Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine
Primary Purpose
Recurrent Thyroid Gland Carcinoma, Stage I Thyroid Gland Papillary Carcinoma, Stage II Thyroid Gland Papillary Carcinoma
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Laboratory Biomarker Analysis
Selumetinib
Sponsored by
About this trial
This is an interventional treatment trial for Recurrent Thyroid Gland Carcinoma
Eligibility Criteria
Inclusion Criteria:
- Histologically or cytologically confirmed papillary thyroid cancer or papillary thyroid cancer with follicular elements
No longer amenable to radioactive iodine therapy or curative surgical resection
- Tumor is no longer iodine avid
- Tumor did not respond to the most recent radioactive iodine treatment
- Patient is ineligible for further radioactive iodine therapy due to medical contraindications (e.g., lung toxicity)
- 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 CT scan
Evidence of disease progression (objective growth of existing tumors)
- New or enlarging measurable lesions within the past 12 months
- If the most recent imaging study is older than 12 months, patients will still be eligible if objectively measurable disease progression is associated with clinical symptoms
- Archival tumor tissue available for mutational analysis
- No known brain metastases
- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
- Life expectancy > 12 weeks
- WBC ≥ 3,000/µL
- ANC ≥ 1,500/µL
- Platelet count ≥ 100,000/µL
- Total bilirubin normal
- AST and ALT < 2.5 times upper limit of normal
- Creatinine normal OR creatinine clearance ≥ 60 mL/min
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception prior to, during, and for 4 weeks after completion of study treatment
- Able to understand and willing to sign a written informed consent document
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib (AZD6244) or its excipient Captisol®
- QTc interval > 450 msec or other factors that increase the risk of QT prolongation
- Arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome), including heart failure that meets NYHA class III and IV definition
- Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
- Concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
- At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C)
- Prior treatment with tyrosine kinase inhibitors that target RET or RAF
- Prior treatment with MEK inhibitors
- Concurrent combination antiretroviral therapy for HIV-positive patients
- Concurrent medication that can prolong the QT interval
- Other concurrent investigational agents
Sites / Locations
- Moffitt Cancer Center
- University of Chicago Comprehensive Cancer Center
- UNC Lineberger Comprehensive Cancer Center
- Fox Chase Cancer Center
- Vanderbilt University/Ingram Cancer Center
- University Health Network-Princess Margaret Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Arm I
Arm Description
Patients receive oral selumetinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression.
Outcomes
Primary Outcome Measures
Objective Response Rate (ORR)
ORR: Complete Response (CR) and Partial Response (PR) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. A conservative estimate of the response rate of the best-studied agent in this disease, doxorubicin, is approximately 5%. Therefore, investigators will assume that selumetinib (AZD6244, NSC 741078) would be worth further pursuit if the response rate (CR+PR) were at least 20%.
Secondary Outcome Measures
Median Progression-Free Survival (PFS)
PFS is defined as the duration of time from start of treatment to time of progression or death. Progression evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive Disease (PD): 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm. Secondary end points include toxicity, progression free survival, and overall survival. Due to the small sample size and absence of high quality historic data for this disease, these analyses were planned to be mostly exploratory and descriptive in nature.
Occurrence of Treatment Related Adverse Events
Number of participants with related adverse events, per category and Grade category. Toxicity assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Overall Survival (OS)
Overall Survival using the Kaplan-Meier method with associated confidence intervals. OS analysis was intended to be mostly exploratory and descriptive in nature.
Full Information
NCT ID
NCT00559949
First Posted
November 16, 2007
Last Updated
December 2, 2016
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00559949
Brief Title
Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine
Official Title
Phase 2 Study of Selumetinib Hydrogen Sulfate in Iodine-131 Refractory Papillary Thyroid Carcinoma and Papillary Thyroid Carcinoma With Follicular Elements
Study Type
Interventional
2. Study Status
Record Verification Date
December 2016
Overall Recruitment Status
Completed
Study Start Date
December 2007 (undefined)
Primary Completion Date
August 2016 (Actual)
Study Completion Date
August 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase II trial is studying how well selumetinib works in treating patients with papillary thyroid cancer that did not respond to radioactive iodine. Selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. Ascertain the objective response rate (complete response and partial response) in patients with iodine I 131-refractory papillary thyroid cancer treated with selumetinib.
SECONDARY OBJECTIVES:
I. Determine the toxicity of this treatment in these patients. II. Determine the pharmacokinetic profile of this treatment in these patients. III. Determine the progression-free and overall survival of these patients. IV. Assess proxy measures of treatment response (thyroglobulin and PET scan) in patients treated with selumetinib.
IV. Compare relevant laboratory correlates between responders and non-responders.
OUTLINE: This is a multicenter study.
Patients receive oral selumetinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression.
Archived tissue is examined for gene mutations, including RET, BRAF, NTRK, and RAS, by fluorescence in situ hybridization and/or polymerase chain reaction and fluorescence melting curve analysis. Protein expression of ERK and phosphorylated ERK is assessed by immunohistochemical staining.
