliomas comparing HSV-tk delivered by adenovirus to retroviral vector producing cells (VPC) administration or to an irrelevant marker gene (B-gal) delivered by adenovirus (Sandmair et al, 2000).  They found disease stabilization and a doubling in survival only the AdV-tk group, 15 months compared to 7.8 months in the control groups.  These results not only corroborate the rationale for the failures seen in previous efficacy studies conducted with retroviral vectors but also highlight the great potential for HSV-tk in adenoviral vectors.

Table 2- Summary of first five completed Phase I trials with AdV-tk

 *PSA-DT: PSA doubling time; PSAR: PSA reduction; TR-PSA: Time to return to initial PSA

Hasenburg et al 2001. Gynecol Oncol. 83:549. Herman et al, 1999. Human Gene Therapy 10:1239:1249. Miles et al 2001. Hum Gene Ther 12: 1955. Shalev et al 2000. J Urology 163:1747. Trask et al, 2000. Molecular Therapy 1:195-203.

Phase II Trial

Our Phase II trial was designed for newly diagnosed, non-metastatic prostate cancer patients.   Subjects received two or three cycles of transrectal ultrasound guided intratumoral injections of 5x10¹¹ particles of AdV-tk (formulation for this indication called ProstAtak™) followed by oral administration of valacyclovir for 14 days per cycle.

ProstAtak™ showed biological activity based on biochemical (PSA) and immunological responses.  PSA levels showed an acute (2 week) rise, indicating increased prostate tumor cell death, with a subsequent decrease to low level nadirs.  The percentage of activated T lymphocytes cells in the peripheral blood increased significantly after treatment in this trial, indicating an activation of the immune system.  Most importantly, however, there was a demonstration of clinical efficacy.

Demonstration of Clinical Efficacy.  A principal concern for the development of ProstAtak™ has been the method for timely evaluation of long-term efficacy. Although ultimately devastating, prostate cancer is a disease that often progresses slowly, thus making it difficult to evaluate products that further delay or stop its progression without a very prolonged clinical study.  Advantagene has identified an approach to overcome this obstacle.