A randomized phase II study of SM-88 plus methoxsalen, phenytoin, and sirolimus in patients with metastatic pancreatic cancer treated in the second line and beyond

Abstract

Background: This trial explores SM-88 used with methoxsalen, phenytoin, and sirolimus (MPS) in pretreated metastatic pancreatic ductal adenocarcinoma (mPDAC) METHODS: Forty-nine patients were randomized to daily 460 or 920 mg oral SM-88 with MPS (SM-88 Regimen). The primary endpoint was objective response rate (RECIST 1.1).

Results: Thirty-seven patients completed ≥ one cycle of SM-88 Regimen (response evaluable population). Disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) did not differ significantly between dose levels. Stable disease was achieved in 9/37 patients (DCR, 24.3%); there were no complete or partial responses. Quality-of-life (QOL) was maintained and trended in favor of 920 mg. SM-88 Regimen was well tolerated; a single patient (1/49) had related grade 3 and 4 adverse events, which later resolved. In the intention-to-treat population of 49 patients, the median overall survival (mOS) was 3.4 months (95% CI: 2.7-4.9 months). Those treated in the second line had an mOS of 8.1 months and a median PFS of 3.8 months. Survival was higher for patients with stable versus progressive disease (any line; mOS: 10.6 months vs. 3.9 months; p = 0.01).

Conclusions: SM-88 Regimen has a favorable safety profile with encouraging QOL effects, disease control, and survival trends. This regimen should be explored in the second-line treatment of patients with mPDAC.

Clinicaltrials: gov Identifier: NCT03512756.

Conflict of interest statement

Dr. Marcus Smith Noel declares that he has held a Consulting or Advisory Role at Celgene, Taiho Pharmaceutical, and Ipsen. He is also a member of the Speakers Bureau for Celgene, Taiho Pharmaceutical, and Daiichi Sankyo/Astra Zeneca.

Semmie Kim declares Employment, Stock, and other Ownership Interests from TYME Inc.

Marion L. Hartley, PhD declares no potential competing interests.

Dr. Steve Wong declares no potential competing interests.

Dr. Vincent Picozzi declares that he has held a Consulting or Advisory Role at TriSalus Life Sciences. He also has Stock and other Ownership Interests in Amgen, Johnson and Johnson, McKesson, Thermo Fisher Scientific, and Cigna. He has received Research Funding from FibroGen, Celgene, Ipsen, NovoCure, Merk, TYME Inc., Abbvie, and NGM Biopharmaceuticals.

Dr. Harry Staszewski declare no potential competing interests.

Dr. Dae Won Kim has received Research Funding from Bold Therapeutics.

Dr. Jan Van Tornout declares employment at TYME Inc. Stock and other Ownership Interests from Bristol‐Myers Squibb, Novartis, Sanofi, TYME Inc., Lilly, and Merck. Has received an Honoraria from TYME Inc. Has held a Consulting or Advisory Role at TYME Inc.

Dr. Philip Agop Philip has held a Consulting or Advisory Role at Celgene, Ipsen, Merck, TriSalus, Daiichi, Syncore, and Taiho. He has been on the Speakers' Bureau for Celgene, Bayer, Ipsen, Novartis, and Incyte. Has received reimbursement for travel, accommodation, and expenses from Rafael Pharmaceuticals, Celgene, and Abbvie. He has received an Honoraria from Celgene, Bayer, Ipsen, Merck, AstraZeneca, TriSalus Life Sciences, Blueprint Medicines, Syncore, and Array BioPharma. He has received Research Funding from Bayer, Incyte, Karyopharm Therapeutics, Merck, Taiho Pharmaceutical, Momenta Pharmaceuticals, Novartis, Plexxikon, Immunomedics, Regeneron, Genentech, TYME Inc., Caris Life Sciences, ASLAN Pharmaceuticals, QED Therapeutics, Halozyme, Boston Biomedical, Advanced Accelerator Applications, Lilly, Taiho Pharmaceuticals, and Merus.

Dr. Vincent Chung has held a Consulting or Advisory Role at Ispen, Gristone Oncology, Westwood Bioscience, and Apeiron Biologics. He has been on the Speakers' Bureau for Ipsen and Celgene. He has received Research Funding from Roche and Merck.

Dr. Allyson J. Ocean has held a Consulting or Advisory Role at TYME Inc., and Celgene. She has been on the Speakers' Bureau at Daiichi Sankyo. Has received reimbursement for travel, accommodation, and expenses from Daiichi Sankyo.

Dr. Andrea Wang‐Gillam declares employment at Jocobio. She has held a Consulting or Advisory Role at AstraZeneca, Merck, Bayer, and Inxmed. Stock and other Ownership Interests at Jacobio. She has received Research Funding from AstraZeneca, Pfizer, Lilly, Verastem, Merck, BioMed Valley Discoveries, Roche, Bristol‐Myers Squibb, Xcovery, Boston Biomedical, Hutchinson MediPharma, Rafael Pharmaceuticals, Gossamer Bio.

© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Patient overall quality‐of‐life scores on treatment, as measured by the EORTC QLQ‐C30 Question 30, and weight by the dose of SM‐88 Regimen. Box and whisker plots showing median, interquartile range, and minimum and maximum values of (A) EORTC QLQ‐C30 Question 30, “How would you rate your overall QOL during the past week?” from pre‐treatment to Cycle 4 on treatment; and (B) weight in pounds pre‐ and post‐treatment by dose group. In (A), scoring ranges from 1 to 7, where 1 = very poor and 7 = excellent. EORTC QLQ‐C30, European Organization for Research and Treatment of Cancer Quality‐of‐Life Questionnaire; QOL, quality‐of‐life

FIGURE 2

Overall survival (OS) of evaluable patients receiving SM‐88 Regimen (n = 37). Simple Kaplan– Meier curve of OS in months for (A) all 37 patients (median 3.9 months; 95% CI: 3.0–5.7), (B) the 20 patients receiving 460 mg/day compared to the 17 patients receiving 920 mg/day (4.9 months [95% CI: 2.2–8.1] vs. 3.6 months [95% CI: 2.6–5.7]; p = 0.79) and (C) patients receiving SM‐88 Regimen after 1 prior line (n = 5), 2 prior lines (n = 18), and 3 or more prior lines (n = 14) of therapy: 8.1 months (95% CI: 3.0 ‐ n/a [not reached]) vs. 3.7 months (95% CI: 2.7–6.6) versus 3.0 months (95% CI: 1.9–5.4); log‐rank p = 0.08

FIGURE 3

OS of evaluable patients by RECIST best response (SD or PD). Kaplan–Meier OS curve for evaluable patients receiving SM‐88 Regimen who achieved stable disease (solid line; mOS = 10.6 months [95% CI: 2.6–30.5]) versus those who had disease progression (hashed line; mOS = 3.9 months [95% CI: 3.0–5.7]). Log‐rank p = 0.01; HR = 0.29 (95% CI: 0.10–0.79). mOS, median overall survival; OS, overall survival; RECIST, response evaluation criteria in solid tumors; SD, stable disease

FIGURE 4

PFS curves for all evaluable patients (n = 37). Kaplan–Meier curve of PFS in months for (A) all 37 evaluable patients (median 1.9 months [95% CI: 1.7‐2.0]), (B) the 20 patients receiving 460 mg/day (1.9 months [95% CI: 1.6–3.0]) compared to the 17 patients receiving 920 mg/day (1.8 months [95% CI: 1.0–2.6]; log‐rank p = 0.25), and (C) patients receiving SM‐88 Regimen after 1 prior line (solid line; n = 5), 2 prior lines (black hashed line; n = 18), and 3 or more prior lines (black dotted line; n = 14) of therapy (3.8 months [95% CI: 0.9 – not reached], 1.8 months [95% CI: 1.5–2.0], and 1.9 months [95% CI: 1.4–2.6]; log‐rank p = 0.44). *A single patient who had received 2 lines of prior treatment showed a prolonged PFS response, with RECIST‐confirmed stable disease at 15 weeks post‐treatment initiation. PFS, progression‐free survival; RECIST, response evaluation criteria in solid tumors