Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine
Study Details
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
-
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.
-
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Arm I Patients receive oral selumetinib twice daily on days 1-28. Treatment repeats every 28 days in the absence of unacceptable toxicity or disease progression. |
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Selumetinib
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Objective Response Rate (ORR) [Up to 2 years]
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) [Up to 2 years]
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 [Up to 2 years]
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) [Up to 2 years]
Overall Survival using the Kaplan-Meier method with associated confidence intervals. OS analysis was intended to be mostly exploratory and descriptive in nature.
Eligibility Criteria
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
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Moffitt Cancer Center | Tampa | Florida | United States | 33612 |
2 | University of Chicago Comprehensive Cancer Center | Chicago | Illinois | United States | 60637 |
3 | UNC Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
4 | Fox Chase Cancer Center | Philadelphia | Pennsylvania | United States | 19111 |
5 | Vanderbilt University/Ingram Cancer Center | Nashville | Tennessee | United States | 37232 |
6 | University Health Network-Princess Margaret Hospital | Toronto | Ontario | Canada | M5G 2M9 |
Sponsors and Collaborators
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: David Neil Hayes, UNC Lineberger Comprehensive Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
- NCI-2009-01056
- NCI-2009-01056
- LOI 7918
- CDR0000574262
- LOI 7918
- 7918
- N01CM62201
- N01CM62203
- N01CM62208
- P30CA076292
- NCT00589940
Study Results
Participant Flow
Recruitment Details | Between December 11, 2007 and June 30, 2009, 39 patients were enrolled at 5 cancer centers in the United States and one cancer center in Canada. |
---|---|
Pre-assignment Detail |
Arm/Group Title | Arm I |
---|---|
Arm/Group 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. Laboratory Biomarker Analysis: Correlative studies Selumetinib: 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. |
Period Title: Overall Study | |
STARTED | 39 |
COMPLETED | 32 |
NOT COMPLETED | 7 |
Baseline Characteristics
Arm/Group Title | Arm I |
---|---|
Arm/Group 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. Laboratory Biomarker Analysis: Correlative studies Selumetinib: 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. |
Overall Participants | 39 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
21
53.8%
|
>=65 years |
18
46.2%
|
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
64
|
Gender (Count of Participants) | |
Female |
13
33.3%
|
Male |
26
66.7%
|
Region of Enrollment (participants) [Number] | |
Canada |
5
12.8%
|
United States |
34
87.2%
|
Outcome Measures
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 |
Outcome Measure Data
Analysis Population Description |
---|
All evaluable participants |
Arm/Group Title | All Evaluable Participants |
---|---|
Arm/Group Description | Participants evaluable according to protocol guidelines at time of analysis. |
Measure Participants | 32 |
Count of Participants [Participants] |
1
2.6%
|
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 |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | All Evaluable Participants |
---|---|
Arm/Group Description | Participants evaluable according to protocol guidelines at time of analysis. |
Measure Participants | 39 |
Median (95% Confidence Interval) [weeks] |
32
|
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 |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | All Evaluable Participants |
---|---|
Arm/Group Description | Participants evaluable according to protocol guidelines at time of analysis. |
Measure Participants | 39 |
Grade 1-2 - Rash |
23
|
Grade 1-2 - Diarrhea |
17
|
Grade 1-2 - Fatigue |
16
|
Grade 1-2 - Peripheral edema |
12
|
Grade 1-2 - Elevated liver enzymes |
9
|
Grade 1-2 - Electrolyte abnormalities |
7
|
Grade 1-2 - Nausea/vomiting |
7
|
Grade 1-2 - Stomatitis |
6
|
Grade 1-2 - Dyspnea |
5
|
Grade 3-4 - Rash |
7
|
Grade 3-4 - Diarrhea |
2
|
Grade 3-4 - Fatigue |
3
|
Grade 3-4 - Peripheral edema |
2
|
Grade 3-4 - Elevated liver enzymes |
0
|
Grade 3-4 - Electrolyte abnormalities |
0
|
Grade 3-4 - Nausea/vomiting |
0
|
Grade 3-4 - Stomatitis |
1
|
Grade 3-4 - Dyspnea |
0
|
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 |
Outcome Measure Data
