Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well sorafenib tosylate works in treating younger patients with relapsed or refractory rhabdomyosarcoma, Wilms tumor, liver cancer, or thyroid cancer. Sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the objective response rate to sorafenib tosylate (sorafenib) in children with relapsed or refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma (HCC), or papillary thyroid carcinoma (PTC). SECONDARY OBJECTIVES: I. To further define and describe the toxicities of sorafenib administered on an oral, twice-daily continuous schedule. II. To further characterize the pharmacokinetics of sorafenib in children with refractory cancer. III. To estimate the progression-free survival on sorafenib for rhabdomyosarcoma, Wilms tumor, and hepatocellular carcinoma and compare to a group of patients enrolled on selected closed Phase II studies of Children Oncology Group (COG). IV. To assess the biologic activity of sorafenib on vascular endothelial growth factor (VEGF) and soluble vascular endothelial growth factor receptor-2 (VEGFR-2) in peripheral blood samples. (Exploratory) V. To evaluate the presence of BRAF mutations and RET/PTC rearrangements in patients with PTC. (Exploratory) OUTLINE: This is a multicenter study. Patients are stratified according to diagnosis (rhabdomyosarcoma vs Wilms tumor vs hepatocellular carcinoma vs papillary thyroid carcinoma). Patients receive sorafenib tosylate orally (PO) twice daily (BID) on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection at baseline and periodically during study for pharmacokinetic studies, and VEGF and VEGFR-2 analysis by ELISA. Previously collected formalin-fixed paraffin-embedded tissue samples, from patients with papillary thyroid carcinoma, are also analyzed for BRAF mutation and RET/PTC rearrangements by PCR. After completion of study treatment, patients are followed up for up to 5 years.

Official Title
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A Phase II Study of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib in Children and Young Adults With Relapsed/Refractory Rhabdomyosarcoma, Wilms Tumor, Hepatocellular Carcinoma, and Papillary Thyroid Carcinoma

Conditions
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Childhood Hepatocellular Carcinoma, Papillary Thyroid Cancer, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Liver Cancer, Recurrent Childhood Rhabdomyosarcoma, Recurrent Thyroid Cancer, Recurrent Wilms Tumor and Other Childhood Kidney Tumors

Intervention / Treatment
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* Drug: sorafenib tosylate
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have had histologic verification of one of the malignancies listed below at original diagnosis or at relapse: Rhabdomyosarcoma (RMS) Wilms tumor Hepatocellular carcinoma (HCC) Papillary thyroid carcinoma (PTC) Patients must have relapsed or refractory disease (RMS, Wilms tumor, HCC, PTC) Patients must have radiographically measurable disease; measurable disease is defined as the presence of at least one lesion on magnetic resonance imaging (MRI) or computed tomography (CT) scan that can be accurately measured with the longest diameter a minimum of 10 mm in at least one dimension (CT scan slice thickness no greater than 5 mm) The following do not qualify as measurable disease: Malignant fluid collections (e.g., ascites, pleural effusions) Bone marrow infiltration Lesions only detected by nuclear medicine studies (e.g., bone, gallium, or positron emission tomography [PET] scans) Elevated tumor markers in plasma or cerebrospinal fluid(CSF) Previously radiated lesions that have not demonstrated clear progression post radiation Leptomeningeal lesions that do not meet the requirements noted above Patients with HCC must be relapsed or refractory to conventional chemotherapy Patients with PTC must be refractory to radioactive iodine (RAI) Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life Patients with known metastasis to the brain will be excluded from trial participation unless treated surgically or with radiotherapy and stable with no recurrent lesions for at least 3 months Rhabdomyosarcoma and Wilms strata: patients must be ≥ 24 months and ≤ 30 years of age at study enrollment Hepatocellular carcinoma (HCC): patients must be ≥ 24 months and < 18 years of age at study enrollment Papillary thyroid carcinoma (PTC): patients must be ≥ 24 months and ≤ 21 years of age at study enrollment Patients must have a Lansky or Karnofsky performance status score of ≥ 50%, corresponding to ECOG categories 0, 1, or 2 Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score Peripheral absolute neutrophil count (ANC) ≥ 1,000/μL Platelet count ≥ 75,000/μL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to enrollment) Hemoglobin 8.0 g/dL (may receive red blood cell[RBC] transfusions) Creatinine clearance or radioisotope glomerular filtration rate(GFR) 70 mL/min OR a serum creatinine based on age/gender as follows: 0.8 mg/dL (2 to < 6 years of age) 1.0 mg/dL (6 to < 10 years of age) 1.2 mg/dL (10 to < 13 years of age) 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age) 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age) Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age SGPT (ALT) ≤ 135 U/L (for the purpose of this study, the ULN for SGPT is 45 U/L) PT, PTT, and INR < 1.5 times ULN Normal serum lipase and amylase (per institutional normal values) No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there is clinical indication for determination A blood pressure (BP) ≤ the 95^th percentile for age, height, and gender; and not receiving medication for treatment of hypertension Patients who are pregnant or breast-feeding are not eligible Negative pregnancy tests must be obtained in girls who are post-menarchal Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method beginning at the signing of the informed consent until at least 30 days after the last dose of the study drug Patients with clinical symptoms of hepatic encephalopathy or ascites are not eligible Patients who have an uncontrolled infection are not eligible Patients with evidence of bleeding diathesis are not eligible Patients with known Gilbert syndrome are not eligible Patients who, in the opinion of the investigator, may not be able to comply with the safety-monitoring requirements of the study are not eligible No concurrent chemotherapy, radiation therapy, immunomodulating agents, or other investigational agents Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study Patients with solid tumors must not have received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (6 weeks if prior nitrosourea) At least 7 days must have elapsed since the completion of therapy with a growth factor (at least 14 days must have elapsed after receiving pegfilgrastim) At least 7 days must have elapsed since completion of therapy with a biologic agent; For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the time during which adverse events are known to occur At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody At least 2 weeks must have elapsed since local palliative radiotherapy (XRT) (small port); ≥ 3 months must have elapsed if prior craniospinal XRT was received, if ≥ 50% of the pelvis was irradiated, or if TBI was received; ≥ 6 weeks must have elapsed if other substantial bone marrow irradiation was given No evidence of active graft-vs-host disease and ≥ 2 months must have elapsed since transplant (stem cell transplant or rescue without total-body irradiation) For patients with papillary thyroid carcinoma (PTC) only: ≥ 3 weeks from prior radioiodine (RAI) treatment Patients requiring corticosteroids that have not been on a stable or decreasing dose of corticosteroid for 7 days prior to enrollment are not eligible Patients who are currently receiving another investigational drug are not eligible Patients who are currently receiving other anti-cancer agents are not eligible Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either graft-versus-host disease post bone marrow transplant or organ rejection post transplant are not eligible for this trial Patients who take cytochrome P450 enzyme-inducing anti-epileptic drugs (phenytoin, carbamazepine, or phenobarbital), rifampin, grapefruit juice, or St. Johns wort will not be eligible for the trial Patients who have received prior treatment with sorafenib are not eligible Patients must not be on therapeutic anti-coagulation; Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial devices is allowed provided that the requirements for prothrombin time(PT), partial thromboplastin time(PTT), and international normalized ratio(INR) are met

