| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic soft tissue sarcoma (STS) in patients ≥65 years old. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic soft tissue sarcoma (STS) in patients ≥65 years old. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective is to investigate whether treatment with oral cyclophosphamide improves the outcome of elderly patients (≥65 years old) with
advanced/metastatic STS, compared with doxorubicin in term of PFS. |
|
| E.2.2 | Secondary objectives of the trial |
Comparison of oral cyclophosphamide versus doxorubicin in terms of additional efficacy endpoints:
Overall survival (OS);
Best response under treatment;
Time until definitive deterioration (TUDD) of health-related quality of life (HRQoL);
Assessment of the toxicity profile of oral cyclophosphamide and doxorubicin, as per NCI CTCAE v5.0.
Assessment of the prognostic value on efficacy (PFS, OS)
Assessment of the geriatric characteristics of the randomized population,
Assessment of compliance to oral metronomic cyclophosphamide (arm B only) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must have signed a written informed consent form prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trust person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient’s consent
2. Age ≥65 years (inclusions will be managed to ensure that at least 50% of the randomized patients are ≥75 years old)
3. Diagnosis of soft-tissue sarcoma histologically confirmed by RRePS (Réseau de Référence en Pathologie des Sarcomes et des Viscères)
4. Metastatic or locally advanced disease not amenable to surgery, radiation, or combined modality treatment with curative intent. Palliative radiation therapy is permitted 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 a CT-scan as defined by response evaluation criteria in solid tumors (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 gated acquisition scanning (MUGA) ≥55%
11. Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation:
a. Absolute neutrophil count (ANC) ≥1,000/mm3
b. Platelets ≥100,000/mm3
c. Hemoglobin ≥9.0 g/dL
d. Serum creatinine ≤2 x upper limit of normal (ULN)
e. Glomerular filtration rate (GFR) ≥50 ml/min/1.73m2 (calculated with MDRD)
f. AST and ALT ≤2.5 x ULN (≤5.0 × ULN for patients with liver involvement of their cancer )
g. Total bilirubin ≤1.5 X ULN
h. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN with liver involvement of their cancer)
i. serum albumin > 25 g/L
j. Prothrombin time (PT)/International normalized ratio (INR) ≤1.5 x ULN
Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring of at least weekly evaluations will be performed until PT/INR is stable based on a measurement that is pre-dose as defined by the local standard of care.
12. Male patients must agree to use adequate contraception for the duration of trial participation and up to 6 months after completing treatment/therapy. Adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care
13. Patients must be affiliated to a Social Security System (or equivalent)
14. Patient is willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures including follow-up
|
|
| E.4 | Principal 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: dermatofibrosarcoma protuberans, desmoid tumor, alveolar or embryonal rhabdomyosarcoma, Desmoplastic small round cell tumor, Kaposi Sarcoma, Gastro-Intestinal stromal tumor, Peripheral neuroectodermal tumors
4. Primary bone sarcoma (including osteosarcoma, Ewing tumor, chondrosarcoma, and chordoma)
5. Symptomatic or known central nervous system (CNS) metastases
6. Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator and history of radiotherapy mediastinal in the last five years
7. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before Day 1 of treatment
8. Active cardio vascular disease including any of the following: Congestive heart failure (New York Heart Association [NYHA] ≥Class 2), unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), acute inflammatory cardiopathy, severe arythmia, high risk of bleeding, cerebrovascular accident within the last 6 months
9. Uncontrolled grade >2 hypertension. (Systolic blood pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite optimal medical management)
10. Ongoing infection ≥Grade 2 according to NCI Common Terminology Criteria for Adverse Events version (CTCAE v. 5.0)
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 urinary tract 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 the subject in this study
16. Substance abuse, medical condition, that may interfere with the patient's participation in the study or evaluation of the study results
17. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in 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 randomization and during the study
21. Patients having received live attenuated vaccine therapy used for prevention of diseases as influenza, chickenpox, zoster, measles, mumps, rubella, tuberculosis, rotavirus or yellow fever within 4 weeks of the first dose of study drug. These vaccinations are not permitted during the study up to 6 months after the last treatment
22. Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is progression-free survival (PFS).
PFS is defined as the time interval between the date of randomization and the date of progression (according to RECIST v1.1) or death, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy:
OS is defined as the time interval between the date of randomization and the date of
death of any cause.
Best response under treatment: Best response (as per RECIST v1.1) recorded from the date of randomization until the end of treatment. Each patient will be assigned one of the following categories: complete response, partial response, stable disease, disease progression, or unevaluable for response (specify reasons, e.g. early death, malignant disease; toxicity; tumor assessment not repeated/incomplete; other). Responses will have to be confirmed at least 4 weeks after the evaluation to exclude measurement errors.
Time until definitive deterioration (TUDD) of Health-related quality of life (HRQoL) is defined as the time interval between the date of randomization and the date of first deterioration of at least 10 points of the HRQoL score compared to baseline score, without any subsequent improvement as detailed further in Bonnetain et al.
HRQoL will be assessed through European Organization for Research and Treatment of Cancer (EORTC) Quality of life questionnaire - Core 30 (QLQ-C30) and Quality of life questionnaire – Elderly cancer patients (QLQ-ELD14).
The QLQ-C30 includes one global health status/quality of life (QoL) scale, five functional scales and three symptom scales. Each scale is scored from 0 to 100. A difference of 10 points or more in a scale indicates a minimal clinically important change.
The QLQ-ELD14 includes 5 sub-scales and 2 isolated items. A difference of 10 points or more in a scale indicates a minimal clinically important change.
HRQoL will be described at various time points and a longitudinal analysis will be conducted.
Toxicity: Adverse events will be graded according to the CTCAE v5.0.
Identification of prognostic factors of PFS and OS.
Geriatric condition. Based on the recent work of the DIALOG task force for definition of GCODE for clinical oncology research, geriatric data will be collected as follows :
1. Social environment: 2 questions
- “Do you live alone?” Y/N
- “Do you have any person able to provide you care and support?” Y/N
2. Functional status: ADL and 4-IADL
3. Mobility: Time Get Up and Go test (TUG)
4. Nutritional Status: Weight loss during the last 6 months and BMI. If one of the test is abnormal, the nutritional status is considered impaired.
- Weight loss during the last 6 months.
- BMI = weight (kg) / height² (m).
5. Cognitive status: Mini-Cog
6. Depressive mood: Mini-GDS
7. Comorbidities: Updated Charlson Comorbidity Index (updated CCI) (maximum=24).
Compliance to oral metronomic cyclophosphamide (arm B only): compliance will be assessed based on data reported by the patients (patient diary). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 21 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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