Preoperative therapy with a drug targeting tumor blood vessels in high-risk soft tissue tumors (sarcomas)

Phase 1

• Conditions: High-risk soft tissue sarcoma; MedDRA version: 18.1Level: HLTClassification code 10041298Term: Soft tissue sarcomas histology unspecifiedSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 15.1Level: HLGTClassification code 10041299Term: Soft tissue sarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10024628Term: Liposarcomas malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10024190Term: LeiomyosarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10023285Term: Kaposi's sarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10001883Term: Alveolar soft part sarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10025224Term: LymphangiosarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10039023Term: RhabdomyosarcomasSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 18.1Level: HLTClassification code 10016634Term: Fibrosarcomas malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

• Registration Number: EUCTR2011-003745-18-DE
• Lead Sponsor: niversity of Heidelberg

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2012-04-02
• Last Update Posted: 30 October 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 35

Inclusion Criteria

1. Subjects must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow-up.

2. Age = 18 years or legal age of consent if different from 18 years.

3. Histologically confirmed diagnosis of high-risk (G2/3, diameter =5 cm) soft-tissue sarcoma of any location (extremities, girdle, trunk, retroperitoneum). The following soft-tissue sarcoma subtypes are eligible:
- Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma)
- So-called fibrohistiocytic (pleomorphic MFH”, giant cell MFH”, inflammatory MFH”)
- Leiomyosarcoma
- Malignant glomus tumors
- Skeletal muscle (pleomorphic and alveolar rhabdomyosarcoma)
- Vascular (epithelioid haemangioendothelioma, angiosarcoma)
- Uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal sarcoma) excluding chondrosarcoma, Ewing tumors / PNET
- Malignant peripheral nerve sheath tumors
- Malignant solitary fibrous tumors
- Adipocytic sarcoma (all subtypes)
- Undifferentiated soft tissue sarcomas not otherwise specified
- Other types of sarcoma (not listed as ineligible, see exclusion criteria)

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Measurable disease according to RECIST 1.1

6. Resectable and non-metastatic tumor, as assessed by the principal investigator based on staging exams (CT scan of the chest, CT or MRI of the abdomen, MRI of the limb in case of extremity soft-tissue sarcoma).

7. Adequate organ system function.

8. Women of childbearing potential must have a negative serum pregnancy test within 14 days of first dose of study treatment and agree to use effective contraception during the study and until after surgery has been performed.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 27
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 8

Exclusion Criteria

1. The following tumor types are ineligible
- Embryonal rhabdomyosarcoma
- Chondrosarcoma
- Osteosarcoma
- Ewing tumors / PNET
- Gastro-intestinal stromal tumors
- Dermofibromatosis sarcoma protuberans
- Inflammatory myofibroblastic sarcoma
- Malignant mesothelioma

2. Prior malignancy. Note: Subjects who have had another malignancy and have been disease-free for 5 years, and subjects with a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma are eligible.

3. History or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis.

4. Prior or concurrent systemic chemotherapy or molecularly targeted therapy for STS or other malignancies within five years before study entry.

5. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to:
- Active peptic ulcer disease
- Active inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), 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.

6. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to:
- Malabsorption syndrome
- Major resection of the stomach or small bowel

7. Corrected QT interval (QTc) > 480 msecs (see section 6.2).

8. Presence of uncontrolled infection.

9. History of any one or more of the following cardiovascular conditions within the past 6 months:
- Cardiac angioplasty or stenting
- Myocardial infarction
- Unstable angina
- Coronary artery bypass graft surgery
- Symptomatic peripheral vascular disease
- Class III or IV congestive heart failure, as defined by the New York Heart Association (NYHA)

10. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of =140 mmHg or diastolic blood pressure (DBP) of = 90mmHg].

11. Cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.
Note: Subjects with recent DVT who have been therapeutically coagulated for at least 6 weeks are eligible.

12. Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement are not considered to be major surgery).

13. Evidence of active bleeding or bleeding diathesis.

14. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage.

15. Recent hemoptysis (>½ teaspoon of red blood within 8 weeks before first dose of study drug).

16. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures.

17. Inability or unwillingness to discontinue use of prohibited medications for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of investigational product and for the duration of the study.

18. Treatment with any of the following therapies:
- radiation therapy, surgery other than incisional biopsy, or tumor embolization, targeting the lesion under study, prior to the first dose of pazopanib OR
- chemotherapy,

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate whether neoadjuvant treatment with pazopanib in patients with soft-tissue sarcoma has therapeutic effects, measured as metabolic response. ;Secondary Objective: - To assess the safety of preoperative pazopanib treatment in patients undergoing resection of soft-tissue sarcoma.<br><br>- To evaluate potential correlation between metabolic (PET-CT), radiological (MRI) and histopathological assessment of tumor response to pazopanib treatment in soft-tissue sarcoma.;Primary end point(s): Metabolic response rate (MRR), defined as the proportion of patients achieving a metabolic response, i.e. a 50% reduction of the mean standardized uptake value (SUVmean) in the post-treatment compared to the pre-treatment FDG-PET-CT.;Timepoint(s) of evaluation of this end point: 22-28 days after initiation of study treatment

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Histopathological response<br>- MRI response, defined as decrease in size according to RECIST 1.1 criteria, decrease in vascularisation according to adapted Choi Criteria, and decrease in apparent diffusion coefficient (ADC) values <br>- Dynamic PET-CT response: change of FDG influx as well as of transport rates k1-k4 and distribution volume VB and fractal dimension. Absolute values of all parameters of FDG kinetics will be used for discriminant analysis evaluation<br>- R0-resectability<br>- Disease-free survival <br>- Local recurrence-free survival<br>- Distant recurrence-free survival <br>- Overall survival<br>- Toxicity<br>- Delay in planned time to resection;Timepoint(s) of evaluation of this end point: Between 22 days and 5 years after initiation of study treatment, depending on end point