Comparison of Oral Cyclophosphamide vs Doxorubicin in ≥65 Years Old Advanced or Metastatic Soft Tissue Sarcoma Patients

Inclusion criteria:

1. Patient must have signed a written informed consent form prior to any trial specificprocedures. When the patient is physically unable to give their written consent, atrust person of their choice, independent from the investigator or the sponsor, canconfirm in writing the patient's consent

2. Age ≥65 years (inclusions will be managed to ensure that at least 50% of therandomized patients are ≥75 years old)

3. Diagnosis of soft-tissue sarcoma histologically confirmed by Réseau de Référence enPathologie des Sarcomes et des Viscères (RRePS)

4. Metastatic or locally advanced disease not amenable to surgery, radiation, orcombined modality treatment with curative intent. Palliative radiation therapy ispermitted only if direct on nontarget lesion

5. Documentation of disease progression within the last 6 months before randomization

6. Measurable disease, defined as at least 1 unidimensionally measurable lesion on aCT-scan as defined by response evaluation criteria in solid tumors version 1.1 (RECIST v1.1)

7. Life expectancy of at least 6 months

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤2

9. G8 score >14

10. Left ventricular ejection fraction (LVEF) value by echocardiogram or Multiple gatedacquisition scanning (MUGA) ≥55%

11. Adequate bone marrow, renal, and hepatic function, as evidenced by the followingwithin 7 days of study treatment initiation:

12. Absolute neutrophil count (ANC) ≥1,500/mm³

13. Platelets ≥100,000/mm³

14. Hemoglobin ≥9.0 g/dL

15. Serum creatinine ≤2 x upper limit of normal (ULN)

16. Glomerular filtration rate (GFR) ≥50 ml/min/1.73m² (calculated with MDRD)

17. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN (≤5.0 × ULN for patients with liver involvement of their cancer )

18. Total bilirubin ≤1.5 X ULN

19. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN with liver involvement of theircancer)

20. serum albumin >25 g/L

21. Prothrombin time (PT)/International normalized ratio (INR) ≤1.5 x ULN Patientswho are therapeutically treated with an agent such as warfarin or heparin willbe allowed to participate provided that no prior evidence of underlyingabnormality in coagulation parameters exists. Close monitoring of at leastweekly evaluations will be performed until PT/INR is stable based on ameasurement that is pre-dose as defined by the local standard of care

22. Male patients must agree to use adequate contraception for the duration of trialparticipation and up to 6 months after completing treatment/therapy. Adequatecontraception is defined as any medically recommended method (or combination ofmethods) as per standard of care

23. Patients must be affiliated to a Social Security System (or equivalent)

24. Patient is willing and able to comply with the protocol for the duration of thestudy including scheduled visits, treatment plan, laboratory tests and other studyprocedures including follow-up

Exclusion Criteria:

1. Previous systemic treatment for advance or metastatic sarcoma

2. Previous neoadjuvant or adjuvant anthracycline treatment for localized sarcoma

3. Soft-tissue sarcoma with the following histological subtypes: dermatofibrosarcomaprotuberans, desmoid tumor, alveolar or embryonal rhabdomyosarcoma, Desmoplasticsmall round cell tumor, Kaposi Sarcoma, Gastro-Intestinal stromal tumor, Peripheralneuroectodermal tumors

4. Primary bone sarcoma (including osteosarcoma, Ewing tumor, chondrosarcoma, andchordoma)

5. Symptomatic or known central nervous system (CNS) metastases

6. Known history of or concomitant malignancy likely to affect life expectancy in thejudgment of the investigator and history of radiotherapy mediastinal in the lastfive years

7. Major surgical procedure, open biopsy, or significant traumatic injury within 28days before Day 1 of treatment

8. Active cardio vascular disease including any of the following: Congestive heartfailure (New York Heart Association (NYHA) ≥Class 2), unstable angina (anginasymptoms at rest), new-onset angina (begun within the last 3 months), acuteinflammatory cardiopathy, severe arrythmia, high risk of bleeding, cerebrovascularaccident within the last 6 months

9. Uncontrolled grade >2 hypertension. (Systolic blood pressure ≥160 mmHg or diastolicpressure ≥100 mmHg despite optimal medical management)

10. Ongoing infection ≥Grade 2 according to NCI Common Terminology Criteria for AdverseEvents version 5.0 (CTCAE v5.0)

11. Known history of human immunodeficiency virus (HIV) infection

12. Known history of chronic hepatitis B or C

13. History of organ allograft

14. Pre-existing acute hemorrhagic cystitis, urinary tract obstruction, acute urinarytract infection

15. Concomitant disease or condition that could interfere with the conduct of the study,or that would, in the opinion of the investigator, pose an unacceptable risk to thesubject in this study

16. Substance abuse, medical condition, that may interfere with the patient'sparticipation in the study or evaluation of the study results

17. Known hypersensitivity to any of the study drugs, study drug classes, or excipientsin the formulation

18. Inability to swallow oral medications, any malabsorption condition.

19. Persons deprived of their liberty or under protective custody or guardianship

20. Participation in another therapeutic trial within the 30 days prior to randomizationand during the study

21. Patients having received live attenuated vaccine therapy used for prevention ofdiseases as influenza, chickenpox, zoster, measles, mumps, rubella, tuberculosis,rotavirus or yellow fever within 4 weeks of the first dose of study drug. Thesevaccinations are not permitted during the study up to 6 months after the lasttreatment

22. Patients unwilling or unable to comply with the medical follow-up required by thetrial because of geographic, familial, social, or psychological reasons