Clinical trial NCT01502410: Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2011-12-30
Enrollment: 20
Sex: ALL
Minimum age (years): 2
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Response by RECIST Criteria v 1.1
timeFrame: 6 cycles (168 days)
Secondary outcomes:
measure: Progression-free Survival According to RECIST Version 1.1
timeFrame: Six months after enrollment
measure: The Number of Patients Who Experience at Least One Grade 3 or Higher CTC Version 4 Toxicity,
timeFrame: six cycles of chemotherapy; expected to be 126 days of treatment
measure: Pharmacokinetic (PK) Parameters of Sorafenib Tosylate
timeFrame: Prior to administration of Sorafenib (baseline), day 15, day 56, day 112 and day 168
measure: Change in VEGF and VEGFR-2
timeFrame: Prior to the administration of sorafenib (baseline) and day 15 of protocol therapy
measure: Presence of BRAF Mutation or RET/PTC Rearrangement
timeFrame: At baseline
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Long Beach
country: United States
facility: Miller Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Madera
country: United States
facility: Children's Hospital Central California
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Denver
country: United States
facility: Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center
state: Colorado
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Fort Myers
country: United States
facility: Lee Memorial Health System
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic - Jacksonville
state: Florida
city: Orlando
country: United States
facility: Florida Hospital
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Clinic - Orlando
state: Florida
city: Pensacola
country: United States
facility: Nemours Children's Clinic - Pensacola
state: Florida
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Tampa
country: United States
facility: Saint Joseph Children's Hospital of Tampa
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii
state: Hawaii
city: Boise
country: United States
facility: Saint Luke's Mountain States Tumor Institute
state: Idaho
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Peoria
country: United States
facility: Saint Jude Midwest Affiliate
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Tulane University Health Sciences Center
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Bethesda
country: United States
facility: Mark O Hatfield-Warren Grant Magnuson Clinical Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Harvard Cancer Center
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University/Karmanos Cancer Institute
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota Medical Center-Fairview
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Children's Hospital and Medical Center of Omaha
state: Nebraska
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Memorial Hospital
state: New Jersey
city: New Brunswick
country: United States
facility: UMDNJ - Robert Wood Johnson University Hospital
state: New Jersey
city: Summit
country: United States
facility: Overlook Hospital
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Bronx
country: United States
facility: Montefiore Medical Center - Moses Campus
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Syracuse
country: United States
facility: State University of New York Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Dayton
country: United States
facility: Dayton Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Oncology Group
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Greenville
country: United States
facility: BI-LO Charities Children's Cancer Center
state: South Carolina
city: Greenville
country: United States
facility: Greenville Cancer Treatment Center
state: South Carolina
city: Knoxville
country: United States
facility: East Tennessee Childrens Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Corpus Christi
country: United States
facility: Driscoll Children's Hospital
state: Texas
city: Dallas
country: United States
facility: Medical City Dallas Hospital
state: Texas
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Norfolk
country: United States
facility: Childrens Hospital-King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Spokane
country: United States
facility: Providence Sacred Heart Medical Center and Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Randwick
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: Hamilton
country: Canada
facility: McMaster Children's Hospital at Hamilton Health Sciences
state: Ontario
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: The Montreal Children's Hospital of the MUHC
state: Quebec
city: Montreal
country: Canada
facility: Centre Hospitalier Universitaire Sainte-Justine
state: Quebec
city: Ste-Foy
country: Canada
facility: Centre Hospitalier Universitaire de Quebec
state: Quebec
Study officials:
affiliation: Children's Oncology Group
name: AeRang Kim, MD
role: PRINCIPAL_INVESTIGATOR
References: