A phase 1/2a, dose-escalation, safety, pharmacokinetic, and preliminary efficacy study of intraperitoneal administration of BC-819 (H19-DTA) in subjects with recurrent ovarian/peritoneal cancer.
BACKGROUND
H19 is a paternally imprinted, oncofetal gene expressed in various embryonic tissues and in 85% of the ovarian tumors. H19-DTA (BC-819) is a DNA plasmid that drives the expression of the diphtheria toxin gene under the regulation of the H19 promoter sequence and therefore is a potential treatment for various tumors that overexpress the H19 gene, among them-ovarian cancer.


OBJECTIVE
To assess the safety and efficacy of intra-peritoneal (IP) instillations of H19-DTA (BC-819) plasmid in treating ovarian/peritoneal cancer patients with advanced recurrent disease.


METHODS
A phase 1-2A multi-centric trial included 14 eligible patients who were either platinum-refractory or platinum-resistant with positive H19 expression. Patients were treated IP with escalating weekly doses of BC-819 for a maximum of 6-9 weeks. Dose-limiting toxicities (DLT) were assessed after the first course of treatment for each patient and each subsequent cohort was enrolled once each subject had completed the first course of treatment and its 4-week follow-up period. The occurrence of adverse events (AEs) and response to treatment were assessed after the induction course and then periodically.


RESULTS
During the study, no DLTs were observed. Only 5 grade 1 and 2 AEs, which occurred in 4 patients were considered as possibly related to BC-819. The best tumor response seen was stable disease. Median survivals of 3.2, 5.3 and 6.5 months were observed for the 60, 120 and 240 mg cohorts, respectively.


CONCLUSIONS
BC-819 can be considered safe and well tolerated in intraperitoneal doses up to 240 mg. Hybridization of intraperitoneal chemotherapy with the biological treatment of BC-819 should be further evaluated in phase 2 and 3 studies.
Department of Obstetrics and Gynecology Carmel Medical Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Ofer
O
Lavie
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
David
D
Edelman
Department of Obstetrics and Gynecology, The Edith Wolfson Medical Center-Holon, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Tally
T
Levy
Department of Gynecology and Obstetrics, Meir Hospital Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Ami
A
Fishman
Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Ayala
A
Hubert
Department of Obstetrics and Gynecology Carmel Medical Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Yakir
Y
Segev
BioCancell Therapeutics Ltd, Jerusalem, Israel. Eli.Raveh@mail.huji.ac.il.|The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. Eli.Raveh@mail.huji.ac.il.
Eli
E
Raveh
BioCancell Therapeutics Ltd, Jerusalem, Israel.|The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Michal
M
Gilon
The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Avraham
A
Hochberg
D000328:Adult; D000368:Aged; D004167:Diphtheria Toxin / Q000235:genetics*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000628:therapy*; D010051:Ovarian Neoplasms / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D062085:RNA, Long Noncoding / Q000235:genetics*
D004167:Diphtheria Toxin; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding
BC-819 (H19-DTA); Intraperitoneal; Recurrent ovarian/peritoneal cancer