SM-88, a Novel Tumor Metabolism–Altering Regimen, Shows Promise as Third-Line Therapy for Metastatic Pancreatic Cancer
San Francisco, CA—Increased understanding of tumor genetics and tumor metabolism has led to improved therapies for cancer. The impact of cancer metabolism on tumor pathways is particularly important in pancreatic cancer. A novel tumor metabolism–altering oral drug known as SM-88 combines the investigative tyrosine derivative (D,L-alpha-metyrosine) with 3 repurposed agents—an mTOR inhibitor (sirolimus), a CYP3A4 inducer (phenytoin), and an oxidative stress catalyst (methoxsalen).
In an early phase of a 2-part single-arm clinical trial, SM-88 has demonstrated promising activity in heavily pretreated patients with metastatic pancreatic cancer, according to results presented at the 2019 Gastrointestinal Cancers Symposium.
More than 66% of evaluable patients with metastatic pancreatic cancer who received SM-88 were alive at a median of 4.3 months of follow-up, said Marcus Smith Noel, MD, Director of Ambulatory Operations for the Division of Hematology/Oncology, James P. Wilmot Cancer Institute, University of Rochester Medical Center, NY.
The estimated mean overall survival for patients with metastatic pancreatic cancer is approximately 4 months, and the estimated survival duration of patients with metastatic pancreatic cancer who enter a clinical trial for third-line therapy is typically 2 months, noted Dr Noel. In this early study, of the 14 patients who received SM-88 as third-line therapy, 79% were alive after a median follow-up of 4.7 months.
The third-line therapy setting in pancreatic cancer “is a population with an unmet need,” Dr Noel said. “We don’t have FDA-approved agents specifically for the third line, so the thought is, if we can use D,L-metyrosine, which is well-tolerated, there may be an opportunity to benefit patients.”
SM-88: 4-Drug Regimen
The novel 4-drug regimen known as SM-88 uses a proprietary dysfunctional tyrosine derivative (D,L-metyrosine) to interrupt the metabolic processes of cancer cells, breaking down their defenses to make them vulnerable to oxidative stress and potentially to cancer-cell 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 plus the 3 other repurposed drugs are designed to capitalize on that, such that they’re going to increase uptake of D,L-metyrosine into the cell, and hopefully that will result in cell death,” he explained.
Promising Responses to SM-88
In part 1 of the 2-part clinical trial known as Tyme-88-Panc, 38 patients were randomized to 230 mg twice daily or to 460 mg twice daily of D,L-alpha-metyrosine. All patients also received 10 mg daily of methoxsalen, 50 mg daily of phenytoin, and 0.5 mg daily of sirolimus. Data from 28 evaluable patients were presented at the meeting.
Of the 28 patients, 50% had received 2 previous lines of therapy, 14.3% had received 3 lines, and 21.4% had received ≥4 lines; these previous therapies included gemcitabine in 89.3% of the patients, fluorouracil in 85.7%, irinotecan in 67.9%, a platinum in 71.4%, and an immunotherapy in 10.7% of the patients.
A total of 17 patients had 2-month imaging data available. Among these 17 patients, 1 patient had a partial response and 7 had stable disease, which translates to a clinical benefit rate of 47.1%. In clinical trials of second-line therapy for metastatic pancreatic cancer, the response rate is typically less than 10%, and in clinical trials of third-line therapies, no responses to treatment are typically seen, Dr Noel emphasized.
Overall, 70% of the patients had a more than 30% decline from baseline in circulating tumor cell (CTC) count that was maintained for at least 1 cycle. The median decrease in CTC burden was 73%. As of January 6, 2019, 67.3% of the 28 evaluable patients were alive. 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,” said Dr Noel.
Overall, SM-88 was well-tolerated. Safety data from the entire cohort of 38 patients who were randomized in that early study show that 84.2% (32) of the patients had a treatment-emergent adverse event, with 16.2% of these events considered possibly related to the study regimen.
In addition, 1 patient in the D,L-alpha-metyrosine 460-mg twice-daily arm had 2 adverse events (rash and arthralgia) that were considered to be dose-limiting toxicities, but the patient resumed treatment after successful management of these events.