Study of SM-88 Shows Promising Results in Advanced Pancreatic Cancer

In Clinical Trials by Barbara Jacoby

By: Gina Columbus

From: targetedonc.com

The investigational agent SM-88 demonstrated promising survival in the phase II TYME-88-Panc study in patients with advanced pancreatic cancer.1,2 The oral modified dysfunctional tyrosine induced a median overall survival (OS) of 6.4 months in patients.

The RECIST clinical benefit rate (CBR) of stable disease (SD) or better was 44% with available imaging, and there was a 92% (HR, 0.08; P = .02) reduction in the risk of death among patients who reached at least SD, according to findings presented at the 2019 World Congress on Gastrointestinal Cancer. Also, the CBR was durable, as the majority of patients who received SM-88 continued to have SD or better at >7 months, Tyme Technologies, Inc., the developer of the investigational agent, reported in a press release.

“Responses are very rare in later line pancreatic cancer so overall response rates are close to zero. The SM-88 trial has demonstrated encouraging new data on efficacy indicators, including a meaningful clinical benefit rate, and a reduction in circulating tumor cells, that both correlate with extended survival,” Allyson Ocean, MD, an associate professor of clinical medicine at Weill Cornell Medicine and NewYork-Presbyterian, said in the press release. “Research results to date also indicate that SM-88 has a favorable toxicity profile. To have both results with one drug is extremely important. There are no FDA-approved treatments for third-line pancreatic cancer and no NCCN or ASCO guideline recommendations. These patients are in desperate need of effective therapies.”

M-88 is a novel oral anticancer regimen consisting of a tyrosine derivative (D,L-alpha-metyrosine), an mTOR inhibitor (sirolimus), a CYP3a4 inducer (phenytoin), and an oxidative stress catalyst (methoxsalen).

In the multicenter, open-label, 2-part, phase II study, investigators evaluated SM-88 in patients with pancreatic ductal adenocarcinoma with radiographic progressive disease who received ≥1 prior line of therapy and had an ECOG performance status ≤2. Patients were randomized to receive either 460 mg daily or 920 mg daily of SM-88, and all patients received methoxsalen at 10 mg daily, phenytoin at 50 mg daily, and sirolimus at 0.5 mg daily.

Part 1 of the study was designed to determine the optimal dosing and whether there was early clinical benefit that would support additional development of SM-88. In data that were presented at the 2019 Gastrointestinal Cancers Symposium, results showed that 67.8% of 28 evaluable patients were alive as of December 31, 2018, which was a median 4.3 months of follow-up after treatment initiation.3

The updated data presented at the 2019 World Congress on Gastrointestinal Cancer included 49 heavily pretreated patients with radiographically progressive metastatic pancreatic cancer who also had significant disease-related morbidity. Baseline characteristics were similar between the intent-to-treat (ITT) population (n = 49) and in the efficacy-evaluable group (n = 38). The median age was 66.5 years, and the majority of patients (>80%) had received ≥2 prior lines of therapy.

The 6.4-month median OS was for the 38 efficacy-evaluable patients. Among the 49 patients in the ITT population, results showed that the preliminary median Kaplan-Meier derived OS was 3.6 months.

“We believe that these outcomes further justify advancing the development of SM-88. These survival results compare very favorably to the analysis of 19 prospective pancreatic cancer trials where the median reported survival after progressing on third-line therapy was 2.0 to 2.5 months based on reported historical trials,” Giuseppe Del Priore, MD, MPH, chief medical officer at Tyme, said in the press release. “Given that there are no effective options to treat this patient population, we plan to move forward with our SM-88 pivotal trial in pancreatic cancer. We are increasingly encouraged that SM-88 has the potential to be a new treatment approach for late-stage pancreatic patients.”

Investigators also performed subgroup analyses that were presented during the meeting. Several screening criteria that were associated with rapidly declining prognostic factors included those who had >2 lines of prior therapy, are >75 years old, and albumin <3.5 g/dl. The company stated that patients who did not have these poor prognostic characteristics did have a better survival trend (HR, 0.36; 95% CI, 0.1-1.3; P = .12).

