SM-88 Shows Efficacy in Pancreatic, Prostate Cancers

Allyson Ocean, MD

Having a late-stage treatment for pancreatic cancer that avoids many of the adverse events (AEs) associated with chemotherapy would be a boon for patients. Investigators say they see that kind of potential in SM-88, a combination metabolic cancer treatment that in studies so far has demonstrated a relatively mild toxicity profile along with other benefits.

“We need better therapies, and if patients are in the second and third lines of treatment, they likely cannot tolerate chemotherapy, especially at the standard dose,” Allyson Ocean, MD, an investigator in the 88-Panc phase II trial of SM-88 in metastatic pancreatic cancer, told OncologyLive^®.

In a May update on 88-Panc, investigators said overall survival of evaluable patients was “trending to be approximately double the reported survival of this patient population.” As reported at the 2019 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, 9 of 28 evaluable patients (32%) were alive at 6 months or longer, with 1 patient having reached 1 year of survival. The expected survival for this patient population would ordinarily be 2 to 2.5 months.¹

The 88-Panc pancreatic cancer trial (NCT03512756), which has tested 2 dose levels of SM-88, also demonstrated improved survival in patients with advanced pancreatic cancer. Of 19 evaluable patients with end-stage pancreatic cancer, 67.8% remained alive at a median follow-up of 4.3 months.²

“This shows that heavily pretreated populations—and a majority of the patients had [3 lines] or more of therapy—maintained stable disease. This is very important. The other thing to point out is that most patients come off protocol not for progression of disease but because of disease-related complications,”³ said Ocean, an associate professor of clinical medicine at Weill Cornell Medicine and NewYork-Presbyterian.

Prior studies demonstrated that pancreatic cancer has an 80% mortality rate within 12 months of initial diagnosis. Recent trials have shown median overall survival of 4 to 6 months in the second-line setting.⁴

In 88-Panc, 47.1% of patients achieved a clinical benefit, including stable disease (7) and partial response (1). Investigators noted that the response rate typically observed in second-line trials is <10%. In third-line trials, no responses are typically observed. In 88-Panc, lesion reductions after 2 months of treatment with SM-88 were noted in 5 patients (n = 17) receiving at least second-line treatment.⁴ Two of those patients, 1 undergoing second-line therapy and the other in fourth line or higher, saw lesion reduction of greater than 30%. In addition, 9 patients had either a CA19-9 or carcinoembryonic antigen test reduction.⁴

Tyme, the company developing SM-88, said updated data would be presented at a major medical meeting sometime in the third quarter of 2019.

“The current survival data, when considering the safety of SM-88, offer new hope to both patients and physicians seeking viable treatment options for advanced patients,” said Vincent Picozzi, MD, director of the Pancreaticobiliary Program at the Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center, and principal investigator in the phase II 88-Panc metastatic pancreatic cancer trial.

SM-88 has also undergone trials in nonmetastatic castration-resistant prostate cancer and metastatic breast cancer and is expected to be tested in Ewing sarcoma and breast cancer in trials starting this year. Later this year, Tyme expects to inaugurate pivotal trials in patients with pancreatic cancer through the second part of phase II 88-Panc.

The investigational agent is a combination of a tyrosine derivative (D,L-α-metyrosine), an mTOR inhibitor (sirolimus), a CYP3a4 inducer (phenytoin), and an oxidative stress catalyst (methoxsalen). SM-88 is thought to have potential as an agnostic anticancer agent through its ability to disrupt the metabolism of the cancer cell, increase signaling activity, and trigger cell apoptosis.

The agent is designed to be absorbed by the cancer cell as though it were a functional tyrosine. Once absorbed, it disrupts protein synthesis and impedes the defenses of the cancer cell, making it vulnerable to oxidative stress and apoptosis.

The protein MUC1 is the key target in this process. Cancer cells have elevated levels of free radicals or reactive oxygen species (ROS), which are created by the less efficient but growth-fueling metabolism that cancer cells use. SM-88 interferes with tumor cells’ ability to manage these elevated ROS levels via MUC1 activity, leading to increased toxicity that ultimately triggers apoptotic signaling and cell death.

As clinicians await commencement of fresh trials involving SM-88, the promising results on toxicity and other measures in pancreatic and prostate cancer raise hope for another useful tool in the cancer-fighting armamentarium.

“To have a new compound with a really good [AE] profile is something that is important,” Ocean said.

