Combined Modality Treatment of Sarcomas of the Extremities

Study design A dose escalation trial of Pazopanib, starting at 400mg daily, orally in combination with the standard 25 x 2Gy preoperative radiotherapy in newly diagnosed extremity sarcoma patients. Dose of pazopanib will be escalated via 600mg to maximally 800mg. Overall treatment time of pazopanib is 40 days.

Treatment plan: Pazopanib Dose level Dose of pazopanib orally, once daily, # patients

• (starting) 400 mg 3
• 600 mg 3
• (maximum) 800 mg 3

Treatment plan: radiotherapy RT is given during 5 weeks with a once daily fraction of 2 Gray (50 Gray in 25 daily fractions)

RT planning: The dose planning should be performed by CT based Intensity Modulated RT (IMRT) or 3 Dimensional Conformal RT (3D-RT) according to the local planning protocol of the participating institute.

Dose specification: According to the ICRU 50/62.

Inclusion criteria

• Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma of and localized to the extremities or head and neck area for which the treatment is a combination of both surgery and radiotherapy (deep seated, > 5cm according to the RECIST 1.1 criteria, grade II/III according to the WHO definition).
• Age > 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Absence of 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.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

6 Able to swallow and retain oral medication. 7. A life expectancy of at least 12 weeks. 8. Adequate organ function.

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Exclusion criteria

• Prior malignancies; except subjects who have had another malignancy and have been disease-free for 5 years, or subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.
• Patients with recurrent sarcomas (even without prior radiotherapy).
• Ewing sarcoma and other PNET family tumours, rhabdomyosarcomas (both pediatric and adult), osteosarcomas.
• Clinically significant gastrointestinal abnormalities which might interfere with oral dosing diagnosed as:

• Active peptic ulcer disease.
• Known intraluminal metastatic lesions with suspected bleeding.
• Inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation.
• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
• Major resection of the stomach or small bowel.
• Uncontrolled hypertension.
• Unstable or serious concurrent condition (e.g., active infection requiring systemic therapy).
• Prolongation of corrected QT interval (QTc) >480 msecs.
• History of any one of more of the following cardiovascular conditions within the past 6 months:

• Cardiac angioplasty or stenting.
• Myocardial infarction.
• Unstable angina.
• Symptomatic peripheral vascular disease.
• Coronary artery by-pass graft surgery.
• Class II, III or IV congestive heart failure as defined by the New York Heart Association (NYHA).
• History of cerebrovascular accident, pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
• Macroscopic hematuria
• Haemoptysis that is clinically relevant within 4 weeks of first dose of study drug.
• Evidence of active bleeding or bleeding diathesis.
• Prior major surgery or trauma within 28 days prior to first dose of study drug and/or presence of any non-healing wound, fracture, or ulcer.
• Chemotherapy or radiation therapy within 2 weeks prior to the first dose of study drug.
• Biological therapy or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer prior to the first dose of study drug.
• Prohibited medications listed in the protocol for 14 days or five half-lives of a drug (whichever is longer) prior to Visit 1 and for the duration of the study should not be taken.
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib.
• Pregnancy or lactating.
• Hypothyroidism.

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