Clinical trial NCT01543802: Study of Preoperative Therapy With Pazopanib (Votrient®) to Treat High-risk Soft Tissue Sarcoma
Official title: A Phase II Window-of-opportunity Study of Preoperative Therapy With Pazopanib (Votrient®) in High-risk Soft Tissue Sarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Sarcoma, Soft-tissue
Keywords: soft-tissue sarcoma
pazopanib
antiangiogenetic treatment
endothelial progenitor cells
preoperative therapy
Lead sponsor: Heidelberg University
Sponsor class: OTHER
Collaborators: name: Universitätsmedizin Mannheim
name: Klinikum Frankfurt Höchst
name: German Cancer Research Center
name: GlaxoSmithKline
name: University Hospital Heidelberg
First posted: 2012-03-05
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to examine if a short-term treatment with pazopanib, an oral drug inhibiting the growth of blood vessel, can reduce the metabolism of soft-tissue sarcomas and thus facilitate their resection when given prior to surgery. Moreover, the study assesses the prognostic and predictive value of several new biomarkers (endothelial progenitor cells, soluble vascular epithelial growth factor),


Eligibility criteria: Inclusion Criteria:

1. 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. Non-metastatic primary tumor or locoregional recurrence of histologically confirmed high-risk (G2/3, diameter ≥5 cm) soft tissue sarcoma (STS) of any location (extremities, girdle, trunk, retroperitoneum); or metachronous solitary metastasis of STS for which surgical resection is planned according to the individual choice of the multidisciplinary treatment team (no grade or size restrictions apply for metastasis).
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
5. Measurable disease according to RECIST 1.1
6. Resectable and solitary tumor, as assessed by the investigator based on staging exams (CT scan of the chest, CT or MRI of the abdomen, MRI of the limb in case of extremity STS).
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.
9. Female subjects who are lactating should discontinue nursing prior to the first dose of study drug and should refrain from nursing throughout the treatment period and for 14 days following the last dose of study drug.

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.
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.
6. Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product
7. Corrected QT interval (QTc) \> 480 msecs (calculation according to Bazett).
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.
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 (more than 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 targeting the lesion under study other than incisional biopsy, or tumor embolization, prior to the first dose of pazopanib OR
    * chemotherapy, immunotherapy, biologic therapy, antiangiogenic therapy, investigational therapy or hormonal therapy, targeting the lesion under study, prior to the first dose of pazopanib OR
    * chemotherapy, immunotherapy, biologic therapy, antiangiogenic therapy, investigational therapy or hormonal therapy, targeting any other lesion / disease, within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib
19. Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment.
20. Any ongoing toxicity from prior anti-cancer therapy that is \> grade 1 and/or that is progressing in severity, except alopecia.

Primary outcomes:
measure: Metabolic response rate
timeFrame: day 22-28 (time of post-treatment PET-CT)
Secondary outcomes:
measure: Percentage of tumor tissue with regressive alterations upon resection ("Histopathological Response")
timeFrame: day 28-35
measure: Decrease in tumor size in MRI according to RECIST 1.1 criteria
timeFrame: baseline and day 22-28
measure: Change of FDG influx as well as of transport rates k1-k4 and distribution volume VB and fractal dimension in dynamic PET-CT ("Dynamic PET-CT Response")
timeFrame: baseline and day 22-28
measure: Number of days for which planned resection is delayed after treatment
timeFrame: day 28-35
measure: Number of patients in which adverse events occur during treatment
timeFrame: day 1-21
measure: Disease-free survival
timeFrame: 3 years
measure: Local recurrence-free survival
timeFrame: 3 years
measure: Distant recurrence-free survival
timeFrame: 3 years
measure: Overall survival
timeFrame: 3 years
measure: Decrease in vascularisation in MRI according to adapted Choi Criteria
timeFrame: baseline and day 22-28
measure: Decrease in MRI apparent diffusion coefficient (ADC) values
timeFrame: baseline and day 22-28
Other outcomes:
Locations:
city: Frankfurt am Main
country: Germany
facility: Klinikum Frankfurt-Höchst
city: Heidelberg
country: Germany
facility: German Cancer Research Center, Medical PET Group - Biological Imaging
city: Heidelberg
country: Germany
facility: University Hospital Heidelberg / National Centre for Tumor Diseases
city: Mannheim
country: Germany
facility: University Hospital Mannheim, Dpt. of Surgery
Study officials:
affiliation: University Hospital Mannheim, Department of Surgery
name: Peter Hohenberger, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ronellenfitsch U, Karampinis I, Dimitrakopoulou-Strauss A, Sachpekidis C, Jakob J, Kasper B, Nowak K, Pilz L, Attenberger U, Gaiser T, Derigs HG, Schwarzbach M, Hohenberger P. Preoperative Pazopanib in High-Risk Soft Tissue Sarcoma: Phase II Window-of Opportunity Study of the German Interdisciplinary Sarcoma Group (NOPASS/GISG-04). Ann Surg Oncol. 2019 May;26(5):1332-1339. doi: 10.1245/s10434-019-07183-4. Epub 2019 Mar 6.
citation: Ronellenfitsch U, Dimitrakopoulou-Strauss A, Jakob J, Kasper B, Nowak K, Pilz LR, Attenberger U, Gaiser T, Egerer G, Frohling S, Derigs HG, Schwarzbach M, Hohenberger P. Preoperative therapy with pazopanib in high-risk soft tissue sarcoma: a phase II window-of-opportunity study by the German Interdisciplinary Sarcoma Group (GISG-04/NOPASS). BMJ Open. 2016 Jan 6;6(1):e009558. doi: 10.1136/bmjopen-2015-009558.