Selumetinib in Treating Patients With Papillary Thyroid Cancer That Did Not Respond to Radioactive Iodine

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT00559949
Collaborator
(none)
39
6
1
104
6.5
0.1

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.

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. 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.

  2. 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

Study Type:
Interventional
Actual Enrollment :
39 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase 2 Study of Selumetinib Hydrogen Sulfate in Iodine-131 Refractory Papillary Thyroid Carcinoma and Papillary Thyroid Carcinoma With Follicular Elements
Study Start Date :
Dec 1, 2007
Actual Primary Completion Date :
Aug 1, 2016
Actual Study Completion Date :
Aug 1, 2016

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:
  • ARRY-142886
  • AZD6244
  • MEK Inhibitor AZD6244
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00559949
    Other Study ID Numbers:
    • NCI-2009-01056
    • NCI-2009-01056
    • LOI 7918
    • CDR0000574262
    • LOI 7918
    • 7918
    • N01CM62201
    • N01CM62203
    • N01CM62208
    • P30CA076292
    • NCT00589940
    First Posted:
    Nov 19, 2007
    Last Update Posted:
    Jan 30, 2017
    Last Verified:
    Dec 1, 2016

    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

    1. Primary Outcome
    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%
    2. Secondary Outcome
    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
    3. Secondary Outcome
    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
    4. Secondary Outcome
    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

    Actuarial OS cannot be estimated due to long survival times in this disease.

    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
    Email hayes@med.unc.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT00559949
    Other Study ID Numbers:
    • NCI-2009-01056
    • NCI-2009-01056
    • LOI 7918
    • CDR0000574262
    • LOI 7918
    • 7918
    • N01CM62201
    • N01CM62203
    • N01CM62208
    • P30CA076292
    • NCT00589940
    First Posted:
    Nov 19, 2007
    Last Update Posted:
    Jan 30, 2017
    Last Verified:
    Dec 1, 2016