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Intensity-Modulated Radiation Therapy and Paclitaxel With or Without Pazopanib Hydrochloride in Treating Patients With Anaplastic Thyroid Cancer

Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIBiomarker/Laboratory analysis, TreatmentTemporarily closed18 and overNCINCI-2011-02614
RTOG-0912, CDR0000688092, U10CA021661, NCT01236547

Trial Description

Summary

This randomized phase II trial is studying the side effects and how well giving intensity-modulated radiation therapy (IMRT) and paclitaxel together with or without pazopanib hydrochloride works in treating patients with anaplastic thyroid cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving radiation therapy and paclitaxel together is more effective with pazopanib hydrochloride in treating thyroid cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To evaluate the safety of IMRT, paclitaxel, and pazopanib. (Run-in component) II. To evaluate and compare overall survival at 1 year from study registration. (Phase II component)

SECONDARY OBJECTIVES:

I. To evaluate local-regional control at 6 and 12 months. (Phase II component) II. To evaluate the rate of grade 4 (Common Terminology Criteria for Adverse Events [CTCAE], v. 4.0) hemorrhage, grade 4 febrile neutropenia, or any grade 5 adverse event assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) III. To evaluate the rates of other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly related to the induction or concurrent treatment components of the protocol regimen. (Phase II component) IV. To evaluate the rate of treatment discontinuation due to toxicity during the induction or concurrent treatment components of the protocol regimen. (Phase II component) V. To evaluate the rate of grade 4 (CTCAE, v. 4.0) hemorrhage or any grade 5 adverse event assessed to be definitely, probably, or possibly related to adjuvant paclitaxel or pazopanib/placebo after concurrent treatment. (Phase II component) VI. To evaluate the rates of other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly related to adjuvant paclitaxel or pazopanib/placebo after concurrent treatment. (Phase II component) VII. To evaluate response (as per Response Evaluation Criteria in Solid Tumors [RECIST]) of the primary site following the treatment component in subjects with measurable disease prior to chemoradiation. (Phase II component)

OUTLINE:

RUN-IN COMPONENT: Patients receive paclitaxel intravenously (IV) over 1 hour once weekly and pazopanib hydrochloride orally (PO) once daily (QD) for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and intensity-modulated radiotherapy (IMRT) 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

RANDOMIZED PHASE II COMPONENT: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

ARM II: Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Eligibility Criteria

Inclusion Criteria:

  • Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a diagnosis that is noted to be "consistent with anaplastic thyroid cancer" with the presence of a thyroid mass is acceptable)
  • If there was a total or partial thyroidectomy completed within 3 months of enrollment, the surgical specimen must show the area of anaplastic thyroid cancer to be at least 1 cm in greatest dimension
  • The following minimum diagnostic workup is required:
  • History/physical examination within 2 weeks prior to registration
  • Imaging of neck and brain (computed tomography [CT] scan or magnetic resonance imaging [MRI]) and chest/abdominal imaging (chest x-ray or chest CT scan, or full body positron emission tomography [PET]/CT are acceptable) within 4 weeks prior to registration
  • NOTE: The CT scan of the neck must be done with contrast or if an MRI is done, with gadolinium; therefore, the CT portion of a full body PET/CT has to be a high resolution CT to be acceptable for eligibility
  • Abdominal imaging must cover the liver and adrenal glands; therefore, separate imaging is not required if these areas are covered by a chest CT scan
  • Electrocardiogram within 10 days prior to registration
  • Zubrod performance status 0-2
  • Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
  • Platelets >= 100,000 cells/mm^3
  • Hemoglobin (Hgb) >= 9.0 g/dL (the use of transfusion or other intervention to achieve Hgb >= 9.0 g/dL is acceptable)
  • Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except for patients with Gilbert syndrome and elevations of indirect bilirubin)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x institutional ULN (patients who have both bilirubin > ULN and AST/ALT > ULN are not eligible unless they have Gilbert syndrome and elevations of indirect bilirubin)
  • Spot urine protein to creatinine ratio (UPCR) < 1 or a 24-hour urine protein collection < 1 gm) within 10 days prior to registration
  • Creatinine < 1.5 mg/dL or within normal institutional limits (if neither criteria is met, the creatinine clearance must be > 50 mL/min^2 per either the Cockcroft-Gault equation, Jeliffe method, or 12- or 24-hour urine collection)
  • Serum electrolytes including sodium, potassium, blood urea nitrogen (BUN), creatinine, glucose, magnesium, phosphate, and calcium within 10 days prior to registration
  • Documentation of the patient's history of QTc prolongation, family history of prolonged QTc, and relevant cardiac disease
  • Evaluation of the patient's medications within 10 days prior to registration with attempt to change any medication that affects cytochrome P450 3A4 (CYP3A4)
  • Blood pressure =< 140/90 within 10 days of registration (must be taken and recorded by a health care professional)
  • If the systolic blood pressure is > 140 and/or diastolic blood pressure is > 90 at the time of registration, the patient's blood pressure must be controlled
  • Systolic blood pressure must be < 140 and diastolic blood pressure must be < 90 on at least 2 separate measurements prior to the start of treatment
  • The treating physician must believe that this is feasible in order to enroll the patient
  • Negative pregnancy test (serum or urine) within 10 days of registration in women of child-bearing potential
  • Women of childbearing potential and male participants who are sexually active must agree to practice adequate contraception during treatment and for 6 months post-treatment
  • The patient must provide study specific informed consent prior to study entry

