Novel Metabolic Therapy Demonstrates Activity in Metastatic Pancreatic Cancer

Marcus Smith Noel, MD

SM-88, a novel compound that attacks oncogenic metabolic pathways, is under development for patients with metastatic pancreatic cancer and other solid tumors, raising the potential for a tumor-agnostic therapy.

The agent is being explored in the phase II Tyme-88-Panc trial in patients with metastatic pancreatic adenocarcinoma that shows radiographic disease progression on or after at least 1 line of any chemotherapy (NCT03512756). The primary endpoint of the single-arm study is overall response rate according to modified RECIST 1.1 criteria as assessed by independent central review of scans. Investigators are seeking to enroll approximately 117 participants through 30 centers in the United States (Figure).

The compound seeks to exploit the Warburg effect, a metabolic process through which cancer cells use aerobic glycolysis to increase glucose uptake and fermentation to promote their own growth, survival, proliferation, and long-term maintenance.¹

Early Data Show Promise

“The thought process is that D,L-alphametyrosine will essentially alter the metabolism of pancreatic cancer,” Marcus Smith Noel, MD, a leading investigator into SM-88, said in an interview with OncologyLive^®. “All cancers are able to thrive in an oxidative environment…an environment that is deprived of nutrients and oxygen. 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.”Noel, an assistant professor at University of Rochester Medicine’s Wilmot Cancer Institute in New York, presented data from part 1 of Tyme- 88-Panc at the 2018 Gastrointestinal Cancers Symposium. Patients were randomly assigned to D,L-alpha-metyrosine at a twice-daily dosage of either 230 mg or 460 mg. In both arms, patients also received 10 mg/day of methoxsalen, 50 mg/ day of phenytoin, and 0.5 mg/day of sirolimus.

With a median of 4.3 months of follow-up after treatment initiation, 67.8% of 28 evaluable patients were still alive as of data cutoff on December 31, 2018. Imaging data at 2 months were available for 17 patients; 1 had a partial response and 7 had stable disease, for a clinical benefit rate of 47.1%.2

Most of the patients in the group, 60.7%, had stage III or IV disease; 50% had received 2 prior lines of therapy, 14.3% had received 3, and 21.4% had received at least 4.

The responses compare favorably with historical data, Noel said. Typically, the response rate observed in second-line studies is less than 10%, with no responses in third-line trials, he noted. In terms of overall survival, he said, a separate literature review of 21 studies found an estimated survival of approximately 2 months among patients with metastatic pancreatic cancer who enter a third-line trial.

Overall, pancreatic cancer has a 12-month survival rate of 10% to 23% and according to recent clinical trial findings in the second-line setting, a median overall survival of 4 to 6 months with chemotherapy and response rates of 1% to 17%, depending on the regimen.³ The third-line setting in pancreatic cancer “is a population with an unmet need,” 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.”

In findings for a safety population of 32 patients, 84.2% experienced all-grade treatment-emergent adverse events (AEs). One patient who was treated with 460 mg twice daily of D,L-metyrosine had 2 AEs (rash and arthralgia) considered to be dose-limiting toxicities but resumed treatment after successful management.⁴

Skin hyperpigmentation is a known event with SM-88 therapy, but there are few other serious AEs, Allyson J. Ocean, MD, a coauther of the Tyme-88-Panc report, said in an interview. “It doesn’t cause bone marrow suppression or alopecia,” said Ocean, an associate professor at Weill Cornell Medicine and a medical oncologist at NewYork-Presbyterian Hospital, both in New York City. “It doesn’t cause common chemotherapy-related adverse effects, and that’s important in this patient population.”

In prostate cancer, SM-88 “is basically starving the cancer of its energy supply,” Ocean said. “The drug incorporates an analogue of an amino acid, which blocks pathways that normally would, if they were activated, feed the cancer.”

SM-88 is being developed by Tyme, a biotechnology company based in New York, New York. In addition to Tyme-88-Panc, the drug is being evaluated in a phase I/II study in patients with nonmetastatic prostate cancer (NCT02796898). Trials are planned in metastatic breast cancer (NCT02562612) and sarcoma (NCT03778996).

In the single-arm study, participants will receive SM-88 daily in an oral formulation. The drug consists of an investigational agent, the tyrosine derivative D,L-alphametyrosine, and 3 repurposed drugs: an mTOR inhibitor, sirolimus; a CYP3A4 inducer, phenytoin; and an oxidative stress catalyst, methoxsalen.

References

1. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells [erratum in Trends Biochem Sci. 2016;41(3):287. doi: 10.1016/j.tibs.2016.01.004]? Trends Biochem Sci. 2016;41(3):211-218. doi: 10.1016/j.tibs.2015.12.001.
2. Noel MS, Wang-Gillam A, Ocean AJ, Del Priore G, Picozzi VJ. Phase II trial of SM-88 in patients with metastatic pancreatic cancer: preliminary results of the 1st stage. Poster presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Board A16/Abstract 200. s22.q4cdn.com/265040820/files/doc_downloads/scientific-presentations/2019/01/Phase-II-trial-of-SM-88-in-patients-with-metastatic-pancreatic-cancer-Preliminary-results-of-the-first-stage.pdf.
3. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. doi: 10.1016/j.ejca.2018.12.007.
4. Noel MS, Wang-Gillam A, Ocean AJ, Del Priore G, Picozzi VJ. Feasibility of SM-88 in pancreatic cancer after multiple prior lines and ECOG ≤2. Poster presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Board G8/Abstract 310. s22.q4cdn.com/265040820/files/doc_downloads/scientific-presentations/2019/Feasibility-of-SM-88-in-PC-after-multiple-prior-lines-and-ECOG-2-(NCT03512756).pdf.