Reacquisition of Radioactive Iodine (RAI) Uptake of RAI-Refractory Metastatic Thyroid Cancers by Pretreatment With the Selective MEK Inhibitor AZD6244 - Full Text View

Sponsor:	Memorial Sloan-Kettering Cancer Center
Collaborators:	Genzyme AstraZeneca
Information provided by (Responsible Party):	Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:	NCT00970359

Purpose

The purpose of this study is to find out if the drug AZD6244 can improve the radioactive iodine uptake by the patient's metastatic thyroid cancer. The investigator will also be testing the tumor specimen taken at the time of your surgery for specific genetic changes to see if one of them in particular (the BRAF oncogene) makes your cancer more likely to become sensitive to radioactive iodine after treatment with the drug.

The investigators want to find out if AZD6244 helps to increase the entry of radioactive iodine into thyroid cancer cells that have spread and are resistant to radioactive iodine therapy, especially if they have the BRAF mutation. To measure how much iodine can enter your cancer, the investigators will use iodine-124, a different form of radioactive iodine. Iodine-124 allows the investigators to measure precisely how much radioactivity can enter the cancer cells, whereas iodine-131 does not. The process of scanning with iodine-124 is called "lesional dosimetry". Iodine-124 is an investigational agent approved by the FDA (Food and Drug Administration) for use in this research study.

Condition	Intervention
Thyroid Cancer	Biological: AZD6244

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Reacquisition of RAI Uptake of RAI-Refractory Metastatic Thyroid Cancers by Pretreatment With the Selective MEK Inhibitor AZD6244: A Pilot Study

Resource links provided by NLM:

MedlinePlus related topics: Cancer Thyroid Cancer Thyroid Diseases

Drug Information available for: Cadexomer iodine Iodine Thyroid

U.S. FDA Resources

Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:

Determine whether RAI uptake in thyroid cancer mets increases after 4 weeks tx with the selective MEK inhibitor AZD6244 in patients with RAI-refractory thyroid cancer. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To determine whether the reacquisition of RAI uptake following AZD6244 treatment results in decrease of size of the thyroid cancer metastases once a treatment with 131I is administered. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

To determine whether treatment with 131I following AZD6244 is accompanied by decrease in serum thyroglobulin. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
To determine whether BRAF mutant tumors are more susceptible to AZD6244 mediated enhancement of RAI uptake compared to BRAF wild-type tumors [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	20
Study Start Date:	September 2009
Estimated Study Completion Date:	September 2012
Estimated Primary Completion Date:	September 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: pts with thyroid cancer with BRAF mutation This is a pilot study involving patients with RAI-refractory metastatic thyroid cancer. Patients meeting inclusion criteria will have their tumor genotyped for BRAF mutational status. Lesional dosimetry will be performed at baseline using 124I-PET, and treatment with the selective MEK inhibitor will be initiated immediately thereafter for 4 weeks. Lesional dosimetry with 124I-PET will be repeated after 4 weeks treatment with the MEK inhibitor (provided there are no AZD6244 delays in treatment) to determine if there has been a significant increase in 124I uptake in the metastatic tumor. Treatment with 131I will be offered to patients whose 124I uptake predicts that a 131I therapeutic dose would deliver > 2000 cGy to the tumor mass.	Biological: AZD6244 Within 1 week of starting the study: Low iodine diet The patient will receive three bottles of capsules containing the drug AZD6244. Each capsule contains 25 milligrams of AZD6244. They will take 3 capsules orally, by mouth twice a day for 4 weeks. AZD6244 should be taken on an empty stomach (either one hour before or 2 hours after meals). AZD6244 capsules should be taken with water only. Lesional dosimetry with iodine-124 PET will be done twice, at the beginning and at the end of the study. This is done the same way that a radioactive iodine scan is done and is spread out over 5 days. It requires injection with human recombinant TSH (Thyrogen) on day 1 and 2, as well as blood tests on day 1 and day 5. On day 3, you will receive the iodine-124 in form of an oral drink, and the PET scan will be obtained on day 5. You will need to follow a low iodine diet starting 5 days before and throughout the process.
Experimental: pts with thyroid cancer without BRAF mutation This is a pilot study involving patients with RAI-refractory metastatic thyroid cancer. Patients meeting inclusion criteria will have their tumor genotyped for BRAF mutational status. Lesional dosimetry will be performed at baseline using 124I-PET, and treatment with the selective MEK inhibitor AZD6244 will be initiated immediately thereafter for 4 weeks. Lesional dosimetry with 124I-PET will be repeated after 4 weeks treatment with the MEK inhibitor (provided there are no AZD6244 delays in treatment) to determine if there has been a significant increase in 124I uptake in the metastatic tumor. Treatment with 131I will be offered to patients whose 124I uptake predicts that a 131I therapeutic dose would deliver > 2000 cGy to the tumor mass.	Biological: AZD6244 Within 1 week of starting the study: Low iodine diet The patient will receive three bottles of capsules containing the drug AZD6244. Each capsule contains 25 milligrams of AZD6244. They will take 3 capsules orally, by mouth twice a day for 4 weeks. AZD6244 should be taken on an empty stomach (either one hour before or 2 hours after meals). AZD6244 capsules should be taken with water only. Lesional dosimetry with iodine-124 PET will be done twice, at the beginning and at the end of the study. This is done the same way that a radioactive iodine scan is done and is spread out over 5 days. It requires injection with human recombinant TSH (Thyrogen) on day 1 and 2, as well as blood tests on day 1 and day 5. On day 3, you will receive the iodine-124 in form of an oral drink, and the PET scan will be obtained on day 5. You will need to follow a low iodine diet starting 5 days before and throughout the process.

