Pazopanib Hydrochloride in Treating Patients With Advanced Thyroid Cancer

Phase 2

Completed

Conditions: Recurrent Thyroid Gland Carcinoma
Stage IVA Differentiated Thyroid Gland Carcinoma AJCC v7
Stage IVC Thyroid Gland Anaplastic Carcinoma AJCC v7
Stage III Thyroid Gland Medullary Carcinoma AJCC v7
Stage IVA Thyroid Gland Medullary Carcinoma AJCC v7
Stage IVC Thyroid Gland Medullary Carcinoma AJCC v7
Stage III Differentiated Thyroid Gland Carcinoma AJCC v7
Stage IVA Thyroid Gland Anaplastic Carcinoma AJCC v7
Thyroid Gland Anaplastic Carcinoma
Stage IVB Differentiated Thyroid Gland Carcinoma AJCC v7

Interventions: Drug: Pazopanib Hydrochloride
Other: Laboratory Biomarker Analysis

Registration Number: NCT00625846

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies the side effects and how well pazopanib hydrochloride works in treating patients with advanced thyroid cancer. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by stopping blood flow to the tumor.

Detailed Description: PRIMARY OBJECTIVE:

I. To establish the safety and efficacy of GW786034 (pazopanib hydrochloride) as a therapeutic in patients afflicted with differentiated, medullary and anaplastic thyroid cancers.

CORRELATIVE OBJECTIVES:

I. Assessment of the impact of therapy with GW786034 on serum/plasma vascular endothelial growth factor (VEGF) levels.

II. To explore the potential relationship between changes in thyroglobulin levels and tumor response in patients with advanced differentiated thyroid cancer known to be thyroglobulin antibody negative.

OUTLINE:

Patients receive pazopanib hydrochloride orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 3 years after registration.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 152

Inclusion Criteria

Histologically or cytologically confirmed differentiated, medullary or anaplastic thyroid cancer that is now advanced or metastatic; NOTE: patients with thyroid lymphomas or sarcomas are specifically excluded, as are patients with metastatic disease from other sites of origin to thyroid
Patients with confirmed differentiated thyroid cancer to be enrolled in the expanded/additional differentiated thyroid cancer (DTC) cohort must be thyroglobulin antibody negative
Zero, one or two prior therapeutic regimens (this includes cytotoxic plus non-cytotoxic therapeutic regimens)
Absence of sensitivity to therapeutic radioiodine (differentiated only)
Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan; NOTE: disease that is measurable by physical examination only is not eligible
Life expectancy > 3 months
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2 (Karnofsky >= 60%)
Leukocytes > 3,000/mcL obtained =< 7 days prior to registration
Absolute neutrophil count > 1,500/mcL obtained =< 7 days prior to registration
Platelets > 100,000/mcL obtained =< 7 days prior to registration
Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) obtained =< 7 days prior to registration (if there is reason to believe that the patient has Gilbert's syndrome, the bilirubin can be fractionated; if the fractionated bilirubin is consistent with Gilbert's syndrome and there is no other possible explanation for the elevated indirect bilirubin, the patient may be eligible for the study if and only if the direct bilirubin is =< 1.5 X institutional ULN)
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) < 2.5 X institutional ULN obtained =< 7 days prior to registration
Creatinine =< 1.5 X ULN obtained =< 7 days prior to registration
Proteinuria =< + on urinalysis (may re-check) obtained =< 7 days prior to registration
International normalized ratio (INR) =< 1.2 X the ULN obtained =< 7 days prior to registration
Blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic); initiation or adjustment of BP medication is permitted prior to registration provided that the average of three BP readings at a visit prior to registration is < 140/90 mmHg
Objective evidence of tumor progression in the 6 month period prior to GW786034 initiation as assessed by:
- Unequivocal progression of objectively measured disease on successive appropriate imaging (e.g. CT scan); in cases of uncertainty of tumor progression, the principal investigator of the study will be available to assist in decisions
Women of child-bearing potential must have a negative serum pregnancy test =< 7 days prior to registration; NOTE: women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; effective contraception is required for all fertile participants in the trial
Ability to understand and the willingness to sign a written informed consent document
Willingness to comply with the requirement of the study
Willingness to donate blood for correlative marker studies; (only applicable to sites within the United States)

