Methionine starvation can powerfully modulate DNA methylation, cell cycle transition, polyamines and antioxidant synthesis of tumor cells, in contrast to normal ones. L-Methioninase is a pyridoxal phosphate dependent enzyme that catalyzes the γ-elimination reaction of L-methionine to methanethiol, α-ketobutyrate and ammonia. Absolute-dependency on exogenous supply of L-methionine, not homocysteine, for growth and proliferation of tumors is the pivotal biochemical criterion for various human cancers.~SGN1 is a genetically modified strain of Salmonella enterica, serotype typhimurium that expresses L-Methioninase. The attenuated live bacterium has been investigated in China for utility in treating advanced solid tumors. The mechanism of action for SGN1 is based on the fact that most tumors are methionine dependent. SGN1 is designed to be used as a tumor therapeutic bacterium that can preferentially replicate and accumulate in tumors and starve them of essential amino acids by delivering the oncolytic enzyme L-Methioninase.~This study is a multi-center phase I clinical trial with 3 parts:~Part 1 & 2 is an open-label, dose escalation phase. Part 1 is the DLT observation period, and the patients will enter part 2 for extension treatment after completing the 28-day DLT observation period. In part 1& 2 of the study will employ a standard 3 + 3 escalating dose design to explore dose limiting toxicities (DLTs) in sequential cohorts to select the maximum tolerated dose (MTD).~In part 2, the treatment may be terminated if the patients withdraws, has unacceptable toxicity, develops disease progression, experiences an AE that cannot be resolved with/without rescue medication in 2 weeks (14 days), death, or loss to follow-up. In such cases, patients will be discontinued and palliative or rescue therapy will be offered to those that terminate early.~Part 3 is an open-label study designed to adopt the optimal biologic dose in no more than 2 specific tumor subtypes. The tumor types will be selected based on safety and preliminary efficacy evaluated in Part 1&2. A preliminary determination of optimal biologic dose shall be defined as the lowest dose that has the highest efficacy rate (i.e., the dose at the beginning of the plateau of the dose-efficacy curve). The dose expansion study will be 10 patients per specific tumor subtype, who may be treated until the patients withdraws, has unacceptable toxicity,has disease progression, has AE that cannot be resolved with/without rescue medication in 2 weeks (14 days),death,or loss to follow-up. SGN1 will be administrated weekly and Tumor assessments are performed every 6 weeks post first dose.
Objectives:To assess the safety and tolerability followed by a dose expansion study to characterize safety, and preliminary efficacy of SGN1, a genetically modified strain of Salmonella enterica, serotype typhimurium that expresses L-Methioninase,in participants with refractory solid tumors.~Study Rationale:The mechanism of action for SGN1 is based on the fact that most tumors are methionine dependent. SGN1 is designed to be used as a tumor therapeutic bacterium that can preferentially replicate and accumulate in tumors and starve them of essential amino acids by delivering the oncolytic enzyme L-Methioninase.~Patient Population:The treatment populations shall be patients presenting with histologically confirmed advanced and/or metastatic solid tumors that are refractory to standard therapy and for which no other conventional therapy exists.