Arms

Assigned Interventions

Experimental: pts with thyroid cancer with BRAF mutation

This is a pilot study involving patients with RAI-refractory metastatic thyroid cancer. Patients meeting inclusion criteria will have their tumor genotyped for BRAF mutational status. Lesional dosimetry will be performed at baseline using 124I-PET, and treatment with the selective MEK inhibitor will be initiated immediately thereafter for 4 weeks. Lesional dosimetry with 124I-PET will be repeated after 4 weeks treatment with the MEK inhibitor (provided there are no AZD6244 delays in treatment) to determine if there has been a significant increase in 124I uptake in the metastatic tumor. Treatment with 131I will be offered to patients whose 124I uptake predicts that a 131I therapeutic dose would deliver > 2000 cGy to the tumor mass.

Biological: AZD6244

Within 1 week of starting the study: Low iodine diet

The patient will receive three bottles of capsules containing the drug AZD6244. Each capsule contains 25 milligrams of AZD6244. They will take 3 capsules orally, by mouth twice a day for 4 weeks. AZD6244 should be taken on an empty stomach (either one hour before or 2 hours after meals). AZD6244 capsules should be taken with water only. Lesional dosimetry with iodine-124 PET will be done twice, at the beginning and at the end of the study. This is done the same way that a radioactive iodine scan is done and is spread out over 5 days. It requires injection with human recombinant TSH (Thyrogen) on day 1 and 2, as well as blood tests on day 1 and day 5. On day 3, you will receive the iodine-124 in form of an oral drink, and the PET scan will be obtained on day 5. You will need to follow a low iodine diet starting 5 days before and throughout the process.

Experimental: pts with thyroid cancer without BRAF mutation

This is a pilot study involving patients with RAI-refractory metastatic thyroid cancer. Patients meeting inclusion criteria will have their tumor genotyped for BRAF mutational status. Lesional dosimetry will be performed at baseline using 124I-PET, and treatment with the selective MEK inhibitor AZD6244 will be initiated immediately thereafter for 4 weeks. Lesional dosimetry with 124I-PET will be repeated after 4 weeks treatment with the MEK inhibitor (provided there are no AZD6244 delays in treatment) to determine if there has been a significant increase in 124I uptake in the metastatic tumor. Treatment with 131I will be offered to patients whose 124I uptake predicts that a 131I therapeutic dose would deliver > 2000 cGy to the tumor mass.