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 30 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 Relapsed/Refractory Rhabdomyosarcoma<br>Patients with relapsed or refractory rhabdomyosarcoma receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. sorafenib tosylate: Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28 pharmacological study: Optional correlative studies laboratory biomarker analysis: Optional correlative studies | Drug: sorafenib tosylate<br>* Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28<br>* Other names: SFN;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|
| Experimental: Group 2 Relapsed/Refractory Wilms tumor<br>Patients with relapsed or refractory Wilms tumor receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. sorafenib tosylate: Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28 pharmacological study: Optional correlative studies laboratory biomarker analysis: Optional correlative studies | Drug: sorafenib tosylate<br>* Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28<br>* Other names: SFN;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|
| Experimental: Group 3 Relapsed/Refractory hepatocellular carcinoma<br>Patients with relapsed or refractory hepatocellular carcinoma receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. sorafenib tosylate: Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28 pharmacological study: Optional correlative studies laboratory biomarker analysis: Optional correlative studies | Drug: sorafenib tosylate<br>* Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28<br>* Other names: SFN;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|
| Experimental: Group 4 Papillary thyroid carcinoma<br>Patients with relapsed or refractory papillary thyroid carcinoma receive sorafenib tosylate PO BID on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. sorafenib tosylate: Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28 pharmacological study: Optional correlative studies laboratory biomarker analysis: Optional correlative studies | Drug: sorafenib tosylate<br>* Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28<br>* Other names: SFN;Other: pharmacological study<br>* Optional correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response by RECIST Criteria v 1.1 | Response rates will be calculated as the number of evaluable patients who are responders. Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD, Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started and Progressive Disease (PD): At least a 20% increase in the sum of the 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. | 6 cycles (168 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival According to RECIST Version 1.1 | Percent probability of being progression free six months following enrollment. Progression-free interval (PFI) will be calculated as the date of enrollment until the end PFI date, where that date is calculated as the date of disease progression, date of death, date of removal of all tumors by surgery or last patient contact, whichever occurs first. | Six months after enrollment | 
| The Number of Patients Who Experience at Least One Grade 3 or Higher CTC Version 4 Toxicity, | Each patient is classified as having experienced grade 3 or higher CTC version 4 toxicity if at any time during protocol therapy such an event is observed for the individual. | six cycles of chemotherapy; expected to be 126 days of treatment | 
| Pharmacokinetic (PK) Parameters of Sorafenib Tosylate | The trough sorafenib concentration is evaluated at baseline (prior to administration of Sorafenib) and 12 hours after administration of Sorafenib on day 15, day 56, day 112 and day 168 in micrograms/ml. | Prior to administration of Sorafenib (baseline), day 15, day 56, day 112 and day 168 | 
| Change in VEGF and VEGFR-2 | Serum VEGF and VEGF receptor 2 Concentration is evaluated at baseline and at day 15 of protocol therapy in picograms/ml. | Prior to the administration of sorafenib (baseline) and day 15 of protocol therapy | 
| Presence of BRAF Mutation or RET/PTC Rearrangement | Descriptive statistics including mean, median, standard deviation, and range will be calculated for baseline for patients with PTC, TG and TG antibody, and presence of BRAF mutation or RET/PTC rearrangement. | At baseline |