Title: Pharmacokinetic Exposure Equivalence and Preliminary Efficacy and Safety from a Randomized Cross over Phase 3 Study (ASCERTAIN study) of an Oral Hypomethylating Agent ASTX727 (cedazuridine/decitabine) Compared to IV Decitabine
Authors: Guillermo Garcia-Manero, MD1, James McCloskey, MD2, Elizabeth A. Griffiths, MD3, Karen W.L. Yee, MD4, Amer M. Zeidan, MBBS, MHS5, Aref Al-Kali, MD6, Kim-Hien Dao, DO, PhD7, H. Joachim Deeg, MD8, Prapti A. Patel, MD9, Mitchell Sabloff, MSc, MD, FRCPC10, Mary-Margaret Keating, MD11, Nancy Zhu, MD12*, Nashat Y. Gabrail, MD13*, Salman Fazal, MD14, Joseph Maly, MD15, Olatoyosi Odenike, MD16, Aditi Shastri, MD17, Amy E. DeZern, MD18, Casey L. O’Connell, MD19, Gail J. Roboz, MD20, Aram Oganesian, PhD21*, Yong Hao, MD, PhD21*, Harold N. Keer, MD, PhD21, Mohammad Azab, MD21 and Michael R. Savona, MD22
1The University of Texas MD Anderson Cancer Center, Houston, TX; 2John Thuerer Cancer Center, Hackensack Medical Center, NJ; 3Roswell Park Comprehensive Cancer Center, Buffalo, NY; 4Princess Margaret Cancer Centre, Toronto, ON, CAN; 5Yale University and Yale Cancer Center, New Haven, CT; 6Mayo Clinic, Rochester, MN; 7Oregon Health & Science University, Portland, OR; 8Fred Hutchinson Cancer Research Center, Seattle, WA; 9University of Texas Southwestern Medical Center, Dallas, TX; 10Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada; 11Hematology/Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada; 12University of Alberta, Edmonton, AB, Canada; 13Gabrail Cancer Center, Canton, OH; 14West Penn Hospital, Allegheny Health Network, Pittsburgh, PA; 15Norton Cancer Institute, Louisville, KY; 16University of Chicago, Chicago, IL; 17Department of Hematology and Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY; 18Johns Hopkins University Hospital, Baltimore, MD; 19USC Keck School of Medicine, University of Southern California, Los Angeles, CA; 20Weill Cornell Medicine, The New York Presbyterian Hospital, New York, NY; 21Astex Pharmaceuticals, Inc., Pleasanton, CA; 22Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN
Introduction: Hypomethylating agents (HMAs) such as decitabine (DEC) or azacitidine (AZA) are FDA approved therapies for patients with different myeloid malignancies as single agent or in combination with venetoclax. Both DEC and AZA require IV infusion for 1 hour or subcutaneous (SC) injections daily for 5-7 days of every 28-day treatment cycle. They both have limited oral bioavailability due to rapid degradation by cytidine deaminase (CDA) in the gut and liver. An orally bioavailable HMA option could reduce clinic visit frequency and reduce infusions/injections related adverse events and burden. ASTX727 is an oral tablet comprised of a fixed-dose combination (FDC) of CDA inhibitor cedazuridine (C) at 100 mg with DEC at 35 mg. In a phase 2 study, C-DEC (ASTX727) demonstrated pharmacokinetic (PK) AUC exposure similar to IV-DEC at 20mg/m2 with comparable clinical activity and safety (Garcia-Manero, et al, 15th Int’l MDS Symposium, 2019). We describe here the results of a phase 3 study designed to demonstrate exposure bioequivalence of oral C-DEC and IV-DEC and generate clinical data using C-DEC in a larger population (ASCERTAIN study).
Methods: The study used a randomized cross over design where patients were randomized 1:1 to either Sequence A: C-DEC (100 mg/35 mg respectively) in Cycle 1 followed by IV-DEC at 20 mg/m2 in Cycle 2, or Sequence B receiving IV-DEC in Cycle 1 followed by C-DEC on Cycle 2 to compare PK (primary endpoint AUC equivalence over 5 days of dosing) and pharmacodynamic (PD) of DNA demethylation using LINE-1 assay. All patients received C-DEC in all subsequent cycles from Cycle 3 onwards until treatment discontinuation to study clinical efficacy and safety of C-DEC. Patients were eligible as per the FDA-approved label (MDS IPSS Intermediate [Int]-1,-2 or high risk[HR] and CMML patients). Clinical responses were assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.
Results: 138 patients were randomized, of whom 133 were treated with median age of 71.0 years (range 44-88), median weight was 83.1 kg (range 45-158), and median BSA was 1.99 m2 (range 1.4-2.9 m2). The IPSS status of the patients were Int-1 in 44%, Int-2 in 20%, and HR in 16%, and 12% of pts had CMML. Patients in the two arms were well balanced regarding cytogenetic risk, baseline hemoglobin, neutrophils, platelets, or red blood cell or platelet transfusion dependence. For the primary end point, the decitabine AUC0-24 (h*ng/mL) 5-Day geometric mean estimate was 856 from the C-DEC and 865 from IV-DEC resulting in an oral/IV AUC ratio of 98.9% (90% CI of 92.7-105.6%). All sensitivity and secondary exposure analyses confirmed the primary results. Comparison of hypomethylating activity as measured by LINE-1 demethylation showed difference between oral C-DEC and IV-DEC demethylation of <1% and the 95% CI of the difference included zero. Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 5% were thrombocytopenia, neutropenia, anemia, febrile neutropenia, and leukopenia). As of the data cutoff, median follow up was 5.2 months ( IQR 3.5-8.0) with 101 patients evaluable for response . Preliminary response analysis of all evaluable patients showed best responses of complete response (CR) in 12 patients (11.9%), marrow (m)CR in 46 (45.5%) including 14 patients (13.9%) with mCR + hematological improvement (HI), hematologic improvement (HI) in 7 (6.9%) resulting in an objective response rate (CR+mCR+ HI) in 65 patients (64%). In addition, of all 133 treated patients, 16 patients (12%) underwent hematopoietic cell transplant. Updated response data will be presented at the meeting.
Summary/Conclusions: This randomized phase 3 study demonstrates that C-DEC, the oral FDC of cedazuridine/decitabine (100 mg/35 mg) resulted in an equivalent DEC exposure to IV-DEC at 20 mg/m2 over 5 days. Safety findings are consistent with those anticipated with IV-DEC with no clinically significant GI toxicity. Preliminary clinical activity is also consistent with published data from IV-DEC. C-DEC is an oral HMA alternative to IV-DEC. Combination studies with other oral agents are being planned.