1939P - phase I clinical results of SQ3370, a doxorubicin-based click chemistry therapeutic in advanced solid tumor patients

Background

Shasqi is a clinical stage biotech that uses click chemistry, a Nobel Prize winning technology, to selectively activate cancer treatments at the tumor. The Click Activated Protodrugs Against Cancer (CAPAC®) platform comprises of 1) tumor targeting agents, which carry an activator, and 2) attenuated cancer drugs, which are selectively activated at the tumor by the targeting agent through click chemistry, maximizing therapeutic index and minimizing toxicities. We have demonstrated clinical proof of concept with SQ3370, which uses an intratumorally injected biopolymer (bp) with a doxorubicin (Dox) protodrug injected systemically (NCT04106492).

Methods

Patients (pts) received 10/20 mL bp and protodrug IV QDx5. Key eligibility: locally advanced or metastatic solid tumors, ≤ 300 mg/m² prior Dox exposure and no limit to prior systemic therapies. Objectives: safety, determining recommended phase 2 dose (RP2D), pharmacokinetics (PK), and immune profiling.

Results

38 pts were treated: 30 with 10 mL bp and 8 with 20 mL bp at 9 escalating protodrug dose levels up to 15x of clinical Dox dose/cycle. Most pts had sarcoma (63% at 10 mL; 88% at 20 mL) and metastases (83% at 10 mL; 63% at 20 mL). 93% (10 mL) and 88% (20 mL) pts received prior systemic therapies including prior Dox in 40% (10 mL) and 88% (20 mL) pts. Median age was 62 (26-92; 10 mL) and 58 (23-84; 20 mL). Frequent AEs in bp group: 10 mL - nausea (17; 57%) and fatigue (15; 50%); 20 mL - anemia (4; 50%) and nausea (4; 50%). Best response was SD in 58% (10 mL) and 71% (20 mL). Disease control rate (CR+ PR+ SD ≥ 60 days) was 58% (10 mL) and 71% (20 mL). MTD was not reached in either bp cohort; myelosuppression was not dose-limiting. Based on systemic Dox exposure, 12x was selected as the RP2D. PK and immune profiling support safety findings and will be presented. SQ3370 induced a shift towards a T-cell permissive tumor immune microenvironment.

Conclusions

SQ3370 is the first clinical click chemistry-based cancer therapy. The results show the following: the biopolymer activates protodrug in patients; that the Dox protodrug is not a vesicant; PK data demonstrates activation of protodrug; reaction achieves liberation of Dox; click chemistry favorably alters PK and safety of the payload.

Clinical trial identification

NCT04106492.

Editorial acknowledgement

Legal entity responsible for the study

Shasqi, Inc.

Funding

Shasqi, Inc.

Disclosure

S.P. Chawla: Financial Interests, Personal, Stocks/Shares, Own stocks.: Cellestia pharma; Financial Interests, Personal, Stocks/Shares, Stocks: Adi Biopharma; Financial Interests, Personal, Ownership Interest, Owner and stocks: Counterpoint; Financial Interests, Institutional, Local PI, Clinical research: Amgen; Financial Interests, Institutional, Local PI, Research: Adi bio, NK Gene, BMS, Rain Therapeutic, Shasqui, Monopar, Ayala, Boeinger; Financial Interests, Personal, Local PI, Research: Rain Therapeutic, Molleculin. V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Local PI, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Financial Interests, Institutional, Local PI, Research funding to conduct clinical trial: Shasqi; Other, Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, Other, I receive research funding from NCI: National Cancer Institute, USA. N. Bui: Financial Interests, Personal, Advisory Role: Springworks, Rain Oncology; Financial Interests, Institutional, Principal Investigator: Shasqi. M. Agulnik: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Deciphera, Aadi Bioscience, Blueprint Medicine, Bayer, Genzyme, Daiichi Sankyo. C.W. Ryan: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, GSK, Pfizer; Financial Interests, Institutional, Local PI: Ayala, BMS, Daiichi Sankyo, Deciphera, Exelixis, Genentech, Novartis, Karyopharm, Merck, Nektar, Pfizer, Xynomic, Rain Therapeutics, PTC Therapeutics, NiKang Therapeutics, Shasqi Therapeutics, PF Argentum IP Holdings, LLC. M. Aleckovic, S. Srinivasan: Financial Interests, Personal, Full or part-time Employment: Shasqi, Inc.; Financial Interests, Personal, Stocks/Shares: Shasqi, Inc. M. Zakharian, S. Abella: Financial Interests, Personal, Full or part-time Employment: Shasqi; Financial Interests, Personal, Stocks/Shares: Shasqi. T. Nguyen: Financial Interests, Personal, Full or part-time Employment, Full time employee at Shasqi: Shasqi Inc.; Financial Interests, Personal, Stocks/Shares, Received the granted ISO and NSO stock options.: Shasqi Inc.. J. Mejía Oneto: Financial Interests, Personal, Other, Founder and CEO of Shasqi.: Shasqi; Financial Interests, Personal, Full or part-time Employment, Founder and CEO of Shasqi.: Shasqi, inc; Financial Interests, Personal, Stocks/Shares, Founder and CEO of Shasqi.: Shasqi; Financial Interests, Personal, Stocks/Shares: Arcus Biosciences Inc, Arvinas Inc, BioNTech SE - ADR, Caribou Biosciences Inc, Day One Biopharmaceuticals, Inc., Design Therapeutics Inc, Jazz Pharmaceuticals plc, Xencor Inc; Financial Interests, Personal, Royalties, Founder and CEO of Shasqi.: University of California; Non-Financial Interests, Member of Board of Directors, Founder and CEO of Shasqi.: Shasqi; Non-Financial Interests, Member: ASCO, AACR. A.D. Guminski: Financial Interests, Personal, Advisory Board: Regeneron, MSD, Pfizer, Merck KgA; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Institutional, Other, Supply of drug for an investigator initiated clinical trial: AstraZeneca; Financial Interests, Institutional, Other, Drug and genomic testing support for an investigator initiated clinical trial: Sun Pharma; Non-Financial Interests, Advisory Role: Shasqi. All other authors have declared no conflicts of interest.