Pazopanib Hydrochloride and Topotecan Hydrochloride in Treating Patients with Locally Advanced or Metastatic Soft Tissue and Bone Sarcomas That Cannot Be Removed by Surgery
This phase II trial studies how well pazopanib hydrochloride and topotecan hydrochloride work in treating patients with soft tissue and bone sarcomas that have from where it started to nearby tissue or lymph nodes or have spread to other places in the body and cannot be removed by surgery. Pazopanib hydrochloride and topotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
- 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 or locally advanced, unresectable: * Soft tissue sarcomas (non-liposarcoma) * Osteosarcoma * 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 >= 10 mm with spiral computed tomography (CT) scan
- Cohort 1: Patients must have had a minimum of 1 and a maximum of 4 prior chemotherapy regimens for recurrent/metastatic disease or locally advanced/unresectable disease; it will be up to the investigator to determine what constitutes a “regimen” in each case; Cohort 2: Patients must have had a minimum of 1 and maximum of any number of prior chemotherapy regimens for recurrent/metastatic disease or locally advanced/unresectable disease; Cohort 3: Patients may have had any number of prior therapies for recurrent/metastatic or locally advanced/unresectable disease; there are no restrictions; all cohorts: The last dose of systemic therapy much have been given at least 28 days prior to initiation of therapy; patients receiving carmustine (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 14 days prior to registration)
- Hemoglobin >= 9 g/dL (5.6 mmol/L) (tested within 14 days prior to registration) * Subjects may not have had a transfusion within 7 days of screening assessment
- Platelets >= 100 x 10^9/L (tested within 14 days prior to registration) * 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) (tested within 14 days prior to registration) * 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 (tested within 14 days prior to registration)
- Total bilirubin =< 1.5 x ULN (tested within 14 days prior to registration)
- Alanine amino transferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (tested within 14 days prior to registration) * 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) >= 50 mL/min (tested within 14 days prior to registration)
- Urine protein to creatinine ratio (UPC) < 1 (tested within 14 days prior to registration) * 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
- 24-hour urine protein, if required < 1 g (tested within 14 days prior to registration) * 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
- 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) * 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; electrocardiography (EKG) for screening must be =< 28 days before registration
- 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)
- Left ventricular ejection fraction < 45% in patients with prior anthracycline use or otherwise at risk for left ventricular systolic dysfunction
- Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >= 140 mmHg or diastolic blood pressure [DBP] 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 (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 approved by principal investigator [PI] and the quality assurance monitor [QAM]) in order for a patient to be eligible for the study
- History of 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 treated with therapeutic anticoagulating agents for at least 6 weeks prior to study treatment are eligible
- Major surgery or trauma within 28 days prior to first dose of study treatment 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 strong inducers and inhibitors of CYP450 listed for at least 14 days prior to the first dose of study drug and for the duration of the study; 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 should be used with caution if another alternative drug is not able to be used * Note: If a medication is incorrectly documented as prohibited in this protocol, documentation from the site pharmacist to the contrary will be acceptable for the purposes of registration
- Treatment with any of the following anti-cancer therapies: * Radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of study treatment
- Administration of any non-oncologic investigational drug within 28 days prior to receiving the first dose of therapy
- 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
Locations & Contacts
Contact: Kelly K. Curtis
Contact: Steven Attia
Contact: Mark Agulnik
Contact: Mohammed M. Milhem
Contact: Scott H. Okuno
Trial Objectives and Outline
I. To determine progression free rate at week 12 for patients with soft tissue sarcoma (STS) treated with pazopanib hydrochloride (pazopanib) plus oral topotecan hydrochloride (topotecan).
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.
I. To estimate the correlation of PFR and OS to levels of soluble (s)VEGFR2 and PIGF.
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.
After completion of study treatment, patients are followed up every 6 months for 2 years (patients with progressive disease) or 5 years (patients without progressive disease).
Trial Phase & Type
Secondary IDs NCI-2014-02583, STU00200112
Clinicaltrials.gov ID NCT02357810