Pazopanib as Front-Line Therapy in Patients With Non-Resectable or Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy

Study Overview
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Brief Summary
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Pazopanib is FDA approved as a second line and beyond treatment for metastatic soft tissue sarcoma. There is a population of elderly and debilitated soft tissue sarcoma patients that are not fit for standard first line chemotherapy that is doxorubicin based. As pazopanib is well tolerated with minimal side effects, the investigators propose a phase II study to evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic disease who are not candidates for cytotoxic chemotherapy.

Official Title
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A Phase II Study of Pazopanib as Front-Line Therapy in Patients With Non-Resectable or Metastatic Soft Tissue Sarcomas Who Are Not Candidates for Chemotherapy

Conditions
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Sarcoma, Soft Tissue, Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: Pazopanib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of nonresectable or metastatic soft tissue sarcoma. The following histologies are excluded: embryonal rhabdomyosarcoma, chondrosarcoma, osteosarcoma, Ewing tumors, primitive neuroectodermal tumors, gastrointestinal stromal tumors, dermatofibrosarcoma protuberans, inflammatory myofibroblastic sarcoma, and mixed mesodermal tumors of the uterus. Evaluable disease by imaging or physical exam OR measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam. Not a candidate for chemotherapy as determined by treatment physician Age ≥ 18 years ECOG performance status ≤ 2 Normal bone marrow and organ function as defined below: Absolute neutrophil count ≥ 1,500/mcl Platelets ≥ 100,000/mcl Hemoglobin ≥ 9.0 g/dL PT or INR ≤ 1.2 x IULN (if not receiving anticoagulation therapy) PTT ≤ 1.2 x IULN (if not receiving anticoagulation therapy) Total bilirubin ≤ 1.5 x IULN or ≤ 3.0 x IULN with normal AST and ALT in patients with Gilbert's disease AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for patients with creatinine levels above 1.5 mg/dL UPC < 1 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for renal function assessment is not acceptable. Notes: Subjects may not have had a transfusion within 7 days of screening assessments. Concomitant elevation of bilirubin and AST/ALT above the IULN is not allowed. Patients receiving anticoagulation therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation. Ability to swallow and retain oral tablets. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. Ability to understand and willingness to sign an IRB approved written informed consent document. Exclusion Criteria: Eligible for cytotoxic chemotherapy. Prior systemic therapy for this type of sarcoma. Neoadjuvant or adjuvant therapy more than two years prior would not apply. Prior treatment with any VEGFR tyrosine kinase inhibitor. Administration of any non-oncologic investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of pazopanib. Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study treatment A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix. Known brain metastases. A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pazopanib or other agents used in the study. Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity (except alopecia). Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled seizure disorder, or psychiatric illness/social situations that would limit compliance with study requirements. Corrected QT interval (QTc) > 480 msecs. History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure as defined by the New York Heart Association Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg or diastolic blood pressure of ≥ 90 mmHg). Note: initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure must be reassessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between antihypertensive medication initiation or adjustment and blood pressure measurement. These three values should be averaged to obtain the mean diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a patient to be eligible for the study. Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease, known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other GI conditions with increased risk of perforation, history of abdominal fistula or intra-abdominal abscess within 28 days prior to beginning study treatment. Clinically significant gastrointestinal abnormalities that may affect absorption of pazopanib, including (but not limited to) malabsorption syndrome or major resection of the stomach or small bowel. History of cerebrovascular accident including transient ischemic attack, pulmonary embolism (PE) (including asymptomatic or previously treated PE), or untreated deep venous thrombosis within the past 6 months. Patients with DVT who are being treated with therapeutic anti-coagulating agents are eligible. Major surgery or trauma within 28 days prior to first dose of pazopanib and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery). Evidence of active bleeding or bleeding diathesis. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. Note: lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions). Large protruding endobronchial lesions in the mail or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed. Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of thee bronchi are allowed. Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of pazopanib). Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test within 14 days of study entry. Known HIV-positivity. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pazopanib<br>Pazopanib will be started at a dose of 200 mg BID for four days, then escalated to a dose of 400 mg BID for four days, then escalated once more to a dose of 800 mg QD for the duration of participation (or until dose reduction, if necessary). Pazopanib should be taken orally without food at least one hour before or two hours after a meal. One cycle of pazopanib is 28 days. | Drug: Pazopanib<br> <br> * Other names: Votrien;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate | Clinical benefit rate = complete response (CR) + partial response (PR) + stable disease (SD) CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). | Until disease progression (median follow-up of 10.83 months with full range 0.787-42.26 months) | 
| Overall Survival (OS) |  | Until death (median follow-up of 10.83 months with full range 0.787-42.26 months) | 
| Median Overall Change in Quality of Life | Quality of life will be measured using the Functional Assessment of Cancer Therapy-General (FACT-G7) validated survey 7 statements where the participant can indicate 0 (not at all) up to 4 (very much). The statements include 1) I have lack of energy; 2) I have pain; 3) I have nausea; 4) I worry that my condition will get worse; 5) I am sleeping well; 6) I am able to enjoy life; 7) I am content with the quality of my life right now. The first 4 statements will negatively affect the total score and the last 3 statements will positively affect the total score Each item is scored and then added together, multiplied by 7, and divided by the number of items Total score calculation ranges from 0-28. The higher the score, the better the quality of life | Change from baseline to end of treatment (median length of treatment 70 days (5-515 days))) | 
| Clinical Outcome Associated With Serum sVEGFR2 Levels (Serum Levels of sVEGFR2 at Each Time Point Will Plotted and Pearson or Spearman's Correlation Coefficient) | The serum levels of sVEGFR2 at each time point will plotted and Pearson or Spearman's correlation coefficient will be calculated to explore their relationship. | From baseline through completion of treatment | 
| Clinical Outcome Associated With Serum PICG Levels (Serum Levels of PIGF at Each Time Point Will Plotted and Pearson or Spearman's Correlation Coefficient) | The serum levels of PIGF at each time point will plotted and Pearson or Spearman's correlation coefficient will be calculated to explore their relationship. | From baseline through completion of treatment |