Long term follow-up of patients with recurrent ovarian cancer after Ad p53 gene replacement with SCH 58500

Abstract

Objective: We have previously reported the safety, efficient gene transfer, and favorable CA125 responses of individuals with recurrent ovarian cancer treated by p53 gene replacement with the adenoviral vector SCH 58500. The purpose of the present investigation was to evaluate the long -term follow -up of these heavily pretreated patients subsequent to SCH 58500 dosing. Methods: Patients ( n = 36 ) were treated with either single -dose SCH 58500 in the phase I study or with multiple doses ( MD ) of SCH 58500 over multiple cycles in combination of platinum -based chemotherapy in the phase I / II portion of the study. Five patients were initially treated in the single -dose group and re -enrolled in the MD group. The MD group was evaluated both without the reenrolled patients as MD1 ( n = 19 ), and as MD2 ( n = 24 ), which included them. Patients who were only treated on the single -dose arm were designated as SD ( n = 12 ). Most patients received additional chemotherapy at the discretion of their physicians on completion of the trial. The current analysis is a retrospective sequential cohort survival analysis. Results: The first patient was treated in March 1997 and the last patient completed SCH 58500 in September 1998. There was no difference in age at diagnosis, Karnofsky performance status, interval between diagnosis to SCH 58500, prior cycles or regimen of chemotherapy, platinum -free interval, percent platinum refractory patients, pretreatment CA125, or largest tumor volume between groups. Both MD groups had a slightly longer chemotherapy -free interval before SCH 58500 than the SD group. Median survival of individuals who received MD SCH 58500 with chemotherapy was 12 -13.0 months, compared to only 5 months for those treated with SD SCH 58500. There are 10 long -term survivors more than 20 months after MD treatment for recurrent disease compared to only 2 long -term survivors after SD SCH 58500. Conclusion: The 12 -to 13.0 -month median survival in a heavily pretreated population with recurrent ovarian cancer compares favorably to the 16 -month median survival for individuals treated with paclitaxel at the time of initial recurrence of this disease and is more than double the 5 -month survival seen with palliative radiotherapy or paclitaxel failure. These data suggest that further study of SCH58500 is clearly indicated.

CAR is a cell–cell adhesion protein in human cancer cells and is expressionally modulated by dexamethasone, TNFα, and TGFβ

“…7 Currently ongoing clinical trials with recombinant adenoviruses reveal that besides varying gene transfer efficiencies, one of the main problems in situ are severe immunological side reactions. 8,9 The synthetic glucocorticoid dexamethasone is an anti-inflammatory drug and is frequently applied in supportive cancer care including clinical trials with recombinant adenoviruses. One of its anti-inflammatory mechanisms is brought about by inhibition of NF-kB activity via glucocorticoid receptor activation.…”

Assessment of p53 gene transfer and biological activities in a clinical study of adenovirus-p53 gene therapy for recurrent ovarian cancer

“…6,7 These studies established the safety and feasibility of regional injections of rAd-p53 SCH 58500 for cancer. Evidence of p53 gene transfer was also shown for most of the human subjects who received high doses of rAdp53 SCH 58500.…”

“…In fact, favorable clinical responses have been reported in several clinical studies where administration of a rAd vector expressing p53 wt gene over multiple cycles was employed to achieve a greater degree of gene transfer. [6][7][8] Animal studies have shown that high titers of antiadenovirus antibodies detected in animals previously treated with recombinant adenoviruses caused transduction efficiency to be diminished or completely abrogated during subsequent dosing. 14,15 It has therefore been the subject of debate as to whether multiple dosing strategies for recombinant adenoviruses are likely to be effective in increasing or maintaining levels of transgene expression in humans.…”

“…6,7 In this subcohort of individuals with recurrent ovarian cancer, we focused on the levels of p53 transgene expression and the assessment of p53 transcriptional activity during multiple cycle administration of rAd-p53 SCH 58500.…”

“…6,7 The primary objective of these studies was to evaluate safety. We were limited in our ability to obtain biological samples, which require invasive procedures, for a more detailed evaluation.…”