Phase 1 Trial of TOS-358 for PI3Kα-Mutated Tumors Begins Dosing


A trial of TOS-358, a first-in-class covalent PI3Kα inhibitor, for various solid tumors dosed its first patient.

Cancer cells | Image credit: © - Adobe Stock

Image credit: © - Adobe Stock

The first patient in a trial of TOS-358, a first-in-class covalent PI3Kα inhibitor, in patients with various solid tumors with known PI3Kα mutations, began treatment according to a press release from Totus Medicines.1

The multicenter phase 1 TOS-358-001 trial (NCT05683418) evaluating the safety and efficacy of TOS-385 includes 2 parts: a dose escalation portion and a dose expansion portion using the recommended phase 2 dose. Investigators will enroll an estimated 241 patients with PI3Kα-mutated tumors including colorectal cancer, gastric cancer, HER2-negative breast cancer, lung cancer, and endometrial cancer.

PI3Kα, which is mutated in approximately 15% of all cancers, can be targeted with PI3K signaling pathway inhibitors, but current pathway inhibitors lack specificity, leading to toxicity, and cannot achieve continuous greater than 95% inhibition needed for best antitumor efficacy.2 TOS-358 is the first highly specific covalent inhibitor of PI3Kα, which demonstrated durable near 100% inhibition of PI3Kα activity in preclinical studies.

The phase 1 portion of the study uses a 3+3 dose escalation design to determine the minimum effective dose and maximum tolerated dose.1 TOS-358 will be investigated orally as once daily or twice daily doses. The phase 1b portion will enroll patients with PIK3Cα mutations or amplifications in separate cohorts based on tumor type including colorectal, gastric, non–small cell lung, breast, squamous cell carcinoma of the head and neck, urothelial and selected gynecological cancers (ovarian cancer, cervical cancer, or endometrial cancer).

Eligible patients must have a PIK3Cα mutation or amplification and have received no prior treatment with PI3K, AKT or mTOR inhibitors, except for patients with breast cancer. They could not have recent systemic anticancer treatment prior to the start of treatment. Additionally, patients with central nervous system metastases were excluded.

The primary end points are dose-limiting toxicities within the first 21 days of treatment and the incidence and severity of adverse events from the start of treatment until 30 days after patients receive the last dose.

Using cellular analysis based on proprietary molecular tags that track drug binding in individual cells, Totus’s Accel™ Platform led to the rapid drug development of TOS-358. This enabled the company to file an investigational new drug application 18 months after the drug’s discovery.

In preclinical animal model studies, TOS-358 was shown to potently and specifically lead to deep and durable PI3Kα inhibition.2 It did not lead to significant hyperglycemia in mice, rats, and dogs at efficacious dose levels, unlike reversible PI3Kα inhibitors. When compared with previous ATP-competitive and allosteric reversible PI3Kα inhibitors across over 30 different PDX and CDX mutant PI3Kα dependent cancer models, TOS-358 demonstrated superior efficacy.

"TOS-358 represents a promising new approach to the treatment of the root cause of nearly 15% of all cancers, and we are excited to be able to advance it into clinical development at such an accelerated rate," said Neil Dhawan, PhD, chief executive officer and co-founder of Totus Medicine, in a press release.1


1. Totus Medicines announces first patient dosed in phase 1 trial of TOS-358 for the treatment of select solid tumors. News release. Totus Medicines. April 13, 2023. Accessed April 17, 2023.

2. MacDougall JR, Bradley J, Mak R, Dhawan N, Chen W. TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models. Cancer Res. 2023;83(7_suppl):4946. doi:10.1158/1538-7445.AM2023-4946

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