Pazopanib Hydrochloride and Topotecan Hydrochloride in Treating Patients With Metastatic Soft Tissue and Bone Sarcomas

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical research study is to learn if pazopanib when given in combination with topotecan can help to control sarcomas. The safety of this drug combination will also be studied. Pazopanib hydrochloride and topotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To determine progression free rate at week 12 for patients with soft tissue sarcoma (STS) treated with pazopanib (pazopanib hydrochloride) plus oral topotecan (topotecan hydrochloride). SECONDARY OBJECTIVES: I. To determine the overall response rate for patients with STS treated with combination pazopanib and topotecan. II. To determine the clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]) for patients with STS treated with combination pazopanib and topotecan. III. To determine median progression-free rate (PFR) for patients with STS treated with combination pazopanib and topotecan. IV. To evaluate overall survival (OS) for patients with STS treated with combination pazopanib and topotecan. V. To assess safety and tolerability for patients treated with combination pazopanib and topotecan. VI. To estimate the PFR for patients with osteosarcoma treated with combination pazopanib and topotecan. VII. To estimate the PFR for patients with liposarcoma treated with combination pazopanib and topotecan. TERTIARY OBJECTIVES: I. To estimate the correlation of PFR and OS to levels of soluble vascular endothelial growth factor receptor 2 (sVEGFR2) and phosphatidylinositol-glycan biosynthesis class F (PIGF). OUTLINE: Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28 and topotecan hydrochloride PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or until discontinuation per patient preference or physician recommendation. After completion of study treatment, patients are followed up every 6 months for 2 or 5 years.

Official Title
-----------------
A Phase II Study of Pazopanib With Oral Topotecan in Patients With Metastatic and Non-resectable Soft Tissue and Bone Sarcomas

Conditions
-----------------
Adult Liposarcoma, Metastatic Liposarcoma, Metastatic Osteosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Liposarcoma, Recurrent Osteosarcoma, Stage IV Adult Soft Tissue Sarcoma