Biological: AZD6244

Within 1 week of starting the study: Low iodine diet

The patient will receive three bottles of capsules containing the drug AZD6244. Each capsule contains 25 milligrams of AZD6244. They will take 3 capsules orally, by mouth twice a day for 4 weeks. AZD6244 should be taken on an empty stomach (either one hour before or 2 hours after meals). AZD6244 capsules should be taken with water only. Lesional dosimetry with iodine-124 PET will be done twice, at the beginning and at the end of the study. This is done the same way that a radioactive iodine scan is done and is spread out over 5 days. It requires injection with human recombinant TSH (Thyrogen) on day 1 and 2, as well as blood tests on day 1 and day 5. On day 3, you will receive the iodine-124 in form of an oral drink, and the PET scan will be obtained on day 5. You will need to follow a low iodine diet starting 5 days before and throughout the process.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Patients > or = to 18 years-old
Patients must have histopathologically confirmed at MSKCC differentiated thyroid carcinoma of follicular cell origin (D-TC-FCO), which includes papillary, follicular, or Hürthle cell histology, along with their respective variants.
Pathology specimen from the original tumor (thyroid) and/or metastases must be available for genotyping.
RAI-refractory metastatic disease on structural imaging, defined as any one of the following (as described in MSKCC protocol 08-066):
- index metastatic lesion non-RAI avid on a diagnostic RAI scan performed up to 2 years prior to enrolment in the current study, OR
- RAI-avid metastatic lesion which remained stable in size or progressed despite RAI treatment 6 months or more prior to entry in the study. Lesions will be assessed by 2 independent observers in nuclear medicine and in endocrinology. There is no minimal size limit for the index lesion.
Patients with FDG avid lesions
Evaluable disease by RECIST
Preliminary reproductive toxicology data indicate that AZD6244 can have adverse effects on embryofetal development and survival at dose levels that do not induce maternal toxicity in mice. For this reason, female patients will need to be post-menopausal or with negative serum pregnancy test if pre-menopausal. Patients of childbearing potential must agree to employ adequate contraception throughout the study.
ANC > 1500 per mm3, platelets > 100,000 per mm3, and hemoglobin > 9 g/dL
ALT/SGOT and AST/SGPT ≤ 2.5 X upper limit of normal (ULN)
Bilirubin ≤ 1.5 X ULN
Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

Patients may not be receiving any other investigational agents.
Patient with chronic renal insufficiency, as defined initially by an estimated creatinine clearance of < 30 ml/minute calculated using the Cockcroft and Gault equation: (140 - age in years) X (weight in kg) X (0.85 if female)/72 X serum Cr. If estimated creatinine clearance is < 30 ml/min, a 24 hour urine creatinine clearance may be collected and a patient would be eligible if the creatinine clearance is >30 ml/min.
Patients unable to follow a low iodine diet, patients requiring medication with high content in iodide (amiodarone), or patients receiving IV iodine containing contrast as part of radiographic procedure.
Patients with clinically significant cardiovascular disease as defined by the following:
- LVEF < institutional LLN
- New York Heart Association grade III or greater congestive heart failure
- uncontrolled hypertension, defined as systolic blood pressure > 180 mmHg OR diastolic blood pressure > 105 mmHg, on at least 2 repeated determinations on separate days within past 3 months
- Uncontrolled coronary artery disease, angina, congestive heart failure, or ventricular arrhythmia requiring acute medical management.
Patient with known hypersensitivity to Thyrogen (human recombinant thyrotropin).
Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in the study.
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
Pregnant women will be ineligible; breast feeding should be discontinued if the mother is treated with AZD6244.
Brain metastases or spinal cord compression unless treated and stable (for at least 3 months) off steroids.
Mean QTc interval >450 ms

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00970359

Contacts

Contact: Alan Ho, MD, PhD	212-639-3311
Contact: James Fagin, MD	646-888-2136

Locations

United States, New York
Memorial Sloan-Kettering Cancer Center	Recruiting
New York, New York, United States, 10065
Contact: Alan Ho, MD. PhD 212-639-3311
Contact: James Fagin, MD 646-888-2136

Sponsors and Collaborators

Memorial Sloan-Kettering Cancer Center

Genzyme

AstraZeneca

Investigators

Principal Investigator:

Alan Ho, MD, PhD

Memorial Sloan-Kettering Cancer Center

More Information

Additional Information:

Memorial Sloan-Kettering Cancer Center This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:	NCT00970359 History of Changes
Other Study ID Numbers:	09-048
Study First Received:	September 1, 2009
Last Updated:	January 20, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Memorial Sloan-Kettering Cancer Center:

thyroid
metastases
AZD6244
09-048

Additional relevant MeSH terms:

Thyroid Neoplasms
Thyroid Diseases
Endocrine Gland Neoplasms
Neoplasms by Site

Neoplasms
Head and Neck Neoplasms
Endocrine System Diseases

ClinicalTrials.gov processed this record on February 09, 2012