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367 Pharmacokinetic and immunologic data from a phase I study of the click chemistry-based therapy SQ3370 in advanced solid tumors and soft-tissue sarcoma provides proof-of-concept for the CAPAC platform
  1. Vivek Bhadri1,
  2. Vivek Subbiah2,
  3. James Strauss3,
  4. Sant Chawla4,
  5. Nam Bui5,
  6. Vineet Kwatra6,
  7. Mia Weiss7,
  8. Kathleen Batty8,
  9. Michael Zakharian9,
  10. Jose Mejia Oneto9,
  11. Sangeetha Srinivasan9,
  12. Nathan Yee9,
  13. Rosalind Wilson9,
  14. M Wayne Saville9 and
  15. Alexander Guminski8
  1. 1Chris O’Brien Lifehouse, Camperdown, Australia
  2. 2MD Anderson Cancer Center, Houston, TX, USA
  3. 3Mary Crowley, Dallas, TX, USA
  4. 4Sarcoma Oncology Santa Monica, Santa Monica, CA, USA
  5. 5Stanford Cancer Institute, Palo Alto, CA, USA
  6. 6Cancer Research South Australia, Adelaide, Australia
  7. 7Washington University, St. Louis, St. Louis, MO, USA
  8. 8Royal North Shore Hospital, St Leonards, Australia
  9. 9Shasqi, Inc., San Francisco, CA, USA


Background Conventional chemotherapeutics lack specificity for tumor tissue and usually have anarrow therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs AgainstCancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allowrelease of active Dox specifically at the tumor site. In animals, SQ3370 allowed for an 8.95-fold increase in dosing with minimal systemic adverse eventsand no cardiotoxicity. SQ3370 treatment of mouse tumor models showed improved overall survival,enhanced T-cell infiltration, and a robust anti-tumor response against both biopolymer-injected andnon-injected lesions,1 suggesting that SQ3370 promotes activation of the native immune systemagainst the tumor.

Methods SQ3370-001 (NCT04106492) is a phase 1 trial open to patients with relapsed/refractory soft-tissue sarcoma or other advanced, potentially anthracycline-responsive solid tumors with an injectablelocal or metastatic lesion and =300 mg/m 2 prior exposure to Dox (or equivalent). Primary objectivesinclude safety, tolerability, and recommended Phase 2 dose. Additional objectives include preliminaryefficacy, plasma and tumor biopsy pharmacokinetics (PK), and immune response by peripheral bloodmass cytometry/tumor IHC.

Results To date, ten patients have been enrolled. SQ3370 treatment has been well-tolerated with nodose-limiting toxicities observed. Plasma PK appeared consistent with preclinical data; rapid conversionof SQP33 protodrug to active Dox occurred but slowed as the residence time of the injected biopolymerlengthened. Systemic exposure to active Dox peaked on days 1–2 post biopolymer injection, followed bya decline on days 3–5. Preliminary tumor analysis shows that substantial local exposure to Dox continues2 weeks after the last SQP33 dose. Immune response analysis of early patient samples suggestsincreased tumor immune cell infiltration that dynamically changes with each cycle of treatment.

Conclusions SQ3370 appears to be well-tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK are consistent; high tumor exposure canbe achieved, so far without the typical clinical adverse events seen with IV Dox and potentiallyimproving the therapeutic index of a frequently-used chemotherapeutic agent.

Trial Registration NCT04106492


  1. Srinivasan S, Yee NA, Wu K, et al. SQ3370 activates cytotoxic drug via click chemistry at tumor andelicits sustained responses in injected and non-injected lesions. Advanced Therapeutics 2021;4(3):2000243.

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