Tumor Metabolism-Altering Regimen Achieves Clinical Benefit in Metastatic Pancreatic Cancer

A novel tumor metabolism-altering oral regimen that combines a tyrosine derivative (D,L-alpha-metyrosine) with 3 repurposed agents (sirolimus, phenytoin, and methoxsalen) has demonstrated promising activity in patients with previously treated metastatic pancreatic cancer.

More than two-thirds of patients who were eligible to undergo evaluation in part 1 of the single-arm, 2-part Tyme-88-Panc trial and were treated with the regimen known as SM-88 were still alive at a median follow-up of 4.3 months, said Marcus Smith Noel, MD, Assistant Professor, Hematology/Oncology, Department of Medicine, and Assistant Professor, Cancer Center, James P. Wilmot Cancer Institute, University of Rochester Medical Center, NY, at the 2019 Gastrointestinal Cancers Symposium.

Furthermore, 79% of the 14 patients who received SM-88 as a third-line therapy were still alive after a median follow-up of 4.7 months, which was approximately 2 months longer than the survival duration typically observed in the third-line setting.

SM-88 uses a proprietary dysfunctional tyrosine derivative to interrupt the metabolic processes of cancer cells, breaking down their defenses to make them vulnerable to oxidative stress and death.

“All cancers are able to thrive in an oxidative environment…an environment that is deprived of nutrients and oxygen,” said Dr Noel. “This denatured agent [D,L-alpha-metyrosine] plus the 3 other repurposed drugs are designed to capitalize on that, such that they’re going to ­increase uptake of D,L-alpha-­metyrosine into the cell, and hopefully that will result in cell death.”

The third-line setting in pancreatic cancer “is a population with an unmet need,” Dr Noel noted. “We don’t have FDA-approved agents specifically for the third line, so the thought is if we can use D,L-alpha-­metyrosine, which is well tolerated, there may be an opportunity to benefit patients.”

The Tyme-88-Panc Trial

In part 1 of the trial, 38 patients were randomized to D,L-alpha-metyrosine 230 mg twice daily or 460 mg twice daily. In both arms, patients also received methoxsalen 10 mg/day, phenytoin 50 mg/day, and sirolimus 0.5 mg/day. Outcomes data from 28 patients who were eligible to undergo evaluation were presented at the meeting.

Fifty percent of the patients had received 2 previous lines of therapy, 14.3% had received 3 previous lines, and 21.4% had received ≥4 previous lines, which included ­gemcitabine (89.3%), fluorouracil (85.7%), irin­otecan (67.9%), a platinum-based chemotherapy (71.4%), and immunotherapy (10.7%).

Two-month imaging data were available for 17 patients. Of these patients, 1 had a partial response and 7 had stable disease, for a clinical benefit rate of 47.1%. In second-line trials of metastatic pancreatic cancer, the response rate is typically <10%, and in third-line trials, no responses are typically observed, Dr Noel noted.

Seventy percent of patients had a >30% decline from baseline in circulating tumor cell count that was maintained for at least 1 cycle. The median decrease in circulating tumor cell burden was 73%.

As of January 6, 2019, 67.3% of the 28 patients eligible to undergo evaluation were still alive. Overall survival continues to be assessed.

“We need to treat more patients to see if that signal holds, and if it does, it will definitely be clinically meaningful. The hope is that we will recruit another 60 to 70 patients in part 2 of the study,” Dr Noel explained.

SM-88 was well-tolerated. Safety data from the 38 patients randomized to receive SM-88 show that 32 (84.2%) patients had a treatment-­emergent adverse event, with 16.2% of adverse events considered possibly related to the study regimen. One patient in the D,L-alpha-­metyrosine 460-mg twice-­daily arm had 2 adverse events (ie, rash and arthralgia) that were considered to be dose-­limiting toxicities, but the patient resumed treatment after successful management of the events.

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