Moreover, key subgroups who did have improved survival outcomes with SM-88 were females (HR, 0.21; 95% CI, 0.06-0.73; = .01) and those with 1 or 2 prior lines of treatment compared with those with >3 or more prior therapies (HR, 0.56; 95% CI, 0.21-1.5; P = .26). Patients with baseline circulating tumor cells (CTCs) ≤50 cells/4 mL also demonstrated a trend toward improved OS (HR, 0.26; 95% CI, 0.06-1.2; P = .08).

Additional analyses were conducted to show the association between CTCs and survival. The median decrease of CTCs was 63%, and 56.3% of patients with CTC decreases had an OS of >180 days compared with 37.5% of those with CTC increases. Patients who had ≥80% CTC reduction (n = 24) trended toward improved OS (HR, 0.4; 95% CI, 0.11-1.5; P = 1.8), and those with ≤50 cells/4 mL at nadir also had favorable OS outcomes (HR, 0.64; 95% CI, 0.2-2.1; P = .45). Patients with the longest survival at 261+, 262+, and 343+ days had both an >80% reduction and <50 cells/4 mL.

Regarding safety, serious adverse events (SAEs) that were potentially treatment-related were reported in 4% of the ITT population, and included abdominal pain, arthralgia, and hypotension. One patient who experienced SAEs remained on treatment. In the ITT population, 94% of patients experienced all-grade AEs, 17% of which were possibly related to treatment, and 12% of which were grade 3/4.

In a July 9, 2019, conference call held by Tyme, Manuel Hidalgo, MD, shared his perspective on the updated data with SM-88.

“First, we have a new mechanism of action; it’s a drug that attacks metabolism. This is one of the first agents in this class of new compounds, which is a new wave of treating cancer. The study shows a few very interesting things. On one end, the drug is oral, which is always an advantage. Second, it is very well tolerated, very safe, which is of utmost importance in a fragile patient population,” explained Hidalgo, chief of the Division of Hematology and Medical Oncology at Weill Cornell Medicine and NewYork-Presbyterian/Weill Cornell Medical Center. “The survival is very encouraging, 6.4 months, in a population where the standard-of-care treatment … [leads to] between 2 and 3 months [OS].”

Hildalgo also offered insight to the association between CTC decreases and favorable OS in the conference call.

“These are very important pieces of data because it is going to help potentially populations that may benefit from the drug in future studies,” he added. “We are really looking forward to having this agent [in] our portfolio to treat patients with advanced refractory pancreatic cancer.”

Following discussions with the FDA, SM-88 will now be explored in a phase II/III clinical trial (NCT03512756) in which patients with metastatic adenocarcinoma of the pancreas whose disease has progressed or reoccurred will be randomized to receive SM-88 (n = ~100) or investigator’s choice of therapy (n = ~100).Patients must have received 2 prior lines of therapy. The primary endpoint is OS; secondary endpoints include CBR, CTCs, and quality of life.

Additionally, SM-88 will also be investigated in the Pancreatic Cancer Action Network’s Precision Promise clinical trial platform, which is exploring multiple therapeutic regimens in patients with pancreatic cancer.

“We are very encouraged by these updated data; we are committing to continuing to advance our oral SM-88 and pivotal studies for pancreatic cancer,” Michele Korfin, RPh, MBA, chief operating officer of Tyme, stated during the conference call. “Patients with pancreatic cancer unfortunately have a very poor prognosis and desperately need additional treatment options. Tyme looks forward to our important partnerships with patients, physicians, advocacy groups, including the Pancreatic Cancer Action Network, to advance better, safer, treatment options for patients with pancreatic cancer.”

References

  1. TYME Presents Updated Data at ESMO GI 2019 from TYME-88-Panc Phase II Study Demonstrating Encouraging Overall Survival Trends in Patients with Advanced Pancreatic Cancer. Tyme Technologies, Inc. Published July 5, 2019. https://bit.ly/2xNYEjr. Accessed July 9, 2019.
  2. Noel MS, Wang-Gillam A, Ocean AJ, et al. SM-88 therapy in high-risk poor prognosis pancreatic cancer (PDAC). Ann Oncol. 2019;30 (suppl_4). doi: 10.1093/annonc/mdz155.058.
  3. 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.
  4. TYME ESMO GI Conference Call. Tyme. Published July 9, 2019. https://bit.ly/2YIEbbx. Accessed July 9, 2019.