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

This study has been completed.
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: December 29, 2011
Last updated: June 16, 2014
Last verified: December 2013

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.

Condition Intervention Phase
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
Drug: sorafenib tosylate
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Objective response by RECIST criteria v 1.1 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed according to the method of Chang

Secondary Outcome Measures:
  • Progression-free survival according to RECIST version 1.1 [ Time Frame: From date of enrollment to the date of disease progression, date of death, date of removal of all tumor by surgery or last patient contact, whichever occurs first, assessed up to 5 years ] [ Designated as safety issue: No ]
    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.

  • Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Pharmacokinetic (PK) parameters of sorafenib tosylate [ Time Frame: At baseline, up to 12 hours and on day 15 of course 1, and prior to odd courses ] [ Designated as safety issue: No ]
    The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).

  • Change in VEGF and VEGFR-2 [ Time Frame: From baseline to day 15 of course 1 ] [ Designated as safety issue: No ]
    Descriptive statistics including mean, median, standard deviation, and range will be calculated for baseline and steady state VEGF and VEGFR-2. Changes from baseline to steady state on treatment with sorafenib will be evaluated using non-parametric paired tests if there is evidence of intra-patient correlation as assessed by Spearman's rank correlation.

  • Presence of BRAF mutation or RET/PTC rearrangement [ Time Frame: At baseline ] [ Designated as safety issue: No ]
    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.

Enrollment: 20
Study Start Date: January 2012
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (sorafenib tosylate)
Patients 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.
Drug: sorafenib tosylate
Given PO
Other Names:
  • BAY 43-9006
  • BAY 43-9006 Tosylate Salt
  • BAY 54-9085
  • Nexavar
  • SFN
Other: pharmacological study
Optional correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Optional correlative studies

Detailed Description:


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).


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.


Ages Eligible for Study:   2 Years to 30 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT01502410

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Sponsors and Collaborators
Principal Investigator: AeRang Kim Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI) Identifier: NCT01502410     History of Changes
Other Study ID Numbers: NCI-2012-00106, NCI-2012-00106, COG-ADVL1121, CDR0000721611, ADVL1121, ADVL1121, U10CA098543
Study First Received: December 29, 2011
Last Updated: June 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Hepatocellular
Kidney Neoplasms
Liver Neoplasms
Rhabdomyosarcoma, Embryonal
Thyroid Diseases
Thyroid Neoplasms
Wilms Tumor
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Genetic Diseases, Inborn
Head and Neck Neoplasms
Kidney Diseases
Liver Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Complex and Mixed
Neoplasms, Connective and Soft Tissue
Neoplasms, Glandular and Epithelial
Neoplasms, Muscle Tissue
Neoplastic Syndromes, Hereditary
Urogenital Neoplasms
Urologic Diseases processed this record on April 23, 2015