PMID- 28154921 OWN - NLM STAT- MEDLINE DCOM- 20170928 LR - 20220410 IS - 1432-0711 (Electronic) IS - 0932-0067 (Print) IS - 0932-0067 (Linking) VI - 295 IP - 3 DP - 2017 Mar TI - 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. PG - 751-761 LID - 10.1007/s00404-017-4293-0 [doi] AB - 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. FAU - Lavie, Ofer AU - Lavie O AD - Department of Obstetrics and Gynecology Carmel Medical Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel. FAU - Edelman, David AU - Edelman D AD - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Levy, Tally AU - Levy T AD - Department of Obstetrics and Gynecology, The Edith Wolfson Medical Center-Holon, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. FAU - Fishman, Ami AU - Fishman A AD - Department of Gynecology and Obstetrics, Meir Hospital Kfar-Saba, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. FAU - Hubert, Ayala AU - Hubert A AD - Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. FAU - Segev, Yakir AU - Segev Y AD - Department of Obstetrics and Gynecology Carmel Medical Center, The Rappaport Faculty of Medicine, Technion, Haifa, Israel. FAU - Raveh, Eli AU - Raveh E AD - BioCancell Therapeutics Ltd, Jerusalem, Israel. Eli.Raveh@mail.huji.ac.il. AD - The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. Eli.Raveh@mail.huji.ac.il. FAU - Gilon, Michal AU - Gilon M AD - BioCancell Therapeutics Ltd, Jerusalem, Israel. AD - The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. FAU - Hochberg, Avraham AU - Hochberg A AD - The Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20170203 PL - Germany TA - Arch Gynecol Obstet JT - Archives of gynecology and obstetrics JID - 8710213 RN - 0 (Diphtheria Toxin) RN - 0 (H19 long non-coding RNA) RN - 0 (RNA, Long Noncoding) SB - IM MH - Adult MH - Aged MH - Diphtheria Toxin/*genetics MH - Female MH - *Genetic Therapy/adverse effects MH - Humans MH - Middle Aged MH - Neoplasm Recurrence, Local/*therapy MH - Ovarian Neoplasms/*therapy MH - Peritoneal Neoplasms/*therapy MH - Plasmids/*administration & dosage/adverse effects/pharmacokinetics MH - RNA, Long Noncoding/*genetics PMC - PMC5315703 OTO - NOTNLM OT - BC-819 (H19-DTA) OT - Intraperitoneal OT - Recurrent ovarian/peritoneal cancer COIS- FUNDING: This work was funded by BioCancell Therapeutic. CONFLICT OF INTEREST: The late Professor Abraham Hochberg, in addition to being a principal investigator in the Hebrew University, served as the chief scientist of BioCancell therapeutics. Eli Raveh & Michal Gilon are both employees at BioCancell in addition to holding research positions at The Hebrew University of Jerusalem. All authors declare that none of the interests mentioned above altered their adherence to any of the journal policies. ETHICAL APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. INFORMED CONSENT: Informed consent was obtained from all individual participants included in the study. EDAT- 2017/02/06 06:00 MHDA- 2017/09/29 06:00 PMCR- 2017/02/03 CRDT- 2017/02/04 06:00 PHST- 2016/08/13 00:00 [received] PHST- 2017/01/10 00:00 [accepted] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/09/29 06:00 [medline] PHST- 2017/02/04 06:00 [entrez] PHST- 2017/02/03 00:00 [pmc-release] AID - 10.1007/s00404-017-4293-0 [pii] AID - 4293 [pii] AID - 10.1007/s00404-017-4293-0 [doi] PST - ppublish SO - Arch Gynecol Obstet. 2017 Mar;295(3):751-761. doi: 10.1007/s00404-017-4293-0. Epub 2017 Feb 3.