title: Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer.
abstract: Stathmin1 (STMN1) is a microtubule modulator that is expressed in multiple cancers and correlates with poor survival. We previously demonstrated in vivo safety of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) and that systemic delivery correlated with antitumor activity. Patients with superficial advanced refractory cancer with no other standard options were entered into trial. Study design involved dose escalation (four patients/cohort) using a modified Fibonacci schema starting at 0.7 mg DNA administered via single intratumoral injection. Biopsy at baseline, 24/48 hours and resection 8 days after injection provided tissue for determination of cleavage product using next-generation sequencing (NGS) and reverse transcription quantitative polymerase chain reaction (RT-qPCR), 5' RLM rapid amplification of cDNA ends (RACE) assay. Serum pharmacokinetics of circulating plasmid was done. Twelve patients were entered into three dose levels (0.7, 1.4, 7.0 mg DNA). No ≥ grade 3 toxic effects to drug were observed. Maximum circulating plasmid was detected at 30 seconds with less than 10% detectable in all subjects at 24 hours. No toxic effects were observed. Predicted cleavage product was detected by both NGS (n = 7/7 patients analyzed, cohorts 1, 2) and RLM RACE (n = 1/1 patients analyzed cohort 3). In conclusion, bi-shRNA STMN1 BIV is well tolerated and detection of mRNA target sequence-specific cleavage product confirmed bi-shRNA BIV mechanism of action.
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas, USA; Texas Oncology, P.A., Dallas, Texas, USA.
authors.forename: Minal
authors.initials: M
authors.lastname: Barve
authors.affiliation: Strike Bio, Inc., Dallas, Texas, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Gradalis, Inc., Dallas, Texas, USA.
authors.forename: Padmasini
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Strike Bio, Inc., Dallas, Texas, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Jay
authors.affiliation: Strike Bio, Inc., Dallas, Texas, USA.
authors.forename: Xiuquan
authors.initials: X
authors.lastname: Luo
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bedell
authors.affiliation: Texas Oncology, P.A., Dallas, Texas, USA; Baylor University Medical Center, Dallas, Texas, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Mennel
authors.affiliation: Gradalis, Inc., Dallas, Texas, USA.
authors.forename: Gladice
authors.initials: G
authors.lastname: Wallraven
authors.affiliation: Department of Surgery, David Geffen School of Medicine at University of California, Los Angeles, California, USA.
authors.forename: Francis Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas, USA; Strike Bio, Inc., Dallas, Texas, USA; Gradalis, Inc., Dallas, Texas, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Senzer
authors.affiliation: Mary Crowley Cancer Research Centers, Dallas, Texas, USA; Texas Oncology, P.A., Dallas, Texas, USA; Strike Bio, Inc., Dallas, Texas, USA; Gradalis, Inc., Dallas, Texas, USA; Medical City Dallas Hospital, Dallas, Texas, USA. Electronic address: jnemunaitis@marycrowley.org.
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.affiliation: Strike Bio, Inc., Dallas, Texas, USA.
authors.forename: Donald D
authors.initials: DD
authors.lastname: Rao
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015552:Injections, Intralesional; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D010957:Plasmids / Q000097:blood; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism*; D050777:Stathmin / Q000235:genetics* / Q000493:pharmacokinetics; D018675:Toxicity Tests; D050257:Tubulin Modulators / Q000494:pharmacology*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; C493995:STMN1 protein, human; D050777:Stathmin; D050257:Tubulin Modulators