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

Papillary Thyroid Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01502410
• Other study ID #: NCI-2012-00106
• Secondary ID: NCI-2012-00106CO
• Status: Completed
• Phase: Phase 2
• Start date: January 2012
• Est. completion date: June 2014

Study information

• Verified date: June 2018
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 30 Years

Eligibility

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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Hepatocellular
• Childhood Hepatocellular Carcinoma
• Kidney Neoplasms
• Liver Neoplasms
• 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
• Rhabdomyosarcoma
• Thyroid Diseases
• Thyroid Neoplasms
• Wilms Tumor

Intervention

Drug:
• sorafenib tosylate
Given PO dosage 200 mg/m2/dose (max dose:400 mg/dose) given every 12 hours on days 1-28

Other:
• pharmacological study
Optional correlative studies
• laboratory biomarker analysis
Optional correlative studies

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Centre Hospitalier Universitaire de Quebec	Ste-Foy	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Mark O Hatfield-Warren Grant Magnuson Clinical Center	Bethesda	Maryland
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Dana-Farber Harvard Cancer Center	Boston	Massachusetts
United States	Montefiore Medical Center - Moses Campus	Bronx	New York
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	University of Illinois	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Lee Memorial Health System	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	University of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	University of Kentucky	Lexington	Kentucky
United States	University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Miller Children's Hospital	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Morristown Memorial Hospital	Morristown	New Jersey
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital and Medical Center of Omaha	Omaha	Nebraska
United States	Childrens Hospital of Orange County	Orange	California
United States	Florida Hospital	Orlando	Florida
United States	Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Oncology Group	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	University of California San Francisco Medical Center-Parnassus	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Saint Joseph Children's Hospital of Tampa	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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