Exclusion Criteria

Anaplastic, differentiated, medullary: a total of > 2 prior therapeutic regimens (this total includes cytotoxic plus non-cytotoxic regimens); Note: enrollment of anaplastic, differentiated, and medullary patients who have had zero, one or two prior therapeutic regimens (cytotoxic plus non-cytotoxic regimens) is allowed - provided therapy ceased > 21 days prior to registration;
- NOTE: the principal investigator of the study should be contacted in the event of uncertainty related patient eligibility based upon prior therapies
Disease that is measurable by physical examination only
Any of the following:
- Radiotherapy =< 4 weeks prior to registration
- Major surgery =< 4 weeks prior to registration
- Radiotherapy to >= 25% of bone marrow
- Concurrent therapy with octreotide unless tumor progression on this therapy has been demonstrated
Any other ongoing investigational agents
History of allergic reactions attributed to compounds of similar chemical or biologic composition to GW786034 (pazopanib) or other agents used in the study
> +1 proteinuria (< 30 mg/dL) on two consecutive dipstick or other urine assessments taken at least 1 week apart; NOTE: (in cases where questions arise related to disparate proteinuria measurements, the study principal investigator [PI] should be consulted for assistance in determining patient study eligibility)
Corrected QT interval (QTc) prolongation (defined as a QTc interval >= 480 msecs) or other significant electrocardiogram (ECG) abnormalities (e.g. frequent ventricular ectopy, evidence of ongoing myocardial ischemia); NOTE: the principal investigator of the study should be contacted in the event of uncertainty related patient eligibility based upon ECG changes
Receiving cytochrome P450 (CYP) interactive concomitant medications; certain medications that act through the CYP450 system are specifically prohibited in patients receiving GW786034 (pazopanib) because in vitro data indicate that the agent has the potential to interact with the cytochrome P450 isoenzymes cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) and cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); certain other agents should be used with caution
Any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow and retain GSK786034 (pazopanib)
Any of the following conditions:
- Serious or non-healing wound, ulcer, or bone fracture
- History of abdominal fistula, gastrointestinal perforation, active diverticulitis, intra-abdominal abscess or gastrointestinal tract bleeding =< 28 days of registration
- Any history of cerebrovascular accident (CVA) =< 6 months
- Current use of therapeutic warfarin; Note: low molecular weight heparin and prophylactic low-dose warfarin (INR < 1.2 X ULN) are permitted; prothrombin time (PT)/partial thromboplastin time (PTT) must meet the inclusion criteria
- History of myocardial infarction, cardiac arrhythmia, admission for unstable angina, cardiac angioplasty or stenting within the last 12 weeks
- History of venous thrombosis in last 12 weeks
- Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; NOTE: a patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible
- History of bleeding disorder, including patients afflicted with hemophilia, disseminated intravascular coagulation, or any other abnormality of coagulation potentially predisposing patients to bleeding
- Poorly controlled depression or anxiety disorder, or recent (=< 6 months) suicidal ideation
Known active and/or untreated brain metastases and/or brain metastases requiring ongoing therapy (e.g. corticosteroids); NOTE: (because of the poor prognosis often associated with brain metastases and because of the potential risk of bleeding in active brain metastases associated with multi-targeted tyrosine kinase inhibitor therapy, patients with active and/or untreated brain metastases and/or those with brain metastases requiring ongoing therapy - e.g. corticosteroids - are excluded from trial enrollment; enrollment will, however, be permitted in cases of patients with longstanding treated and inactive brain metastases not requiring ongoing therapy, providing that stability of brain metastases has been demonstrated for a period of 3 months or greater as assessed by intracranial imaging - and providing that there is no indication of increased vascularity of the treated metastases by magnetic resonance imaging (MRI) imaging conducted =< 14 days prior to registration; when questions arise related to these criteria, the PI of the trial, Dr. Keith Bible, should be contacted for assistance on eligibility)
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would or might reasonably be expected to limit compliance with study requirements
Pregnant women; NOTE: (breastfeeding should be discontinued if the mother is treated with GW786034/pazopanib)
Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy; NOTE: (appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated)
Receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of GW786034 (pazopanib); NOTE: the eligibility of patients will be determined following review of their case by the principal investigator; efforts should be made to switch patients who are taking enzyme-inducing anticonvulsant agents to other medications
Receiving any concomitant medications that are associated with a risk of QTc prolongation and/or Torsades de Pointes; NOTE: these medications should be discontinued or replaced with drugs that do not carry these risks, if possible