Blood samples are collected periodically for pharmacokinetic analysis and biomarker assessment (thyroglobulin and antithyroglobulin autoantibodies).
After completion of study therapy, patients are followed periodically for up to 2 years.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Recurrent Thyroid Gland Carcinoma, Stage I Thyroid Gland Papillary Carcinoma, Stage II Thyroid Gland Papillary Carcinoma, Stage III Thyroid Gland Papillary Carcinoma, Stage IV Thyroid Gland Papillary Carcinoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
39 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Arm I
Arm Type
Experimental
Arm Description
Patients receive oral selumetinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression.
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Selumetinib
Other Intervention Name(s)
ARRY-142886, AZD6244, MEK Inhibitor AZD6244
Intervention Description
Selumetinib was administered orally as a free base suspension at a dose of 100 mg twice daily for 28-day cycles. Those participants experiencing Common Terminology Criteria for Adverse Events (CTCAE) v3.0 grade 3 toxicity or worse had their dose reduced to 50 mg twice daily and then to 50 mg once daily, if necessary.
Primary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
ORR: Complete Response (CR) and Partial Response (PR) evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). CR: Disappearance of all target lesions. PR: At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. A conservative estimate of the response rate of the best-studied agent in this disease, doxorubicin, is approximately 5%. Therefore, investigators will assume that selumetinib (AZD6244, NSC 741078) would be worth further pursuit if the response rate (CR+PR) were at least 20%.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Median Progression-Free Survival (PFS)
Description
PFS is defined as the duration of time from start of treatment to time of progression or death. Progression evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST). Progressive Disease (PD): 20% increase in the sum of appropriate diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, as well as an absolute increase of at least 0.5 cm. Secondary end points include toxicity, progression free survival, and overall survival. Due to the small sample size and absence of high quality historic data for this disease, these analyses were planned to be mostly exploratory and descriptive in nature.
Time Frame
Up to 2 years
Title
Occurrence of Treatment Related Adverse Events
Description
Number of participants with related adverse events, per category and Grade category. Toxicity assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Time Frame
Up to 2 years
Title
Overall Survival (OS)
Description
Overall Survival using the Kaplan-Meier method with associated confidence intervals. OS analysis was intended to be mostly exploratory and descriptive in nature.
Time Frame
Up to 2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically or cytologically confirmed papillary thyroid cancer or papillary thyroid cancer with follicular elements
No longer amenable to radioactive iodine therapy or curative surgical resection
Tumor is no longer iodine avid
Tumor did not respond to the most recent radioactive iodine treatment
Patient is ineligible for further radioactive iodine therapy due to medical contraindications (e.g., lung toxicity)
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 CT scan
Evidence of disease progression (objective growth of existing tumors)
New or enlarging measurable lesions within the past 12 months
If the most recent imaging study is older than 12 months, patients will still be eligible if objectively measurable disease progression is associated with clinical symptoms
Archival tumor tissue available for mutational analysis
No known brain metastases
ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
Life expectancy > 12 weeks
WBC ≥ 3,000/µL
ANC ≥ 1,500/µL
Platelet count ≥ 100,000/µL
Total bilirubin normal
AST and ALT < 2.5 times upper limit of normal
Creatinine normal OR creatinine clearance ≥ 60 mL/min
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception prior to, during, and for 4 weeks after completion of study treatment
Able to understand and willing to sign a written informed consent document
History of allergic reactions attributed to compounds of similar chemical or biologic composition to selumetinib (AZD6244) or its excipient Captisol®
QTc interval > 450 msec or other factors that increase the risk of QT prolongation
Arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome), including heart failure that meets NYHA class III and IV definition
Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g., inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption
Concurrent uncontrolled illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
At least 4 weeks since prior radiotherapy or chemotherapy (6 weeks for nitrosoureas or mitomycin C)
Prior treatment with tyrosine kinase inhibitors that target RET or RAF
Prior treatment with MEK inhibitors
Concurrent combination antiretroviral therapy for HIV-positive patients
Concurrent medication that can prolong the QT interval
Other concurrent investigational agents
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David Neil Hayes
Organizational Affiliation
UNC Lineberger Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Moffitt Cancer Center
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
UNC Lineberger Comprehensive Cancer Center
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
Vanderbilt University/Ingram Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
University Health Network-Princess Margaret Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
22241789
Citation
Hayes DN, Lucas AS, Tanvetyanon T, Krzyzanowska MK, Chung CH, Murphy BA, Gilbert J, Mehra R, Moore DT, Sheikh A, Hoskins J, Hayward MC, Zhao N, O'Connor W, Weck KE, Cohen RB, Cohen EE. Phase II efficacy and pharmacogenomic study of Selumetinib (AZD6244; ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma with or without follicular elements. Clin Cancer Res. 2012 Apr 1;18(7):2056-65. doi: 10.1158/1078-0432.CCR-11-0563. Epub 2012 Jan 12.
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Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine
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