Exclusion Criteria:

  • Known active invasive malignancy (except for nonmelanomatous skin cancer, differentiated thyroid cancer, or the presence of prostate cancer confined to the prostate with a prostate specific antigen [PSA] =< 1 ng/mL for more than 6 months)
  • Prior systemic chemotherapy for anaplastic thyroid cancer
  • No patients who have had chemotherapy or radiotherapy within 4 weeks of registration (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered > 4 weeks previously
  • Patients receiving other investigational agents
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
  • Patients with any of the following cardiovascular conditions within the past 6 months:
  • Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
  • Admission for unstable angina
  • Myocardial Infarction
  • Cardiac angioplasty or stenting
  • Coronary artery bypass graft surgery
  • Pulmonary embolism, untreated deep venous thrombosis (DVT), or DVT that has been treated with therapeutic anticoagulation for less than 6 weeks
  • Arterial thrombosis
  • Symptomatic peripheral vascular disease
  • Class II-IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (a patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible for the study)
  • Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible
  • Patients with an arrhythmia are excluded; patients with atrial fibrillation, supraventricular tachycardia, or bradycardia are eligible as these conditions must be well controlled with medication or a pacemaker
  • Patients who require heparin (other than low-molecular weight heparin)
  • Patients with any condition that may impair the ability to swallow or absorb oral medications/investigational product including:
  • Prior surgical procedures affecting absorption including, but not limited to, major resection of stomach or small bowel
  • Active peptic ulcer disease
  • Malabsorption syndrome
  • Patients with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including:
  • Active peptic ulcer disease
  • Known intraluminal metastatic lesions
  • Inflammatory bowel disease (e.g., ulcerative colitis, Crohn disease) or other gastrointestinal conditions that increase the risk of perforation
  • History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
  • History of hemoptysis within 30 days of registration
  • Patients who have minimal bleeding from the mouth that is clearly not related to a source in the lungs i.e., surgery such as a non-lung biopsy are eligible only after good hemostasis has been documented
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic
  • Prior allergic reaction to the study drug(s) involved in this protocol
  • QTc prolongation defined as a QTc interval >= 480 msecs or other significant electrocardiogram (EKG) abnormalities are ineligible
  • Known brain metastases
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with pazopanib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
  • Certain medications that act through the CYP450 system are specifically prohibited in patients receiving pazopanib and others should be avoided or administered with extreme caution
  • Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinivir, retonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; although, in exceptional circumstances, they may be administered in conjunction with lowering the dose of pazopanib by 50% of what would otherwise be administered; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib
  • Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are strictly prohibited
  • Medications that have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution

Trial Contact Information

Trial Lead Organizations/Sponsors

National Cancer Institute

Eric ShermanPrincipal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01236547
ClinicalTrials.gov processed this data on February 11, 2014

Note: Information about this trial is from the ClinicalTrials.gov database. The versions designated for health professionals and patients contain the same text. Minor changes may be made to the ClinicalTrials.gov record to standardize the names of study sponsors, sites, and contacts. Cancer.gov only lists sites that are recruiting patients for active trials, whereas ClinicalTrials.gov lists all sites for all trials. Questions and comments regarding the presented information should be directed to ClinicalTrials.gov.

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