Tolerance: A 3 Arm Randomized Study on Health-related QoL of Elderly Patients With Advanced Soft Tissue Sarcoma

Sponsor

European Organisation for Research and Treatment of Cancer - EORTC (Other)

Overall Status

Recruiting

CT.gov ID

NCT04780464

Collaborator

(none)

185

Enrollment

Locations

Arms

58.6

Anticipated Duration (Months)

92.5

Patients Per Site

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multi-centre, open label, randomized phase 3 selection study (1:2:2 randomization).

After confirmation of the eligibility criteria, 185 patients will be randomized 1:2:2 to either the control arm (doxorubicin 60-75 mg/m² IV every 3 weeks) or experimental arm 1 (doxorubicin 12 mg/m2 IV every week) or experimental arm 2 (cyclophosphamide 100 mg orally BD plus prednisolone 10-20 mg orally on day 1 to day 7 of each 14 day cycle).

HRQoL assessment will be performed every 3 weeks during the first 12 weeks and every 12 weeks thereafter until month 12 after start of treatment.

Disease evaluation will be performed every 12 weeks until progression. The primary endpoint of the study is difference among the study arms in physical and role functioning at 12 weeks.

Condition or Disease	Intervention/Treatment	Phase
Advanced Soft-tissue Sarcoma	Drug: Doxorubicin Drug: Doxorubicin Drug: Cyclophosphamide Oral Product Drug: Prednisolone Drug: Prednisone	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

185 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

a 3 Arm Randomized Study on Health-related Quality of Life of Elderly Patients With Advanced Soft Tissue Sarcoma Undergoing Doxorubicin Alone Every Three Weeks or Doxorubicin Weekly or Cyclophosphamide Plus Predniso(lo)ne Treatment

Actual Study Start Date :

Apr 11, 2022

Anticipated Primary Completion Date :

Jun 1, 2025

Anticipated Study Completion Date :

Mar 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard doxorubicin	Drug: Doxorubicin 60 to 75 mg/m² intravenous, every 3 weeks for max 6 cycles until PD Other Names: Adriamycin;
Experimental: Metronomic doxorubicin	Drug: Doxorubicin 12 mg/m2 intravenous weekly for a maximum of 450 mg/m2 until PD Other Names: Adriamycin;
Experimental: Metronomic oral cyclophosphamide + prednisolone or prednisone	Drug: Cyclophosphamide Oral Product 100 mg BD on day 1 to day 7 of each 14 day cycle until PD Drug: Prednisolone 10-20 mg on day 1 to day 7 of each 14 day cycle until PD Drug: Prednisone 10-20 mg on day 1 to day 7 of each 14 day cycle until PD for those Countries where Prednisolone in tablets is not available

Arm

Intervention/Treatment

Active Comparator: Standard doxorubicin

Drug: Doxorubicin

60 to 75 mg/m² intravenous, every 3 weeks for max 6 cycles until PD

Other Names:

Adriamycin;

Experimental: Metronomic doxorubicin

Drug: Doxorubicin

12 mg/m2 intravenous weekly for a maximum of 450 mg/m2 until PD

Other Names:

Adriamycin;

Experimental: Metronomic oral cyclophosphamide + prednisolone or prednisone

Drug: Cyclophosphamide Oral Product

100 mg BD on day 1 to day 7 of each 14 day cycle until PD

Drug: Prednisolone

10-20 mg on day 1 to day 7 of each 14 day cycle until PD

Drug: Prednisone

10-20 mg on day 1 to day 7 of each 14 day cycle until PD for those Countries where Prednisolone in tablets is not available

Outcome Measures

Primary Outcome Measures

Health-related Quality of Life [4 years after first patient in]
Difference in physical and role functioning at 12 weeks

Secondary Outcome Measures

Tumour response [5.5 years after first patient in]
tumor response according to RECIST criteria (version 1.1)
Progression-free-survival [5.5 years after first patient in]
Progression-free-survival from the date of randomization to the date of first progression or death, whatever comes first
Overall survival [5.5 years after first patient in]
Overall survival from the date of randomization to the date of death, whatever the cause

Eligibility Criteria

Criteria

Ages Eligible for Study:

65 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically proven advanced unresectable or metastatic soft tissue sarcoma
Representative formalin fixed, paraffin embedded tumor blocks or a minimum of 10 unstained tissue slides, either from the primary tumor or a metastatic lesion, must be available for histological central review. Histological central review is not required before treatment start but it is mandatory to send at least 10 unstained tumor slides (blocks optional) at time of study entry. Local histopathological diagnosis will be accepted for entry into this trial.
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
absolute neutrophil count (ANC) ≥ 1.5 x 109/L
platelet count ≥ 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 in appendix E); no proteinuria ≥ grade 2 (CTCAE version 5.0);
Hepatic function: bilirubin ≤ 1.0 x ULN of institutional limits, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤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 according to appendix D are eligible.
Completion of EORTC QLQ-C30 and EORTC QLQ-ELD14 at baseline.
Assessment of G8 geriatric screening tool
Assessment of Katz Index of Independence in Activities of Daily Living (ADL)
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 chemotherapy and for a period of 12 months after the last dose of cyclophosphamide-based chemotherapy to avoid exposing the embryo.
Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations including commitment to completing questionnaires during the course of the study.

Exclusion Criteria:

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 of the investigational regimen are not eligible for this trial.
Known contraindication to imaging tracer or contrast medium and 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