Supplementary Online Content

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1 Supplementary Online Content Chawla SP, Papai Z, Mukhametshina G, et al. First-line aldoxorubicin vs doxorubicin in metastatic or locally advanced unresectable soft-tissue sarcoma: a phase 2b randomized clinical trial. JAMA Oncol. Published online September 17, doi: /jamaoncol etable 1. Distribution of Enrolled Patients by Country etable 2. Treatment-Emergent Adverse Events Occurring in 10% of Patients in Either Cohort etable 3. Serious Adverse Events Occurring in Any Patient in Either Cohort etable 4. Summary of Cardiac Events on Study This supplementary material has been provided by the authors to give readers additional information about their work.

2 etable 1. Distribution of Enrolled Patients by Country Country Number of Patients US 37 Romania 9 Hungary 26 Russia 16 Ukraine 10 Australia 15 India 13

3 etable 2. Treatment-Emergent Adverse Events Occurring in 10% of Patients in Either Cohort Aldoxorubicin (n=83) Doxorubicin (n=40) Number of patients (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Any TEAE a 79 (95.2) 66 (79.5) 32 (80.0) 23 (57.5) Hematologic AE All grades Grade 3 or 4 All grades Grade 3 or 4 Anemia 36 (43.4) 14 (16.9) 13 (32.5) 8 (20.0) Neutropenia 33 (39.8) 24 (28.9) 7 (17.5) 5 (12.5) Leukopenia 15 (18.1) 8 (9.6) 4 (10.0) 2 (5.0) Febrile neutropenia 13 (15.7) 12 (14.5) 7 (17.5) 7 (17.5) Thrombocytopenia 11 (13.3) 7 (8.4) 6 (15.0) 2 (5.0) Nonhematologic AE All grades Grade 3 or 4 All grades Grade 3 or 4 Nausea 38 (45.8) 3 (3.6) 11 (27.5) Stomatitis 26 (31.3) 5 (6.0) 5 (12.5) 1 (2.5) Fatigue 24 (28.9) 3 (3.6) 6 (15.0) Alopecia 23 (27.7) 12 (30.0) Decreased appetite 20 (24.1) 3 (3.6) 2 (5.0) Vomiting 19 (22.9) 3 (3.6) 7 (17.5) Asthenia 15 (18.1) 2 (2.4) 5 (12.5) 1 (2.5) Pyrexia 14 (16.9) 1 (1.2) 3 (7.5) Constipation 12 (14.5) 2 (5.0) Mucosal inflammation 10 (12.0) 4 (4.8) 2 (5.0) Abdominal pain 9 (10.8) 2 (2.4) 2 (5.0) 1 (2.5) Diarrhea 7 (8.4) 1 (1.2) 7 (17.5) Abbreviations:, none reported in this category; AE, adverse event; TEAE, treatmentemergent AE. a Any given patient may have experienced more than one AE.

4 etable 3. Serious Adverse Events Occurring in Any Patient in Either Cohort Aldoxorubicin (n=83) Any SAE a, n (%) Study drugrelated SAE a,b, n (%) Any SAE a, n (%) Doxorubicin (n=40) Study drugrelated SAE a,b, n (%) 32 (38.6) 25 (30.1) 8 (20) 7 (17.5) BLOOD AND LYMPHATIC SYSTEM DISORDERS Febrile neutropenia 11 (13.3) 11 (13.3) 5 (12.5) 5 (12.5) Anemia 6 (7.2) 5 (6.0) 3 (7.5) 3 (7.5) Leukopenia 3 (3.6) 3 (3.6) Thrombocytopenia 2 (2.4) 2 (2.4) 1 (2.5) 1 (2.5) Neutropenia 1 (1.2) 1 (1.2) Pancytopenia 1 (1.2) 1 (1.2) Leukocytosis 1 (1.2) CARDIAC DISORDERS Atrial tachycardia 1 (1.2) Atrial fibrillation 1 (2.5) GASTROINTESTINAL DISORDERS Vomiting 3 (3.6) 3 (3.6) Stomatitis 2 (2.4) 2 (2.4) 1 (2.5) 1 (2.5) Gastritis 1 (1.2) 1 (1.2) Diarrhea 1 (1.2) 1 (2.5) 1 (2.5) Constipation 1 (1.2) Gastrointestinal hemorrhage 1 (1.2) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Pyrexia 3 (3.6) 1 (1.2) Mucosal inflammation 1 (1.2) 1 (1.2) 1 (2.5) 1 (2.5) HEPATOBILIARY DISORDERS Cholecystitis 1 (1.2) Cholecystitis acute 1 (1.2) IMMUNE SYSTEM DISORDERS Hypersensitivity 1 (2.5) INFECTIONS AND INFESTATIONS Cellulitis 3 (3.6) Pneumonia 1 (1.2) 1 (1.2) 1 (2.5) 1 (2.5) Gastroenteritis 1 (1.2) 1 (1.2) Neutropenic sepsis 1 (1.2) 1 (1.2) Oral herpes 1 (1.2) 1 (1.2) Pertussis 1 (1.2) 1 (1.2) Urinary tract infection 1 (1.2) 1 (1.2) Lower respiratory tract infection 1 (1.2)

