Studies

Full description

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).

Health-related quality of life (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.

Inclusion criteria

1. Histologically proven advanced unresectable or metastatic soft tissue sarcoma
2. 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.
3. 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)
4. WHO performance status 0 – 2
5. Life expectancy based on other significant morbidity of ≥ 6 months
6. 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.
7. Progressive disease at entry based on RECIST 1.1
8. Patients amenable to receive doxorubicin according to investigator’s assessment
9. Adequate haematological and organ function assessed prior to randomization:
10. 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

11. 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);

12. 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.

13. 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.

13. Completion of EORTC QLQ-C30 and EORTC QLQ-ELD14 at baseline.

14. Assessment of G8 geriatric screening tool

15. Assessment of Katz Index of Independence in Activities of Daily Living (ADL)

16. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:

17. 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.

18. 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.

19.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

1. Symptomatic or known brain metastasis
2. Any prior treatment with anthracyclines
3. Any prior systemic treatment for metastatic STS
4. Inability to swallow and/ or retain oral tablets
5. Rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
6. Hypersensitivity to doxorubicin, cyclophosphamide, prednisolone or to any of their metabolites or to any of their excipients
7. Uncontrolled severe illness, including but not limited to:
8. Congestive heart failure
9. Angina pectoris
10. Acute inflammatory heart disease
11. Myocardial infarction within 1 year before randomization
12. Arterial hypertension defined as blood pressure ≥ 150/100 mm Hg despite optimal medical therapy
13. Uncontrolled cardiac arrhythmia
14. Increased haemorragic tendency
15. Uncontrolled diabetes
16. Bone marrow aplasia
17. Psychosis
18. Active or uncontrolled infections among which those requiring systemic antibiotics or antimicrobial therapy.
19. Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
20. Vaccination with live vaccines within 30 days prior to study entry
21. 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.
22. Known contraindication to imaging tracer or contrast medium and contraindication to MRI
23. 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

Full Description

To prospectively and retrospectively collect data of patients with bone or soft tissue sarcoma in the Netherlands to improve the knowledge and therefore the treatment care. Besides to create a continuous basis for a large variety of research purposes including prognostic and predictive research, health care policies and cost-effectiveness studies.

Inclusion criteria

1. Age ≥ 18 years
2. Histologically proven bone or soft tissue sarcoma, excluding Gastrointestinal Stromal Tumours

Exclusion criteria

1. Altered mental status that would prohibit the understanding of any giving of informed consent

Locations Netherlands

• Radboudumc
• Radiotherapiegroep

Contact

Name: dr. P.M. Braam
E-mail: p.braam@radboudumc.nl
Phone: +31-243614515
Address: Radboudumc, Geert Grooteplein Zuid 32, 6525 GA Nijmegen

Documenten:

Full description

Currently, soft tissue sarcomas (STS) are preoperatively irradiated in a conventionally fractionated regimen of 25 x 2 Gy in five weeks. Recent radiobiological investigations, however, suggest sensitivity to (modest) hypofractionation. Within this study, patients will be randomized to receive either the conventional schedule of 25 x 2 Gy or a shorter preoperative regimen of 14 x 3 Gy, in the hypothesis that both the postoperative wound complication rate until 30 days after surgery, as well as the local control probability at two years are comparable in both arms.

Inclusion criteria

1. Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, trunk and chest wall or the head and neck area, for which the standard treatment is a combination of and radiotherapy and surgery (deep seated and/or > 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition)
2. Absence of regional and/or distant disease. Patients staged by at least a CT scan of the chest (. Staging may also be performed by FDG-PET scanning and or total body MRI scans. Patients with an uncertain metastatic status (e.g. small indifferent lung nodules) and patients with a low metastatic burden not precluding the application of both preoperative radiotherapy and definitive surgery, are allowed to participate
3. WHO Performance Status ≤ 2
4. Able and willing to undergo preoperative radiotherapy
5. Able and willing to undergo definitive surgery
6. Able and willing to comply with regular follow-up visits
7. Able and willing to complete patient reported outcome questionnaires (health-related quality of life and cost effectiveness)
8. Able and willing to undergo randomization
9. Age ≥ 18 years

Exclusion criteria

1. Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma
2. Patients with recurrent sarcomas who underwent prior radiotherapy to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative RT, patients are eligible)
3. Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), osteosarcomas
4. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
5. Female patients who are pregnant
6. Intention to perform an isolated limb perfusion, instead of a tumor resection
7. Neoadjuvant chemotherapy to be scheduled between end of radiotherapy and definitive surgery (neoadjuvant chemotherapy before radiotherapy is allowed)