Analysis Population Description |
---|
All participants |
Arm/Group Title | All Evaluable Participants |
---|---|
Arm/Group Description | Participants evaluable according to protocol guidelines at time of analysis. |
Measure Participants | 39 |
Median (95% Confidence Interval) [months] |
NA
|
Adverse Events
Time Frame | From first on treatment date to 30 days post last off treatment date, 7 years, 8 months. | |
---|---|---|
Adverse Event Reporting Description | All participants were evaluated for adverse events. | |
Arm/Group Title | All Participants | |
Arm/Group Description | All participants on study. | |
All Cause Mortality |
||
All Participants | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
All Participants | ||
Affected / at Risk (%) | # Events | |
Total | 7/39 (17.9%) | |
Cardiac disorders | ||
Atrial fibrillation | 1/39 (2.6%) | 1 |
General disorders | ||
Death NOS | 2/39 (5.1%) | 2 |
Metabolism and nutrition disorders | ||
Dehydration | 1/39 (2.6%) | 1 |
Nervous system disorders | ||
Memory impairment | 1/39 (2.6%) | 1 |
Syncope | 1/39 (2.6%) | 1 |
Psychiatric disorders | ||
Confusion | 1/39 (2.6%) | 1 |
Respiratory, thoracic and mediastinal disorders | ||
Pneumonitis | 1/39 (2.6%) | 1 |
Vascular disorders | ||
Hypotension | 1/39 (2.6%) | 1 |
Other (Not Including Serious) Adverse Events |
||
All Participants | ||
Affected / at Risk (%) | # Events | |
Total | 39/39 (100%) | |
Blood and lymphatic system disorders | ||
Anemia | 10/39 (25.6%) | 21 |
Eye disorders | ||
Blurred vision | 3/39 (7.7%) | 4 |
Extraocular muscle paresis | 3/39 (7.7%) | 3 |
Eye disorders - Other, specify | 2/39 (5.1%) | 2 |
Gastrointestinal disorders | ||
Abdominal pain | 3/39 (7.7%) | 3 |
Constipation | 5/39 (12.8%) | 5 |
Diarrhea | 21/39 (53.8%) | 34 |
Dry mouth | 6/39 (15.4%) | 6 |
Dysphagia | 3/39 (7.7%) | 4 |
Flatulence | 3/39 (7.7%) | 3 |
Gastrointestinal disorders - Other, specify | 2/39 (5.1%) | 2 |
Mucositis oral | 6/39 (15.4%) | 8 |
Nausea | 9/39 (23.1%) | 15 |
Vomiting | 5/39 (12.8%) | 6 |
General disorders | ||
Fatigue | 24/39 (61.5%) | 37 |
Edema face | 7/39 (17.9%) | 13 |
Edema limbs | 14/39 (35.9%) | 22 |
Fever | 3/39 (7.7%) | 4 |
Flu like symptoms | 2/39 (5.1%) | 5 |
Pain | 6/39 (15.4%) | 6 |
Infections and infestations | ||
Bronchial infection | 2/39 (5.1%) | 2 |
Infections and infestations - Other, specify | 5/39 (12.8%) | 6 |
Sinusitis | 2/39 (5.1%) | 2 |
Upper respiratory infection | 2/39 (5.1%) | 2 |
Investigations | ||
Alanine aminotransferase increased | 8/39 (20.5%) | 12 |
Alkaline phosphatase increased | 3/39 (7.7%) | 4 |
Aspartate aminotransferase increased | 6/39 (15.4%) | 10 |
Creatinine increased | 2/39 (5.1%) | 9 |
Lymphocyte count decreased | 6/39 (15.4%) | 14 |
Neutrophil count decreased | 4/39 (10.3%) | 4 |
Platelet count decreased | 3/39 (7.7%) | 4 |
Weight gain | 4/39 (10.3%) | 4 |
Weight loss | 2/39 (5.1%) | 2 |
White blood cell decreased | 4/39 (10.3%) | 7 |
Metabolism and nutrition disorders | ||
Anorexia | 7/39 (17.9%) | 10 |
Hyperglycemia | 11/39 (28.2%) | 24 |
Hyperkalemia | 5/39 (12.8%) | 9 |
Hypoalbuminemia | 7/39 (17.9%) | 19 |
Hypocalcemia | 6/39 (15.4%) | 8 |
Hypomagnesemia | 3/39 (7.7%) | 4 |
Hypophosphatemia | 3/39 (7.7%) | 3 |
Musculoskeletal and connective tissue disorders | ||
Back pain | 2/39 (5.1%) | 2 |
Generalized muscle weakness | 3/39 (7.7%) | 5 |
Pain in extremity | 3/39 (7.7%) | 3 |
Nervous system disorders | ||
Dizziness | 3/39 (7.7%) | 4 |
Dysgeusia | 5/39 (12.8%) | 6 |
Headache | 4/39 (10.3%) | 7 |
Peripheral motor neuropathy | 2/39 (5.1%) | 2 |
Peripheral sensory neuropathy | 5/39 (12.8%) | 8 |
Psychiatric disorders | ||
Depression | 2/39 (5.1%) | 2 |
Respiratory, thoracic and mediastinal disorders | ||
Bronchopulmonary hemorrhage | 2/39 (5.1%) | 2 |
Cough | 4/39 (10.3%) | 5 |
Dyspnea | 9/39 (23.1%) | 10 |
Pneumonitis | 3/39 (7.7%) | 3 |
Respiratory, thoracic and mediastinal disorders - Other, specify | 4/39 (10.3%) | 4 |
Voice alteration | 2/39 (5.1%) | 2 |
Skin and subcutaneous tissue disorders | ||
Alopecia | 3/39 (7.7%) | 3 |
Dry skin | 4/39 (10.3%) | 4 |
Palmar-plantar erythrodysesthesia syndrome | 3/39 (7.7%) | 5 |
Rash acneiform | 12/39 (30.8%) | 27 |
Rash maculo-papular | 15/39 (38.5%) | 33 |
Skin and subcutaneous tissue disorders - Other, specify | 5/39 (12.8%) | 9 |
Vascular disorders | ||
Thromboembolic event | 2/39 (5.1%) | 4 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
Name/Title | Dr. David Neil Hayes |
---|---|
Organization | UNC Lineberger Comprehensive Cancer Center |
Phone | 919-966-3786 |
hayes@med.unc.edu |
- NCI-2009-01056
- NCI-2009-01056
- LOI 7918
- CDR0000574262
- LOI 7918
- 7918
- N01CM62201
- N01CM62203
- N01CM62208
- P30CA076292
- NCT00589940