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Proffered Paper – Supportive and palliative care

4204 - Assessment of Cardiotoxicity (CT) Associated with Doxorubicin (dox) in Patients (pts) with Advanced Soft Tissue Sarcoma (STS) in a Phase 3 Randomized Trial

Date

28 Sep 2019

Session

Proffered Paper – Supportive and palliative care

Topics

Supportive and Palliative Care

Tumour Site

Presenters

Robin Lewis Jones

Citation

Annals of Oncology (2019) 30 (suppl_5): v683-v709. 10.1093/annonc/mdz283

Authors

R.L. Jones1, A.J. Wagner2, A. Kawai3, A. Shahir4, V. Soldatenkova5, J. Wright5, W.D. Tap6

Author affiliations

  • 1 Medical Oncology, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
  • 2 Medical Oncology, Dana-Farber Cancer Institute, 02215 - Boston/US
  • 3 Musculoskeletal Oncology Dept., National Cancer Center Hospital, 104-0045 - Tokyo/JP
  • 4 Medical Oncology, Eli Lilly and Company, GU20 6PH - Erl Wood/GB
  • 5 Medical Oncology, Eli Lilly and Company, 46285 - Indianapolis/US
  • 6 Sarcoma Medical Oncology Service, Memorial Sloan Kettering Cancer Center, 10065 - New York/US

Resources

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Abstract 4204

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.Table:

1671O

Cumulative Dox Dose (Pooled)Overall
<300mg/m2 (n = 181)300 to ≤ 500mg/m2 (n = 114)>500mg/m2 (n = 211)Dox-Olaratumab (n = 257)Dox-Placebo (n = 249)
Any≥G3Any≥G3Any≥G3Any≥G3Any≥G3
Cardiac dysfunctiona0018 (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 LVEFb44 (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 < 50% and/or >10% from baseline.

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.

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.

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