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2 (MTC)	Pazopanib Hydrochloride	Patients with medullary thyroid cancer (MTC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Expansion Cohort (DTC)	Pazopanib Hydrochloride	Patients with confirmed, differentiated thyroid cancer (DTC) who are thyroglobulin antibody negative receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohort 1 (DTC)	Laboratory Biomarker Analysis	Patients with differentiated thyroid cancer (DTC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohort 1 (DTC)	Pazopanib Hydrochloride	Patients with differentiated thyroid cancer (DTC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohort 3 (ATC)	Laboratory Biomarker Analysis	Patients with anaplastic thyroid cancer (ATC) receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Expansion Cohort (DTC)	Laboratory Biomarker Analysis	Patients with confirmed, differentiated thyroid cancer (DTC) who are thyroglobulin antibody negative receive 800 mg pazopanib hydrochloride PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Overall Response Rate (in Cohorts 1-3)	Up to 3 years	The tumor response rate is defined as the percentage of eligible patients who fulfill RECIST 1.0 for a complete or partial response at two consecutive assessments at least 8 weeks apart for patients in Cohorts 1-3. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Confirmed Tumor Response (in the Differentiated Thyroid Cancer Expansion Cohort)	Up to 3 years	The confirmed tumor response rate is defined as the percentage of eligible patients who fulfill RECIST 1.0 for a complete or partial response at two consecutive assessments at least 8 weeks apart for patients with differentiated thyroid cancer who are thyroglobulin antibody negative. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

Name	Time	Method
Progression-Free Survival at 3 Months (Cohort 3 Only)	Time from registration to the date of progression or last follow-up, whichever comes first, assessed up to 3 months	Progression free survival at 3 months (PFS6) is defined as the proportion of patients alive and without progression at 3 months. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.
Toxicity as Measured by the Percentage of Patients Reporting a Grade 3+ Adverse Event Deemed Possibly, Probably, or Definitely Related to Treatment	Up to 3 years	Toxicity (defined as grade 3+ adverse events deemed possibly, probably, or definitely related to treatment) will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The percentage of patients with grade 3+ adverse events deemed possibly, probably, or definitely related to treatment are reported for patients in Cohorts 1-3.
Progression-Free Survival at 6 Months (Cohorts 1 and 2 Only)	Time from registration to the date of progression or last follow-up, whichever comes first, assessed up to 6 months	Progression free survival at 6 months (PFS6) is defined as the proportion of patients alive and without progression at 6 months. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.

Trial Locations

Locations (22): Johns Hopkins University/Sidney Kimmel Cancer Center
🇺🇸
Baltimore, Maryland, United States
Park Nicollet Clinic - Saint Louis Park
🇺🇸
Saint Louis Park, Minnesota, United States
National University Hospital Singapore
🇸🇬
Singapore, Singapore
Johns Hopkins Singapore
🇸🇬
Singapore, Singapore
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Mayo Clinic in Florida
🇺🇸
Jacksonville, Florida, United States
University of Iowa/Holden Comprehensive Cancer Center
🇺🇸
Iowa City, Iowa, United States
Mayo Clinic in Arizona
🇺🇸
Scottsdale, Arizona, United States
National Cancer Centre
🇸🇬
Singapore, Singapore
Minnesota Oncology Hematology PA-Maplewood
🇺🇸
Maplewood, Minnesota, United States
Fairview Ridges Hospital
🇺🇸
Burnsville, Minnesota, United States
Fairview-Southdale Hospital
🇺🇸
Edina, Minnesota, United States
Sir Charles Gairdner Hospital
🇦🇺
Nedlands, Western Australia, Australia
Unity Hospital
🇺🇸
Fridley, Minnesota, United States
Chinese University of Hong Kong-Prince of Wales Hospital
🇨🇳
Shatin, Hong Kong, China
United Hospital
🇺🇸
Saint Paul, Minnesota, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Abbott-Northwestern Hospital
🇺🇸
Minneapolis, Minnesota, United States
University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
University of Wisconsin Hospital and Clinics
🇺🇸
Madison, Wisconsin, United States