1671OAssessment of cardiotoxicity (CT) associated with doxorubicin (dox) in patients (pts) with advanced soft tissue sarcoma (STS) in a phase III randomized trial

Abstract Background The ANNOUNCE trial evaluated the efficacy of the anti-PDGFR alpha antibody olaratumab + dox versus placebo + dox in adults with STS. CT was a secondary safety objective. Methods Treatment included dox 75mg/m2 on Day 1 of a 21-day cycle for up to 8 cycles, with olaratumab/placebo on Days 1, 8 until progression. Use of the cardioprotectant dexrazoxane was allowed with any cycle and recommended with Cycle 5 and beyond. Pts were monitored for left ventricular ejection fraction (LVEF) decreases after 4, 6, 8 cycles and electrocardiogram (ECG) changes in cycles 1 to 9; both were then monitored every 3 months for 1 year, every 6 months for 1 year, then annually. Eligible pts had a LVEF of ≥ 50% at baseline, and were without QTc prolongation, active symptoms of cardiac arrhythmia/dysfunction, and prior anthracycline exposure or mediastinal/pericardial radiation. Results Median age was 57 years. Medical history included cardiac disorders (n = 33; 6.5%) and ECG abnormalities (n = 1; 0.2%). Of the 506 treated pts from both arms, 504 (99.6%) had at least 1 dox dose, of which, 64.0% received at least 1 dose of dexrazoxane, with 61.0% of these pts starting before Cycle 6. Median dox exposure was 6 cycles/450mg/m2; median duration of CT evaluation was 28 weeks. One pt died due to acute cardiac failure after a cumulative dox dose of 441mg/m2. Adverse events (AEs) of cardiac dysfunction/decreased LVEF are summarized (Table). ECG abnormalities considered AEs occurred in 15 (3.0%) pts. Conclusions The ANNOUNCE trial prospectively evaluated CT in a large cohort of dox-treated adults with STS, most of whom received dexrazoxane for cardioprotection. Although LVEF decreases were common with routine monitoring, symptomatic cardiac dysfunction was reported infrequently. Frequency of CT was similar in both arms. Longer safety follow-up may be warranted to determine the true rate of CT with higher cumulative doses of dox. Table . 1671O Cumulative Dox Dose (Pooled) Overall 300 to ≤ 500mg/m2 (n = 114) >500mg/m2 (n = 211) Dox-Olaratumab (n = 257) Dox-Placebo (n = 249) Any ≥G3 Any ≥G3 Any ≥G3 Any ≥G3 Any ≥G3 Cardiac dysfunction a 0 0 18 (15.8) 9 (7.9) 8 (3.8) 2 (0.9) 12 (4.7) 5 (1.9) 14 (5.6) 6 (2.4) Number of Dox Cycles (Pooled) Lowest Post-baseline 4 Cycles (n = 201) 6 Cycles (n = 153) 8 Cycles (n = 158) Dox-Olaratumab (n = 200) Dox-Placebo (n = 201) Decreased LVEF b 44 (21.9) 36 (23.5) 49 (31.0) 96 (48.0) 98 (48.8) Data are presented as n (%). Abbreviations: Dox, doxorubicin; G, grade; LVEF, left ventricular ejection fraction. a Cardiac dysfunction was defined by pre-selected terms from Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query “cardiac failure,” omitting non-specific terms “edema” and “peripheral edema.” b LVEF decrease by  10% from baseline. Clinical trial identification NCT02451943. Editorial acknowledgement Karen Paulsrud, RPh, with Eli Lilly and Company, provided medical writing support. Legal entity responsible for the study Eli Lilly and Company. Funding Eli Lilly and Company. Disclosure R.L. Jones: Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Epizyme; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: Merck; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Tracon. A.J. Wagner: Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy, Research grant / Funding (institution): Five Prime; Advisory / Consultancy: Nanocarrier; Honoraria (self): Novartis; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Aadi Bioscience; Research grant / Funding (institution): Karyopharm. A. Kawai: Honoraria (self), Advisory / Consultancy: Eli Lilly and Company. A. Shahir: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. V. Soldatenkova: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. J. Wright: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. W.D. Tap: Shareholder / Stockholder / Stock options: Certis Oncology Solutions; Shareholder / Stockholder / Stock options: Atropos Therapeutics; Honoraria (self), Advisory / Consultancy: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: Immune Design; Honoraria (self), Advisory / Consultancy: Adaptimmune; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Blueprint; Honoraria (self), Advisory / Consultancy: Loxo; Honoraria (self), Advisory / Consultancy: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Agios Pharmaceuticals; Honoraria (self), Advisory / Consultancy: NannoCarrier; Advisory / Consultancy: Plexxikon Pharmaceuticals; Licensing / Royalties: Companion Diagnostic for CDK4 inhibitors; Officer / Board of Directors, Editor in Chief: Sarcoma Journal; Officer / Board of Directors, Treasurer: Connective Tissue Oncology Society.