Intervention / Treatment
-----------------
* Drug: Pazopanib Hydrochloride
* Drug: Oral Topotecan Hydrochloride
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients 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 Patients must have a histologically confirmed diagnosis of: Metastatic soft tissue sarcomas (non-liposarcoma) Metastatic osteosarcoma Metastatic liposarcoma- high grade, de-differentiated, or myxoid Note: pathology is not required to be reviewed at the treating institution; a copy of the pathology report is sufficient for eligibility purposes Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Patients must have measurable disease within 4 weeks prior to registration by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10mm with spiral computed tomography (CT) scan Patients must have had a minimum of 1 and a maximum of 4 prior chemotherapy regimens for recurrent/metastatic disease; it will be up to the investigator to determine what constitutes a regimen in each case; the last dose of systemic therapy much have been given at least 4 weeks prior to initiation of therapy; patients receiving BCNU or mitomycin C must have received their last dose at least 6 weeks prior to initiation of therapy Patients with brain metastasis are eligible for participation only if they have been treated with definitive surgery or radiation (surgery ± radiotherapy, radiosurgery, or gamma knife) and meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids or enzyme-inducing anticonvulsants in prior 12 week interval Absolute neutrophil count (ANC) >= 1.5 X 10^9/L (tested within 7 days prior to Registration) Hemoglobin >= 9 g/dL (5.6 mmol/L) Subjects may not have had a transfusion within 7 days of screening assessment Platelets >= 100 X 10^9/L Subjects may not have had a transfusion within 7 days of screening assessment Prothrombin time (PT) or international normalized ratio (INR) =< 1.2 X upper limit of normal (ULN) Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range for the desired level of anticoagulation Activated partial thromboplastin time (aPTT) =< 1.2 X ULN Total bilirubin =< 1.5 X ULN Alanine amino transferase (ALT) and aspartate aminotransferase (AST) =< 2.5 X ULN Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted Serum creatinine =< 1.5 mg/dL (133 umol/L) or, if > 1.5 mg/dL: calculated creatinine clearance (ClCR) >= 30 mL/min to >= 50 mL/min Urine protein to creatinine ratio (UPC) < 1 If UPC >= 1, then a 24-hour urine protein must be assessed; subjects must have a 24-hour urine protein value < 1 g to be eligible; use of urine dipstick for renal function assessment is not acceptable Females of child-bearing potential (FOCBP) and males must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 30 days following completion of therapy; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; Note: a FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) FOCBP must have a negative pregnancy test within 7 days prior to registration on study Note: female patients 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 Are able to swallow and retain oral tablets Exclusion Criteria: Patients with any of the following sarcoma histologic subtypes will not be eligible for participation: Alveolar soft-part sarcoma Chondrosarcoma Dermatofibrosarcoma Ewing sarcoma Gastrointestinal stromal tumor (GIST) Kaposi sarcoma (non-human immunodeficiency virus [HIV] and HIV related disease) Mixed mesodermal tumor/carcinosarcoma Low grade (grade 1) sarcomas Rhabdomyosarcoma (embryonal, alveolar, pleomorphic) Interdigitating dendritic sarcoma Giant cell tumor of the bone Patients must not have received prior treatment with pazopanib or topotecan Patients must not have an active secondary malignancy Prior malignancy, unless they have been disease-free for 3 years, or have a history of completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: Active peptic ulcer disease Known intraluminal metastatic lesion/s with risk of bleeding 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 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 Corrected QT interval (QTc) > 480 msecs using Bazett's formula History of any one or more of the following cardiovascular conditions within the past 12 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) Poorly controlled hypertension [defined as systolic blood pressure (SBP) of >= 140 mmHg or diastolic blood pressure (DBP) of >= 90mmHg Note: initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry; following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals; at least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement; these three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure; the mean SBP / DBP ratio must be < 140/90 mmHg (or 150/90 mm Hg, if this criterion deemed safe by principal investigator [PI] and the quality assurance monitor [QAM]) in order for a patient to be eligible for the study Patients with a history of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism, or untreated deep venous thrombosis (DVT); patients with DVT must have received appropriate therapy for at least 6 months to be considered eligible 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 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 Large protruding endobronchial lesions in the main 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 the bronchi are allowed Recent hemoptysis (>= 1/2 teaspoon [2.5 mL]) of red blood within 8 weeks before first dose of study drug Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with patient's safety, provision of informed consent, or compliance to study procedures Unable or unwilling to discontinue use of inducers and inhibitors of cytochrome P450 (CYP450) listed for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study; cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrates can be administered, but investigators will need to be aware of possible increased or decreased effectiveness of the non-study drug and this should be recorded in concomitant medications; breast cancer resistance protein (BCRP) and p-glycoprotein (PgP) inducers and inhibitors will be also prohibited Treatment with any of the following anti-cancer therapies: Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of therapy Chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of therapy 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 Any ongoing toxicity related to prior anti-cancer therapy that is > grade 1 and/or that is progressing in severity (exceptions include alopecia, fatigue, and hematologic toxicities) Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to pazopanib or topotecan