Table. TEAEs With SM-88 in Patients With Pancreatic Cancer Following Multiple Prior Lines of Therapy, %⁴

She was impressed with the AE profile that has emerged from 88-Panc. In results from the first stage of the pancreatic cancer trial, the regimen was well tolerated with no treatment-related grade 4/5 events; 55.6% of treated subjects (20/36) had 94 AEs, with 18.0% (17/94) being at least possibly treatment related; 3 were grade 3 (arthralgia, fatigue and asthenia). In a breakout of patients with multiple prior lines of therapy, 1 patient on 460-mg, twice-daily dosage experienced 2 AEs considered dose limiting: rash and arthralgia. These were successfully managed, and the patient resumed treatment (Table).⁵

AEs with the highest incidence in the trial (N = 36) included abdominal pain, 18 (50.0%); dyspnea, 8 (22.2%); fatigue, 8 (22.2%); constipation 7 (19.4%); decreased appetite, 7 (19.4%); and back pain, 6 (16.7%).⁵

Investigators noted the findings’ high significance, considering that roughly half of patients on currently approved therapies for pancreatic cancer may experience severe AEs and almost all will experience AEs. “In a heavily pretreated pancreatic cancer subject population with extensive comorbidities, SM-88 was well tolerated,” the authors wrote.⁵

“It is still early, and we cannot make any strong statements in terms of efficacy, but it is very encouraging to see a compound with early efficacy in late-stage pancreatic cancer. Now we are able to offer an agent to our patients in a clinical trial framework that may improve outcomes and not make them sick,” Ocean said.

Impressive findings have also been reported for biomarker measures of activity for SM-88. In 88-Panc, 70% of 23 patients experienced a greater than 30% decline in circulating tumor cell (CTC) count for at least 1 cycle, and a median CTC decrease of 73% was reported.⁶

In updated data from a phase II trial of SM-88 in patients with nonmetastatic castration-resistant prostate cancer (mCRPC), 82% (14) of patients treated with SM-88 had an improved prostate-specific antigen (PSA) doubling time. The overall median PSA doubling time at enrollment was 5.3 months and improved to 6.5 months after therapy (P = .02). In addition, 67% (10) of patients who received SM-88 had a decline in CTCs of >30%.⁷

Besides demonstrating low toxicity, the agent may afford clinicians the opportunity to delay hormone therapy, which would improve quality of life (QOL) for patients undergoing treatment for cancer. When patients receive androgen deprivation therapy (ADT), their testosterone levels drop, resulting in AEs such as hot f lashes, sexual problems, weight gain, and loss of muscle and bone, all of which add up to a decrease in QOL, Benjamin A. Gartrell, MD, lead study author in the w mCRPC trial, told OncologyLive^®.

“One thing we are very interested in doing is taking a population of patients who are currently receiving [ADT] or hormonal therapy and figuring out if it is possible to delay the time until the patient needs hormonal therapy. That is what we are trying to do with SM-88,” said Gartrell, an assistant professor of urology at Albert Einstein College of Medicine and a medical oncologist at Montefiore Medical Center.

In the study, 96% of patients reported no hot flashes, 83% said they did not lose their sex drive, and 61% said the treatment did not affect their sexual performance. Responding to a posttherapy survey, 74% of patients reported their QOL as “excellent.”⁸

“SM-88 is a nonhormonal therapy and is not associated with any of these AEs. In this clinical trial, we did not see any of the typical hormone-associated AEs or any deterioration of QOL,” Gartrell said. “We believe that patients would like to avoid ADT, which is a hormonal medicine, for as long as possible.”

Further plans call for developing SM-88 for use in patients with nonmetastatic prostate cancer who have undergone local therapy and have a rising PSA. The current standard of care for these patients is to initiate hormone therapy to lower testosterone. Men would receive SM-88 or placebo.

References

1. TYME provides business update and reports fourth quarter and fiscal year 2019 financial and operating results [news release]. New York, NY: TYME; May 29, 2019.www.globenewswire.com/news-release/2019/05/29/1856249/0/en/TYME-Provides-Business-Update-and-Reports-Fourth-Quarter-and-Fiscal-Year-2019-Financial-and-Operating-Results.html.
2. Noel MS, Wang-Gillam A, Ocean AJ, et al. Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage. Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 200.
3. Scalea B. SM-88 shows promise in advanced pancreatic cancer. Onclive^® website.https://www.onclive.com/web-exclusives/sm88-shows-promise-in-advanced-pancreatic-cancer. Published January 30, 2019. Accessed June 5, 2019.
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: American Society of Clinical Oncology Gastrointestinal Cancers Symposium 2019; January 17-19, 2019; San Francisco, CA. media4.asco.org/235/13534/168752/168752_poster_big_1.jpg.
5. Noel MS, Wang-Gillam A, Ocean AJ, Chawla S, Del Priore G, Picozzi VJ. Phase II trial of SM-88 in patients with metastatic pancreatic cancer: preliminary results of the 1st stage. J Clin Oncol. 2019;37(suppl 4; abstr 200). https://meetinglibrary.asco.org/record/168775/poster.
6. Noel MS, Wang-Gillam A, Ocean AJ, et al. Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage. Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 200.
7. Gartrell BA, Del Priore G, Retter AS, et al. Evaluating non-hormonal therapy in a phase II trial of SM-88 for rising PSA prostate cancer. J Clin Oncol. 2019;37(suppl 7; abstr 83). doi: 10.1200/JCO.2019.37.7_suppl.83.
8. Scalea B. SM-88 safe, active in nonmetastatic CRPC. OncLive® website. onclive.com/web-exclusives/sm-88-safe-active-in-nonmetastatic-crpc?p=1. Published February 22, 2019. Accessed May 21, 2019.