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Title A Randomized Phase II Study of Concurrent Intensity Modulated Radiation Therapy (IMRT), Paclitaxel and Pazopanib (NSC 737754)/Placebo, For the Treatment of Anaplastic Thyroid Cancer

IRB RTOG0912

CC CC00120

Hospital Main Campus

Stage N/A

Phase Phase 2

Disease Head and Neck, Thyroid

Drug Paclitaxel , Pazopanib

Description

1. Primary Objective for Run-In Components
   • To evaluate the safety of IMRT, paclitaxel, and pazopanib suspension
2. Primary Objective for Phase II Component
   • To evaluate and compare overall survival at 1 year from study registration
3. Secondary Objectives for Phase II Component
   • To evaluate local-regional control at 6 and 12 months;
   • To evaluate the rate of grade 4 (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;
   • 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;
   • To evaluate the rate of treatment discontinuation due to toxicity during the induction or concurrent treatment components of the protocol regimen;
   • To evaluate response (as per RECIST) of the primary site following the treatment component in subjects with measurable disease prior to chemoradiation.

Inclusion Criteria

1. 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);

   Note: Tissue collection for central review is mandatory (see Section 10.2), but central review is not required for eligibility. Due to the aggressiveness of this disease, treatment will be started prior to central review.

2. 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.
3. The following minimum diagnostic workup is required:
   • History/physical examination within 2 weeks prior to registration;
   • Imaging of neck and brain (CT scan or MRI) and chest/abdominal imaging (chest x-ray or chest CT scan, or full body 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;
4. Zubrod Performance Status 0-2;
5. Age ≥ 18 years of age;
6. CBC/differential within 10 days prior to registration on study, with adequate bone marrow and organ function defined as follows:
   • Absolute neutrophil count (ANC) ≥ 1500 cells/mm³
   • Platelets ≥ 100,000 cells/mm³
   • Hemoglobin ≥ 9.0 g/dl (Note: The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable);
7. Adequate hepatic function within 10 days prior to registration, defined as follows:
   • Total bilirubin < 1.5 x institutional ULN (except for patients with Gilbert’s syndrome and elevations of indirect bilirubin);
   • AST or ALT < 2.5 x institutional ULN; Note: patients who have both bilirubin > ULN and AST/ALT > ULN are not eligible (unless they have Gilbert syndrome and elevations of indirect bilirubin).
8. Adequate renal function, defined as follows:
   • 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; Note: if neither criteria is met, the creatinine clearance must be > 50 ml/min/1.73m² per either 1) the Cockcroft-Gault equation; 2) Jeliffe method; or 3) 12- or 24-hour urine collection.
9. (10/28/10) Serum electrolytes including sodium, potassium, BUN, creatinine, glucose, magnesium, phosphate, and calcium within 10 days prior to registration;
10. Documentation of the patient’s history of QTc prolongation, family history of prolonged QTc, and relevant cardiac disease within 10 days prior to registration;
11. Evaluation of the patient’s medications within 10 days prior to registration with attempt to change any medication that affects CYP3A4 (see Sections 7.5.1.4, 9.2, and Appendix VII).
12. Blood pressure < 140/90 within 10 days of registration (must be taken and recorded by a health care professional); Note: 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 (see Section 4.1.3), and the treating physician must believe that this is feasible in order to enroll the patient.
13. PT/INR/PTT within 1.2 x the upper limit of normal within 10 days prior to registration unless the patient is receiving Coumadin and has a stable INR that is in range for the desired level of anticoagulation;
14. Negative pregnancy test (serum or urine) within 10 days of registration in women of childbearing potential;
15. 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;
16. The patient must provide study specific informed consent prior to study entry.

Exclusion Criteria

1. Known active invasive malignancy (except non-melanomatous skin cancer or anaplastic thyroid cancer; the presence of prostate cancer confined to the prostate with a PSA < 1 for more than 6 months also is allowed);
2. Prior systemic chemotherapy for anaplastic thyroid cancer;
3. 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;
4. Patients receiving other investigational agents.
5. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
6. 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 which has been treated with therapeutic anticoagulation for less than 6 weeks arterial thrombosis;
   • Symptomatic peripheral vascular disease;
   • Class II or IV heart failure as defined by the NYHA functional classification system (see Appendix III); Note: a patient who has a history of Class II heart failure and is asymptomatic on treatment may be considered eligible for the study.
7. 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. Comprehensive lists of agents that that are associated with a risk for QTc prolongation and/or Torsades de Pointes can be found in Appendix VI.
8. Patients who require heparin (other than low-molecular weight heparin);
9. Patients with any condition that may impair the ability to 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.
10. 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’s disease) or other gastrointestinal conditions which increase the risk of perforation;
    • history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 28 days prior to beginning study treatment.
11. History of hemoptysis within 30 days of registration. Note: patients who have minimal bleedingfrom the mouth, which is clearly not related to a source in the lungs, i.e. surgery such as a nonlungbiopsy, are eligible only after good hemostasis has been documented;
12. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements;
13. 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.
14. Prior allergic reaction to the study drug(s) involved in this protocol;
15. QTc prolongation defined as a QTc interval > 480 msecs or other significant EKG abnormalities are ineligible; Note: if unsure about EKG abnormality, the treating physician should discuss this with Drs. Sherman or Bible.
16. Known brain metastasis;
17. 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.
18. 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 (see Section 7.1).
    • Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are strictly prohibited (see Section 7.5.1.4.2).
    • Medications that have narrow therapeutic windows and are substrates of CYP3A4, CYP2D6, or CYP2C8 should be avoided and, if necessary, administered with caution (see Section 7.4).
    • A list of medications that are specifically prohibited or those that should be used with caution during this trial of pazopanib can be found in Section 9.0. Comprehensive lists of agents that could affect pazopanib through the cytochrome P450 system can be found in Appendix VII.