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Phase 1 Trial of Bi-shRNA STMN1 BIV in Refractory Cancer

Minal Barve1, Zhaohui Wang2, Padmasini Kumar3

  • 1Mary Crowley Cancer Research Centers, Dallas, Texas, USA; Texas Oncology, P.A., Dallas, Texas, USA.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|January 27, 2015
PubMed

Insights

Bifunctional shRNA STMN1 bilamellar invaginated vesicles (BIV) demonstrated safety and confirmed mechanism of action in patients with advanced cancers. This novel therapy showed antitumor activity with no severe toxic effects observed.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Therapy

Background:

  • Stathmin1 (STMN1) is a microtubule modulator overexpressed in various cancers, linked to poor patient survival.
  • Previous studies confirmed the in vivo safety and antitumor activity of bifunctional (bi) shRNA STMN1 bilamellar invaginated vesicle (BIV) delivery.

Purpose of the Study:

  • To evaluate the safety, tolerability, and mechanism of action of intratumoral bi-shRNA STMN1 BIV in patients with advanced, refractory cancers.

Main Methods:

  • A dose-escalation Phase I clinical trial was conducted using a modified Fibonacci schema.
  • Patients received single intratumoral injections of bi-shRNA STMN1 BIV at escalating doses (0.7, 1.4, 7.0 mg DNA).
  • Tumor biopsies and serum samples were analyzed using next-generation sequencing (NGS), RT-qPCR, and 5' RLM RACE to confirm target engagement and pharmacokinetics.

Main Results:

  • Twelve patients were enrolled across three dose cohorts; no drug-related adverse events of Grade 3 or higher were observed.
  • Circulating plasmid levels peaked within 30 seconds and were <10% by 24 hours post-injection.
  • The predicted mRNA cleavage product was detected in 7/7 patients by NGS and 1/1 patient by RLM RACE, confirming the bi-shRNA BIV mechanism of action.

Conclusions:

  • Bi-shRNA STMN1 BIV is well-tolerated in patients with advanced cancers.
  • The detection of the target cleavage product validates the drug's mechanism of action.
  • This study supports further investigation of bi-shRNA STMN1 BIV as a potential cancer therapeutic.

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