Advanced/metastatic soft tissue sarcoma MedDRA version: 20.0 Level: PT Classification code 10075333 Term: Soft tissue sarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Doxorubicin
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Doxorubicin hydrochloride
Other descriptive name: Doxorubicin
Concentration unit: mg/ml milligram(s)/millilit
Sponsors
European Organisation for Research and Treatment of Cancer (EORTC)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Histologically proven advanced unresectable or metastatic soft tissue sarcoma (STS) • Representative formalin fixed, paraffin embedded tumor blocks or slides, either from the primary tumor or a metastatic lesion, must be available for central review. • Age = 65 years of age (patients between 65 and 69 years old are eligible if G8 score = 14; patients = 70 years old are eligible independent of G8 score) • WHO performance status 0 – 2 • Life expectancy based on other significant morbidity of = 6 months • Presence of measurable disease (according to RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT + MRI. • Progressive disease at entry based on RECIST 1.1 • Patients amenable to receive doxorubicin according to investigator's assessment • Adequate haematological and organ function assessed prior to randomization: - Haematological function: * haemoglobin = 9.0 g/dL or 5.6 mmol/L * neutrophils (ANC) = 1.5 x 109/L * platelets = 100 x 109/L - Coagulation: partial thromboplastin time (PTT) = 1.0 times upper limit of normal (1.0 x ULN) of institutional limits and prothrombin time (PT) = 1.0 x ULN of institutional limits - Renal function: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2 (calculated by the MDRD formula); no proteinuria = grade 2 (CTCAE version 5.0); - Hepatic function: bilirubin = 1.0 x ULN of institutional limits, alanine aminotransferase/ serum glutamate-pyruvate transaminase (SGPT) or aspartate aminotransferase/ serum glutamic-oxaloacetic transaminase (SGOT) =1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved. - Cardiac function: clinically normal function based on the institutional lower limit of normal for left ventricular ejection fraction (LVEF) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead electrocardiogram (ECG) without clinically relevant abnormalities. Measurement should include investigator assessment of a potential participant’s risk for heart failure with a validated clinical classification system, i.e. the New York Heart Association Functional Classification. Only patients with NYHA class 1 and 2 are eligible. • Completion of EORTC QLQ-C30 and EORTC QLQ-ELD14. • Assessment of G8 geriatric screening tool • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: - With female partners of childbearing potential, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy. Men must refrain from donating sperm during this same period. Contraception should be considered for the female partners of childbearing potential as well. - With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for a period of 6 months after the last dose of doxorubicin-based chemothera
Exclusion criteria
Exclusion criteria: • Gastrointestinal stromal tumors (GISTs) • Symptomatic or known brain metastasis • Any prior treatment with anthracyclines • Any prior systemic treatment for metastatic STS • Inability to swallow and/ or retain oral tablets • Rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption • Hypersensitivity to doxorubicin, cyclophosphamide, prednisolone or to any of their metabolites or to any of their excipients • Uncontrolled severe illness, including but not limited to: - Congestive heart failure - Angina pectoris - Acute inflammatory heart disease - Myocardial infarction within 1 year before randomization - Arterial hypertension defined as blood pressure = 150/100 mm Hg despite optimal medical therapy - Uncontrolled cardiac arrhythmia - Increased haemorragic tendency - Uncontrolled diabetes - Bone marrow aplasia - Psychosis - Active or uncontrolled infections among which those requiring systemic antibiotics or antimicrobial therapy. - Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow. • Vaccination with live vaccines within 30 days prior to study entry • Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment. • Known contraindication to MRI • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and its active requirements (including completion of questionnaires) and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is to assess whether a higher HRQoL, in terms of impact of the disease and its treatment on physical and role functioning, is achieved with metronomic schedules of doxorubicin or cyclophosphamide plus prednisolone versus the standard doxorubicin treatment.;Secondary Objective: • To assess whether there is an improvement in quality of life, in terms of impact of the disease and its treatment on social, emotional and cognitive functioning as well as self-reported symptoms and overall quality of life/health perception, among patients treated with metronomic doxorubicin, patients treated with metronomic cyclophosphamide plus prednisolone and patients treated with standard doxorubicin regimen. • To assess whether there is a difference in the progression free survival, overall survival and tumor response among patients treated with metronomic doxorubicin, patients treated with metronomic cyclophosphamide plus prednisolone and patients treated with standard doxorubicin regimen. • To assess the toxicity profile of the three treatment arms • To assess the tolerability of the three treatment arms;Primary end point(s): • Difference in physical and role functioning at 12 weeks. • Physical functioning (PF) is one of the functional scale scores of the EORTC QLQ-C30 questionnaire. The scale score is based on the mean score of 5 items measuring patients' self-reported ability to perform physical activities. The scale score can range from 0-100 with higher scores indicating better functioning. • Role functioning (RF) is one of the other functional scale scores of the EORTC QLQ-C30 questionnaire. The scale score is based on the mean score of 2 items measuring patients' self-reported ability to perform daily tasks related to household, work or recreation. The scale score can range from 0-100 with higher scores indicating better functioning.;Timepoint(s) of evaluation of this end point: • Difference in physical and role functioning a | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Difference in all other EORTC QLQ-C30 scales at 12 weeks • Sensitivity: Difference in physical and role functioning at 24 weeks • Difference in progression free survival (PFS) at 12 weeks according to the RECIST 1.1 • Efficacy: PFS, overall survival (OS), tumour response (RECIST 1.1) • Safety: Adverse Events (AEs) according to CTCAE v5.0 • Tolerability: treatment discontinuation, delay and/or reduction;Timepoint(s) of evaluation of this end point: • Difference in all other EORTC QLQ-C30 scales at 12 weeks • Sensitivity: Difference in physical and role functioning at 24 weeks • Difference in progression free survival (PFS) at 12 weeks according to the RECIST 1.1 | — |
Countries
Cyprus, Denmark, Germany, Italy, Jordan, Netherlands, Spain, United Kingdom
Contacts
Public ContactRegulatory Affairs Department
European Organisation for Research and Treatment of Cancer (EORTC)
Outcome results
None listed