Medical Summary
This is a randomized, open-label multicenter Phase II trial to compare the efficacy of chemotherapy vs. chemotherapy in combination with the p53 adenoviral vector, SCH 58500. Standard chemotherapy is curative in less than half of the newly diagnosed patients and there is no standard of care for persistent or relapsing disease. Up to 80% of ovarian cancer patients have tumors demonstrating p53 mutations. Pre-clinical studies indicate that reintroduction of wild-type p53 in cells mutant or null for the gene resulted in inhibition of cell proliferation and cell death via apoptosis. SCH 58500 is a novel antineoplastic agent consisting of a recombinant adenoviral vector containing the cloned human wild-type p53 tumor suppressor gene. SCH 58500 is a replication incompetent adenovirus due to deletion of the adenoviral E1 region, with a low likelihood for recombination resulting in viral replication. In patients dosed with SCH 58500 no evidence of infectious or live virus was detected in any of the patient samples tested, providing evidence of low risk to the environment and safety to health care workers with SCH 58500. The Phase I study of SCH 58500 administered intraperitoneally for ovarian cancer patients demonstrated the safety of single and multiple IP instillations alone and in combination with chemotherapy. The biological activity of SCH 58500 was confirmed with p53 transgene expression in post biopsy specimens . The antineoplastic activity of SCH 58500 has been studied both in vitro and in vivo. SCH 58500-mediated suppression of tumor cell growth has been observed with a variety of p53-altered tumor cell lines, including those of colorectal, hepatocellular, non-small cell lung, breast, and ovarian origin. Tumor cell lines which are not p53-altered, as well as non-malignant cells in culture, exhibit little growth suppression from SCH 58500. In vivo studies have similarly shown tumor suppressive effects associated with SCH 58500-mediated gene therapy. In an ovarian tumor xenograft model, all mice treated with SCH 58500 had reduced tumor burden compared to controls. SCH 58500 combined with cisplatin, doxorubicin, 5-FU, methotrexate, etoposide, or taxol inhibited cell proliferation more effectively than chemotherapy alone in ovarian tumor cells. Responses were independent of the type of p53 gene mutation in the cells, and cells expressing mutant p53 protein were indistinguishable from p53 null cells. The anti tumor effects of combination therapy with rAd/p53 and taxol were also evaluated in vivo. In the model of ovarian cancer, a dose of SCH 58500 which had relatively minimal anti-tumor effect by ifself had significantly enhanced efficacy when combined with taxol. There was enhanced efficacy using the three drug combination of rAd/p53, cisplatin, and taxol in the ovarian tumor model. Additionaly, a synergistic anti-proliferative activity was observed in tissue. The rationale for this study is based on the observation that in vivo animal experiments have demonstrated that injection with SCH 58500 to a tumor xenograft from a tumor expressing mutant p53 phenotype will result in tumor shrinkage and disappearance. The ability to safely administer SCH 58500 by the intraperitoneal route of administration in a dose rising study plus chemotherapy in patients with ovarian cancer has been confirmed. Gene transfer and expression has also been confirmd by measuring mRNA in post injection samples of ascites or laparoscopic biopsies. In addition, metastatic ovarian or peritoneal tumors may be confined to the peritoneal cavity with small volume implants studding visceral surfaces, amenable to intraperitoneal therapy. Preclinical data indicate there is at least additive effects when chemotherapy is added to SCH 58500. Therefore, in patients there is the potential for improved outcome when SCH 58500 is combined with chemotherapy. The primary objective of this trial is to determine the progression free survival of SCH 58500 in combination with chemotherapy in cancer patients with persistent ovarian or primary peritoneal cancer following first line chemotherapy. The secondary objectives are to assess the response rate, overall survival, and expand the safety profile in combination with chemotherapy. Persistent Stage III ovarian or primary peritoneal cancer patients who have p53 mutant/null tumors will be randomized to one of 3 chemotherapy regimens versus the same chemotherapy plus SCH 58500.

References:

1. Will, KN, et. al., Human Gene Therapy 1994:5, 1079-1088.
2. Nielsen, LL, et. al., Human Gene Therapy 1998:9, 681-694).
3. Nielsen., LL, et. al., Clin. Cancer Res. 1998:4, 835-846.

Lay Summary
Ovarian cancer cells are amongst those that frequently have an abnormality of a gene called P53. This gene normally functions in cells to control their growth and division. In tumor cells with abnormal P53, the growth is uncontrolled, resulting in the development of tumor masses. This protocol is designed to examine the potential benefit of delivering normal P53 genes in combination with chemotherapy in ovarian cancer that has not responded, or grew back, after initial chemotherapy. The P53 is in a virus, which is very effective at helping it enter cells, and it is injected into the abdomen. This has proven to be safe, in preliminary studies in patients, and in animal models it results in shrinkage of tumors.

To be eligible, patients must be fully ambulatory, have received only one type of prior chemotherapy (however many cycles), and have good kidney and liver function. We will require a summary of prior therapy, and will also examine the pathology from the original Diagnosis.

1. Female patients, age >(or =)18 years old, of any race.
2. Histologically confirmed Stage III epithelial ovarian or primary peritoneal cancer. The following cell types are eligible: serious adenocarcinoma, mucinous adenocarcinoma, clear cell adenocarcinoma, Transitional cell, adenocarcinoma NOS, endometroid adenocarcinoma, mixed epithelial carcinoma.
3. Performance status of >(or=) 80% (Karnofsky score).
4. Persistence disease defined as histologially confirmed persistence disease on second look laparoscope (<(or =)2 cm size) or CT scans with residual disease <(or =)2 cm, following completion of 6 cycles of front line chemotherapys
5. Hematologic, renal and hepatic function defined as:
   Neutrophils>(or=)1.5 x 10⁹/L
   Platelets >(or=)100 x 10⁹/L
   Creatinine <2(or=) mg/dL
   Total bilirubin <2(or=) x upper limit of normal
   SGOT <2(or=) x upper limit of normal
   Alk phos <2 x upper limit of normal
   
6. Evidence of mutant or null p53 gene in primary tumour by DNA sequencing.
7. Serologically positive for anti-adenovirus antibodies at screening.
8. Flat plate x-ray of the abdomen with contrast or CT peritoneogram or technetium scan confirming free flow of peritoneal fluid if randomized to SCD 58500.
9. Must have recovered from the toxic effects of prior chemotherapy.
10. If URI (upper respiratory infection) symptoms presented or if clinical concern, an ELISA assay of urine and stood or rectal swab must be preformed and all results must be negative prior to the administration of SCH 58500.
11. A small pre- or post-operative pleural effusion is allowed, unless known to be cytologically positive (pleurodesis is not required.