Reference Detail

Ref Type

Journal Article

PMID

(12082455)

Authors

Buller RE, Runnebaum IB, Karlan BY, Horowitz JA, Shahin M, Buekers T, Petrauskas S, Kreienberg R, Slamon D, Pegram M

Title

A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer gene therapy	9	7	2002 Jul	553-66	Cancer Gene Ther

URL

Abstract Text

To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53.SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5 x 10(10) to 7.5 x 10(12) particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5 x 10(13) particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5 x 10(13) particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3.No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen.CT scans are not a valid measure of response to i.p. SCH 58500 due to extensive adenoviral-induced inflammatory changes. Intraperitoneal SCH 58500 is safe, well tolerated, and combined with platinum-based chemotherapy can be associated with a significant reduction of serum CA125 in heavily pretreated patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
SCH 58500	SCH 58500	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
SCH 58500		SCH-58500\|ACN53	p53 Gene Therapy 4	SCH 58500 is a recombinant adenoviral vector encoding wild-type human TP53 that may introduces TP53 into tumor cells, leading to tumor cell apoptosis (PMID: 12082455).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	ovarian cancer	predicted - sensitive	Ad.p53-DC vaccine	Phase I	Actionable	In Phase I and Phase II clinical trials, various forms of p53 gene therapy (such as adenoviral-p53) have been shown to be generally safe and have demonstrated clinical efficacy in patients with ovarian cancer (PMID: 12082455; PMID: 19621448; PMID: 21927947; PMID: 15297186; PMID: 12082456).	15297186 21927947 19621448 12082455 12082456