Abstract 547P
Background
Conventional chemotherapeutics lack specificity for tumor tissue and usually have a low therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor site while minimizing systemic exposure, is based on intratumoral injection of a protodrug-activating biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuated protodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allow release of active Dox specifically at the tumor site. Preclinical data suggest that it may also activate an antitumor immune response.
Methods
SQ3370-001, a first-in-human phase 1 study, is currently open and enrolling patients with relapsed/refractory advanced solid tumors who have an injectable lesion potentially responsive to Dox. Primary objectives: safety, tolerability, and recommended phase 2 dose. Additional objectives: assessment of PK in plasma and tumor biopsies, initial efficacy, and immune response.
Results
To date, seven patients have been enrolled. Treatment has been generally well-tolerated with no dose-limiting toxicity. Plasma PK appears consistent with preclinical data; the plasma concentration of SQP33 protodrug increases while that of active Dox decreases as the residence time of the injected biopolymer lengthens. Plasma exposure to active Dox peaks at days 1-2 post biopolymer injection, followed by a decline on days 3-5. Plasma Dox exposure has not exceeded levels reported with IV Dox, even at an SQP33 dose of 2.7 times the molar equivalent of the IV Dox maximum dose of 75 mg/m2. Preliminary tumor analysis suggests substantial local exposure to Dox continues 2 weeks after the last SQP33 dose, possibly due to sustained local release of Dox.
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 data are consistent, indicating that high tumor levels can be achieved while limiting systemic exposure. Dose escalation continues.
Clinical trial identification
NCT04106492.
Editorial acknowledgement
Legal entity responsible for the study
Shasqi, Inc.
Funding
Shasqi, Inc.
Disclosure
V. Subbiah: Financial Interests, Institutional, Research Grant: Shasqi, Inc. V. Bhadri: Financial Interests, Institutional, Research Grant: Shasqi, Inc. N. Bui: Financial Interests, Institutional, Research Grant: Shasqi, Inc. K. Batty: Financial Interests, Institutional, Research Grant: Shasqi, Inc. M. Strach: Financial Interests, Institutional, Research Grant: Shasqi, Inc.. M. Zakharian: Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc. S. Smith: Financial Interests, Personal, Other, Paid consultant: Shasqi, Inc. N.A. Yee: Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc. S. Srinivasan: Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc. M.W. Saville: Financial Interests, Personal, Officer: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc.; Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc. J.M. Mejía Oneto: Financial Interests, Personal, Member of the Board of Directors: Shasqi, Inc.; Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc.; Financial Interests, Personal, Officer: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc. A. Guminski: Financial Interests, Institutional, Research Grant: Shasqi, Inc.