Randomized Phase III Trial of Oral Cyclophosphamide Versus Doxorubicin in Patients Aged 65 and Older with Advanced or Metastatic Soft Tissue Sarcoma
- Trial ID
- 2024-510653-10-00
- Protocol
- UC-0103/1802
- Sponsor
- Unicancer
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate whether treatment with oral **cyclophosphamide** improves the outcome of elderly patients (≥65 years old) with advanced or metastatic soft tissue sarcoma (STS) compared to **doxorubicin**, specifically in terms of progression-free survival (PFS). This is clinically relevant as it aims to determine a potentially more effective treatment option for this patient population, which could lead to improved management of STS in elderly patients.
Secondary objectives include:
- Comparison of oral cyclophosphamide versus doxorubicin in terms of additional efficacy endpoints: overall survival (OS), best response under treatment, and time until definitive deterioration 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, including PFS and OS.
- Assessment of the geriatric characteristics of the randomized population.
- Assessment of compliance to oral metronomic cyclophosphamide (arm B only).
Participants
The clinical trial involves participants diagnosed with **advanced or metastatic soft tissue sarcoma** (STS) who are aged 65 years or older. The study population includes both male and female subjects, with no vulnerable populations selected. Participants are required to have a life expectancy of at least six months and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include a histologically confirmed diagnosis of soft-tissue sarcoma, measurable disease progression within the last six months, and suitability to receive doxorubicin. Participants must have adequate bone marrow, renal, and hepatic function, and a left ventricular ejection fraction (LVEF) of at least 55%. Lifestyle considerations such as diet and physical activity are not detailed in the trial data. The trial population was selected based on their ability to comply with the study protocol, including scheduled visits and treatment plans.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, controlled study designed to evaluate the efficacy of oral **cyclophosphamide** compared to **doxorubicin** in patients aged 65 years or older with advanced or metastatic soft tissue sarcoma. The trial is structured as a Phase III study and aims to assess progression-free survival (PFS) as the primary endpoint. The trial is expected to run from June 2021 to April 2025, with participant involvement lasting up to 18 months, depending on the treatment arm and individual response to therapy.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as adequate organ function and a life expectancy of at least six months. Following randomization, participants will attend regular follow-up visits to monitor treatment response, adverse events, and overall health status. These visits will include assessments of disease progression using RECIST v1.1 criteria, as well as evaluations of health-related quality of life and geriatric conditions. The end-of-study visit will occur after the completion of the treatment period or upon early termination from the study.
Early termination from the study may occur if a participant experiences unacceptable toxicity, disease progression, or withdrawal of consent. Participants will be closely monitored for adverse events, which will be graded according to CTCAE v5.0. The study will also collect data on secondary endpoints, including overall survival, best response under treatment, and compliance with oral cyclophosphamide in the relevant treatment arm. The trial's design ensures that at least 50% of the randomized patients are 75 years or older, reflecting the study's focus on the elderly population with this condition.
Treatment
The clinical trial involves the administration of several treatments, including **Filgrastim**, **Cyclophosphamide**, **Doxorubicin**, and **Dexrazoxane Hydrochloride**. **Filgrastim** is provided as a solution for injection or infusion in a pre-filled syringe. It is administered intravenously with a maximum daily dose of 5 µg/kg and a total maximum dose of 30 µg/kg over a treatment period of up to 6 days. The active substance, filgrastim, is a protein of non-human origin, and its role in the trial is auxiliary.
**Cyclophosphamide** is administered orally in tablet form. The maximum daily dose is 200 mg, with a total maximum dose of 2800 mg over a treatment period of 1 day. Cyclophosphamide serves as the test treatment in this study, aiming to improve outcomes in elderly patients with advanced or metastatic soft tissue sarcoma.
**Doxorubicin** is provided as a solution for infusion and is administered intravenously. The maximum daily dose is 75 mg/m², with a total maximum dose of 435 mg/m² over a treatment period of up to 18 weeks. Doxorubicin acts as a comparator treatment in the trial, allowing for the evaluation of its efficacy against cyclophosphamide.
**Dexrazoxane Hydrochloride** is administered as a powder for solution for infusion, also intravenously. The maximum daily dose is 750 mg/m², with a total maximum dose of 4500 mg/m² over a treatment period of up to 6 days. Dexrazoxane Hydrochloride serves an auxiliary role in the trial, potentially providing cardioprotective effects during treatment with doxorubicin.
Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The trial aims to assess the progression-free survival (PFS) of patients receiving these treatments, with a focus on the efficacy of oral cyclophosphamide compared to doxorubicin in elderly patients with advanced or metastatic soft tissue sarcoma.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival (PFS)**. PFS is defined as the time interval between the date of randomization and the date of disease progression, as determined by RECIST v1.1 criteria, or death, whichever occurs first. This endpoint will provide a direct measure of the treatment's impact on delaying disease progression in patients with advanced or metastatic soft tissue sarcoma.
Secondary endpoints include overall survival (OS), which is the time interval from randomization to death from any cause, and the best response under treatment, categorized as complete response, partial response, stable disease, disease progression, or unevaluable for response. These responses will be confirmed at least four weeks after evaluation to ensure accuracy. Additionally, the time until definitive deterioration (TUDD) of health-related quality of life (HRQoL) will be assessed using the Quality of Life Questionnaire - Core 30 (QLQ-C30) and the Quality of Life Questionnaire – Elderly Cancer Patients (QLQ-ELD14). TUDD is defined as the time from randomization to the first deterioration of at least 10 points in the HRQoL score compared to baseline, without subsequent improvement.
Toxicity will be evaluated according to the CTCAE v5.0, and prognostic factors for PFS and OS will be identified. Geriatric conditions will be assessed based on the DIALOG task force's G-CODE for clinical oncology research, including social environment, functional status, mobility, nutritional status, cognitive status, depressive mood, and comorbidities. Compliance with oral metronomic cyclophosphamide in the relevant treatment arm will be monitored through patient-reported data in a diary.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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
- Age ≥65 years (inclusions will be managed to ensure that at least 50% of the randomized patients are ≥75 years old)
- Diagnosis of soft-tissue sarcoma histologically confirmed by RRePS (Réseau de Référence en Pathologie des Sarcomes et des Viscères)
- 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
- Documentation of disease progression within the last 6 months before randomization
- 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
- Life expectancy of at least 6 months
- Eastern Cooperative Oncology Group (ECOG) performance status ≤2
- Patient suitable to receive doxorubicin as assessed by the investigator
- Left ventricular ejection fraction (LVEF) value by echocardiogram or Multiple gated acquisition scanning (MUGA) ≥55%
- Adequate bone marrow, renal, and hepatic function, as evidenced by the following within 7 days of study treatment initiation: a. Absolute neutrophil count (ANC) ≥1,500/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.
- 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
- Patients must be affiliated to a Social Security System (or equivalent)
- 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
Exclusion Criteria
- Previous systemic treatment for advance or metastatic sarcoma
- Previous neoadjuvant or adjuvant anthracycline treatment for localized sarcoma
- 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
- Primary bone sarcoma (including osteosarcoma, Ewing tumor, chondrosarcoma, and chordoma)
- Symptomatic or known central nervous system (CNS) metastases
- 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
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before Day 1 of treatment
- 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
- Uncontrolled grade >2 hypertension. (Systolic blood pressure ≥160 mmHg or diastolic pressure ≥100 mmHg despite optimal medical management)
- Ongoing infection ≥Grade 2 according to NCI Common Terminology Criteria for Adverse Events version (CTCAE v. 5.0)
- Known history of human immunodeficiency virus (HIV) infection
- Known history of chronic hepatitis B or C
- History of organ allograft
- Pre-existing acute hemorrhagic cystitis, urinary tract obstruction, acute urinary tract infection
- 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
- Substance abuse, medical condition, that may interfere with the patient's participation in the study or evaluation of the study results
- Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation
- Inability to swallow oral medications, any malabsorption condition.
- Persons deprived of their liberty or under protective custody or guardianship
- Participation in another therapeutic trial within the 30 days prior to randomization and during the study
- 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
- Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 04 Jun 2021 | 214 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
FILGRASTIM | Other | — | INTRAVENOUS | 5 | 6 | SUB07627MIG |
CYCLOPHOSPHAMIDE | Test | — | ORAL | 200 | 1 | SUB06859MIG |
DOXORUBICIN | Comparator | — | INTRAVENOUS USE | 75 | 18 | SUB06391MIG |
DEXRAZOXANE HYDROCHLORIDE | Other | — | INTRAVENOUS | 750 | 6 | SUB01631MIG |