5 Septic shock 1 (2.5) 1 (2.5) Tooth infection 1 (2.5) METABOLISM AND NUTRITION DISORDERS Dehydration 1 (1.2) 1 (2.5) 1 (2.5) NEOPLASMS BENIGN, MALIGNANT, AND UNSPECIFIED Tumor hemorrhage 1 (1.2) NERVOUS SYSTEM DISORDERS Transient ischemic attack 1 (1.2) RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS Pleurisy 1 (1.2) Pulmonary embolism 1 (1.2) Pneumothorax 1 (2.5) VASCULAR DISORDERS Deep vein thrombosis 2 (2.4) Embolism 1 (1.2) 1 (1.2) Hypovolemic shock 1 (1.2) Abbreviations:, none reported in this category; SAE, serious adverse event. a Any given patient may have experienced more than 1 SAE. b Includes SAEs that are possibly or definitely related to study drug.

6 etable 4. Summary of Cardiac Events on Study Aldoxorubicin Doxorubicin Patients with ECHO or MUGA at baseline, n 82 a 39 a Median LVEF at baseline (range), % 60.5 ( ) 63.0 ( ) Patients with 10% drop in LVEF, by timepoint, n/n (%) Cycle 2 3/62 (4.8) 2/26 (7.7) Cycle 4 4/50 (8.0) 7/20 (35.0) Cycle 6 2/37 (5.4) 2/11 (18.2) End of treatment 1/51 (2.0) 4/26 (15.4) 2 months post-end of treatment 1/27 (3.7) 3/9 (33.3) 5 months post-end of treatment 0/16 1/3 (33.3) 8 months post-end of treatment 1/9 (11.1) 0/2 11 months post-end of treatment 0/6 0/0 Any cycle c 9/74 (12.2) 10/34 (29.4) Patients with LVEF 50%, n (% c ) 0/75 3/35 (8.6) Median (range) serum troponin, by timepoint, ng/ml Baseline 0.01 (0.00, 19.31) 0.01 (0.01, 3.79) Cycle (0.00, 17.70) 0.01 (0.00, 17.75) Cycle (0.00, 10.03) 0.02 (0.01, 37.70) Cycle (0.01, 15.64) 0.08 (0.00, 85.59) End of treatment 0.01 (0.00, 23.83) 0.06 (0.00, ) 2 months post-end of treatment 0.01 (0.00, 16.85) 0.02 (0.00, 24.91) 5 months post-end of treatment 0.01 (0.00, 0.01) 0.01 (0.00, 0.02) Abbreviations: ECHO, echocardiography; LVEF, left ventricular ejection fraction; MUGA, multigated acquisition scan. a One patient in each treatment arm had a nonnumeric baseline ECHO or MUGA value and was not included here. b Percent based on number of patients with at least 1 change from baseline value at any post-baseline cycle: aldoxorubicin (n=74) and doxorubicin (n=34). c Percent based on number of patients with at least 1 non-missing LVEF value at any postbaseline cycle: aldoxorubicin (n=75) and doxorubicin (n=35).