Low Dose Continuous Cyclophosphamide vs Standard Doxorubicin in Advanced Sarcoma Elderly Patients

To compare the efficacy, as measured by time to treatment failure, of metronomic cyclophosphamide with respect to doxorubicin in elderly patients affected by mSTS.

This phase III randomized clinical trial was designed to compare metronomic Cyclophosphamide with standard Doxorubicin for the first-line treatment of elderly cancer patients with advanced inoperable or metastatic STS:

i) ARM A (experimental): Metronomic Cyclophosphamide ii) ARM B (control): Doxorubicin up to six cycles

Eligibility Criteria:
Inclusion Criteria:

Patients may be included in the study only if they meet all the following criteria:

1. Histologically proven diagnosis of soft tissue sarcoma.
2. Advanced unresectable or metastatic soft tissue sarcoma not previously treated with chemotherapy for metastatic disease.
3. At least one measurable lesion according to RECIST1.1 criteria.
4. Availability of a tumor sample (primary and/or metastatic sites).
5. Age ≥ 70 years (70-75 years if UNFIT at G8; \>75 independent of G8 score)
6. ECOG PS 0-2.
7. Life expectancy of at least 12 weeks.
8. Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl.
9. Adequate hepatic function, defined as: Total bilirubin ≤ 1.5 time the upper-normal limits (ULN) of the normal values, ASAT (SGOT) and/or ALAT (SGPT) ≤ 2.5 x ULN (or \<5 x ULN in case of liver metastases)
10. Alkaline phosphatase ≤ 2.5 x ULN (or \<5 x ULN in case of liver metastases).
11. Creatinine clearance ≥ 30 mL/min.
12. Normal cardiac function, with left ventricular ejection fraction (LVEF) ≥50%.
13. Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator
14. Geriatric assessment by means of G8 screening tool and CRASH score.
15. Will and ability to comply with the protocol.
16. Written informed consent to study participation.

Exclusion Criteria:

* Patients will be excluded from the study for any of the following reasons:

  1. Previous treatment for metastatic disease.
  2. Previous (neo) adjuvant chemotherapy with anthracyclines.
  3. Radiotherapy to any site within 4 weeks before the study.
  4. Untreated brain metastases or spinal cord compression or primary brain tumors.
  5. Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
  6. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication.
  7. Treatment with any investigational drug within 30 days prior to enrollment or 2 investigational agent half-lives (whichever is longer)
  8. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
  9. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
  10. Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
  11. Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
  12. Sexually active males unwilling to practice contraception during the study and until 6 months after the last trial treatment.