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pazopanib hydrochloride, topotecan hydrochloride)<br>Patients receive pazopanib hydrochloride PO QD on days 1-28 and topotecan hydrochloride PO on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Pazopanib Hydrochloride<br>* Given PO<br>* Other names: Votrient;Drug: Oral Topotecan Hydrochloride<br>* Given PO<br>* Other names: Oral Hycamtin;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival at 12 Weeks for Patients With Soft Tissue Sarcoma (STS) Treated With Pazopanib and Oral Topotecan | PFS will be defined from the time of enrollment to the study until progression of disease or death from any cause, as assessed by RECIST 1.1 and measured at 12 weeks after treatment initiation for patients with STS. PFS estimates will be calculated using Kaplan-Meier methods Progression is defined as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression. | At 12 weeks from treatment initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) for Patients With Soft Tissue Sarcoma (STS) Treated With Combination Pazopanib and Topotecan. | ORR is defined as the percentage of patients with Complete Response (CR) plus those with Partial Response (PR) as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients best response to treatment will be used in ORR. Complete Response - Disappearance of all target and non target lesions Partial Response - At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD | During treatment, assessed at 6 weeks, 12 weeks, 20 weeks and then every 2 cycles where one cycle = 28 days and range of cycles completed by patients 1-33. | 
| Clinical Benefit Rate (CBR) for Patients With Soft Tissue Sarcoma (STS) Treated With Combination Pazopanib and Topotecan. | CBR is defined as the percentage of patients with Complete Response (CR) plus those with Partial Response (PR) plus those with Stable Disease (SD) as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Patients best response to treatment will be used in CBR where, in general the following definitions are used: Complete Response - Disappearance of all target and non target lesions Partial Response - At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum LD since the treatment started. | During treatment, assessed at 6 weeks, 12 weeks, 20 weeks and then every 2 cycles where one cycle = 28 days and range of cycles completed by patients 1-33. | 
| Overall Survival (OS) for Patients With Soft Tissue Sarcoma (STS) Treated With Combination Pazopanib and Topotecan. | OS will be defined from start of study until death from any cause and estimates will be calculated using Kaplan-Meier methods. At time of Kaplan-meier calculations patients included the analysis who have not experienced the event will be censored at the last date of documentation of survival status. | During treatment where one cycle = 28 days and range of cycles completed by patients 1-33, then for 2 years (for patients with progression) and 5 years (for patients without progression) following discontinuation of treatment | 
| Number of Patients With Significant Adverse Events, Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 | Toxicities will be tabulated and summarized by the number of patients experiencing each toxicity at grade 3 or grade 4 | From treatment initiation until 30 days post last treatment, at the beginning of each cycle where 1 cycle=28 days. Range of cycles completed by patients 1-33 cycles | 
| Median Progression Free Survival (PFS) for Patients With Soft Tissue Sarcoma (STS) Treated With Combination Pazopanib and Topotecan. | PFS will be defined from the time of enrollment to the study until progression of disease or death from any cause, as assessed by RECIST 1.1. PFS estimates will be calculated using Kaplan-Meier methods. Patients included in the analysis, who did not experiences the event at the time of the calculation were censored from the last documentation of being progression free. Progression is defined as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression. | During treatment, assessed at 6 weeks, 12 weeks, 20 weeks and then every 2 cycles where one cycle = 28 days and range of cycles completed by patients 1-33. And then for up to 5 years post treatment discontinuation. | 
| Progression Free Survival in Patients With Osteosarcoma Treated With Combination Pazopanib and Topotecan. | PFS will be defined from the time of enrollment to the study until progression of disease or death from any cause, as assessed by RECIST 1.1. PFS estimates will be calculated using Kaplan-Meier methods. Patients included in the analysis, who did not experiences the event at the time of the calculation were censored from the last documentation of being progression free. Progression is defined as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression. | During treatment, assessed at 6 weeks, 12 weeks, 20 weeks and then every 2 cycles where one cycle = 28 days and range of cycles completed by patients 1-33. Then for up to 5 years post treatment discontinuation | 
| Progression Free Survival for Patients With Liposarcoma Treated With Combination Pazopanib and Topotecan. | PFS will be defined from the time of enrollment to the study until progression of disease or death from any cause, as assessed by RECIST 1.1. PFS estimates will be calculated using Kaplan-Meier methods. Patients who did not experiences the event at the time of the calculation were censored from the last documentation of being progression free. Progression is defined as at least a 20% increase in the sum of the Longest Diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Progression must also involve an increase in size of measurable lesions by at least 5 mm, to minimize the possibility that small changes in a small number of target lesions is falsely interpreted as progression. | During treatment, assessed at 6 weeks, 12 weeks, 20 weeks and then every 2 cycles where one cycle = 28 days and range of cycles completed by patients 1-33. Then up to 5 years post treatment discontinuation. |