Abstract
The novel drug SM-88 seems to be a promising therapy for previously treated patients with advanced pancreatic ductal adenocarcinoma. In a phase II trial, the modified dysfunctional tyrosine derivative was well tolerated and elicited responses or led to stable disease in 44% of patients.
The novel drug SM-88 (Tyme) holds promise for previously treated patients with advanced pancreatic ductal adenocarcinoma (PDAC), according to data presented in July at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer 2019 in Barcelona, Spain. In a phase II trial, the drug was well tolerated, and 44% of patients experienced partial responses or stable disease.
Cancer cells readily take up SM-88 (racemetyrosine), a modified dysfunctional tyrosine derivative, as if it were a functional amino acid. Researchers hypothesize that SM-88 then disrupts protein synthesis, leading to oxidative stress and apoptosis. SM-88 is administered with the oxidative stress catalyst methoxsalen, the P450 3A4 inducer phenytoin, and the mTOR inhibitor sirolimus (Rapamune; Pfizer) to amplify its effects.
In previous trials, SM-88 had shown activity in 15 solid and hematologic cancers, including PDAC, prompting researchers to launch the phase II TYME-88-Panc trial.
At the Congress, researchers reported that 38 evaluable patients with metastatic pancreatic cancer—over 80% of whom had received at least two prior lines of therapy—had a median overall survival (OS) of 6.4 months; 11 of 25 patients with imaging results had partial responses or stable disease, with most experiencing at least stable disease for 7 months or longer. Patients had a median reduction in circulating tumor cells (CTC) of 63%, and 10 of 24 evaluable patients who had at least an 80% reduction in CTCs trended toward longer OS. In general, the drug was well tolerated, with two patients experiencing treatment-related adverse events classified as grade 3 or 4.
“The bottom line is we demonstrated an increase in survival on two fronts: overall survival greater than what others have reported,” which is typically 2 to 4 months, and improved survival in patients with a greater reduction of CTCs, says Giuseppe Del Priore, MD, MPH, Tyme's chief medical officer. Tyme will now advance SM-88 to a phase III trial.
Noelle LoConte, MD, of the University of Wisconsin–Madison, who is not involved in the trial, is intrigued by the results, particularly the durable responses. “For me it passes the sniff test of, ‘Would I put my patients on this study? Yes, I would,’ and, ‘Do I think it's worth investing in a phase III? Yes, I do.’” However, she isn’t convinced that CTCs are a meaningful clinical biomarker of response in pancreatic cancer given the disease's aggressive nature.
Michael Hollingsworth, PhD, of the University of Nebraska Medical Center in Omaha, who is also not connected to the trial, thinks that the results are compelling considering that these patients have few, if any, other treatment options. In addition to continuing clinical testing, he would like to see the researchers drill down on the drug's mechanism to gain a clearer understanding of how it works.
“I think there are lots of things that you could imagine this drug was doing, and I think understanding the mechanism of action would give them better insight into how to combine it better with other drugs,” he says.
SM-88 will be the first investigational agent included in the Pancreatic Cancer Action Network Precision Promise trial launching later this year, says Anirban Maitra, MD, of The University of Texas MD Anderson Cancer Center in Houston, who is on the trial's steering committee. The multiarm trial has an adaptive design, meaning that therapies deemed effective will undergo continued study, whereas therapies deemed ineffective will be phased out, with the goal of enabling “more efficient and rapid drug development, and potentially drug approvals, for pancreatic cancer.” –Catherine Caruso
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