Abstract PO-054: A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP)
Authors: Skorupan Nebojsa , Ahmad Mehwish I. , Steinberg Seth M. , Trepel Jane B. , Cridebring Derek , Han Haiyong , Von Hoff Daniel D. , Alewine Christine 
Published: November 2021

Abstract
Background: Adenosquamous carcinoma of the pancreas (ASCP) is a very rare and highly aggressive variant of pancreatic ductal adenocarcinoma (PDA), accounting for 0.5-4% of all pancreatic cancer cases in the US. Current data indicates that epigenetic changes and Myc overexpression lead to squamous transdifferentiation of pancreatic tumor cells and development of ASCP. Minnelide is an oral anti-super-enhancer drug that inhibits Myc expression in preclinical models of ASCP. Oral Minnelide has been previously tested in the clinic where a Phase I study determined a recommended phase 2 dose of 2 mg/day. Major toxicities included neutropenia and sepsis. We hypothesize that Minnelide will be safe and effective in patients with advanced ASCP. Methods: This Phase II open label, single arm study being conducted at the NIH Clinical Center in Bethesda, MD (NCT04896073) will enroll up to 25 evaluable participants with advanced ASCP that has been previously treated. Eligibility criteria include: histologically confirmed ASCP (≥30% malignant squamous component), presence of metastatic, recurrent, or locally advanced unresectable disease, and progression or intolerance ≥1 prior systemic treatment for advanced disease. All participants will self-administer Minnelide at 2mg PO daily on days 1-21 of each 28-day cycle, for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Restaging scans will be performed every 8 weeks. Optional biopsies will be requested at baseline, mid-cycle 1 and at time of progression. The primary objective is to determine the antitumor activity of Minnelide by evaluating the disease control rate. Secondary objectives are determination of drug safety in this patient population, progression free survival, and overall survival. Exploratory objectives include assessment of Minnelide effect on tumor cell epigenetics, Myc expression and immune cell populations using on-treatment tumor biopsy tissues. Changes in circulating tumor DNA and circulating immune cell populations upon treatment will also be evaluated. A Simon optimal two-stage phase II trial design will be used. If 3 of the first 12 patients experience disease control, then enrollment will continue up to 25 evaluable participants. If ≥8 of 25 participants experience disease control this would rule out an unacceptably low clinical benefit of 20% in favor of 40% (α = 0.1, β = 0.2). This trial opened for accrual in July 2021.
Citation Format: Nebojsa Skorupan, Mehwish I. Ahmad, Seth M. Steinberg, Jane B. Trepel, Derek Cridebring, Haiyong Han, Daniel D. Von Hoff, Christine Alewine. A phase II trial of the super-enhancer inhibitor Minnelide in advanced refractory adenosquamous carcinoma of the pancreas (ASCP) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-054.