A randomized, phase II trial of oral azacitidine (CC-486) in patients with resected pancreatic adenocarcinoma at high risk for recurrence

• Published in: Clinical epigenetics 2022-12, Vol.14 (1), p.166, Article 166
• Main Authors: Heumann, Thatcher R, Baretti, Marina, Sugar, Elizabeth A, Durham, Jennifer N, Linden, Sheila, Lopez-Vidal, Tamara Y, Leatherman, James, Cope, Leslie, Sharma, Anup, Weekes, Colin D, O'Dwyer, Peter J, Reiss, Kim A, Monga, Dulabh K, Ahuja, Nita, Azad, Nilofer S
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Adenocarcinoma - drug therapy; Adult; Aged; Aged, 80 and over; Antimitotic agents; Antineoplastic agents; Azacitidine; Biopsy; Cancer; Cancer therapies; Care and treatment; Chemoradiotherapy; Chemotherapy; Clinical trials; Diseases; DNA Methylation; DNA methyltransferase; Epigenetic inheritance; Epigenetics; Fatalities; Female; Health aspects; Humans; Hypotheses; Male; Medical prognosis; Metastases; Metastasis; Middle Aged; Neoplasm Recurrence, Local - drug therapy; Pancreas; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - surgery; Patients; Pharmacodynamics; Product development; Relapse; Tumor suppressor genes; Tumors
• ISSN: 1868-7075; 1868-7083; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-022-01367-8

Of the only 20% of patients with resectable pancreatic ductal adenocarcinoma (rPDA), cancer recurs in 80% of cases. Epigenetic dysregulation is an early hallmark of cancer cells acquiring metastatic potential, and epigenetic modulators may reactivate tumor suppressor genes, delay recurrence, and sensitize PDA to future chemotherapy. This was a randomized phase II study (NCT01845805) of CC-486 (oral DNA methyltransferase inhibitor azacitidine) vs. observation (OBS) in rPDA patients harboring high-risk features (stage pN1-2, R1 margins, or elevated CA 19-9 level) with no evidence of disease following standard adjuvant therapy. Patients were randomized to oral CC-486 treatment (300 mg daily on days 1-21 on a 28-day cycle) or OBS for up to 12 cycles or until disease relapse/unacceptable toxicities. Following recurrence, records of next-line therapies, imaging, and survival were obtained. The primary endpoint was progression-free survival (PFS)-time from randomization to recurrence (imaging/biopsy confirmed or death). Secondary endpoints included OS and PFS and ORR and metastatic PFS with subsequent next-line systemic therapy in metastatic setting. Forty-nine patients (24 in CC-486 arm, 25 in OBS arm) were randomized: median age 66 (range 36-81), 53% male, 73% node positive, 49% elevated CA 19-9, 20% R1 resection, 63% and 100% received perioperative concurrent chemoradiation and chemotherapy, respectively. Median time from surgery to randomization was 9.6 mo (range 2.9-36.8). For the CC-486 arm, median treatment duration was 5.6 mo (range 1.3 to 12.8) with 14 treatment-related grade 3 or 4 AEs among 5 patients (22%) resulting in dose-reduction. Four patients (17%) discontinued therapy due to AEs. With median follow-up of 20.3mo (IQR 12.8, 41.4), 38 (79%) of evaluable patients recurred (34 imaging-confirmed, 4 clinically). Median PFS in imagining-confirmed cases was 9.2 and 8.9mo (HR 0.94, 95% CI 0.46-1.87, p = 0.85) for CC-486 and OBS patients, respectively. Median OS (2-yr OS%) was 33.8 (50%) and 26.4 mo (61%) in CC-486 and OBS patients, respectively. (HR 0.98, 95% CI 0.46-2.05, p = 0.96). ORR with subsequent chemotherapy in the metastatic setting was minimal in both arms. Treatment with CC-486 following adjuvant therapy did not prolong time-to-relapse in patients with high-risk rPDA or improve disease response on 1st-line metastatic therapy.