A Phase 2 interventional study of Laboratory Biomarker Analysis and Selumetinib in Recurrent Thyroid Gland Carcinoma, Stage I Thyroid Gland Papillary Carcinoma and Stage II Thyroid Gland Papillary Carcinoma, sponsored by National Cancer Institute (NCI). Completed at 6 sites in 2 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2017-01-30.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
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.
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.
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Inclusion Criteria:
No longer amenable to radioactive iodine therapy or curative surgical resection
Evidence of disease progression (objective growth of existing tumors)
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 · Drug: Selumetinib
Correlative studies
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.
Also known as: ARRY-142886, AZD6244, MEK Inhibitor AZD6244
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%.
Time frame: Up to 2 years
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.
Time frame: Up to 2 years
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.
Time frame: Up to 2 years
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.
Time frame: Up to 2 years
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.
| Milestone | Arm I |
|---|---|
| Started | 39 |
| Completed | 32 |
| Not completed | 7 |
| Withdrew: Progressive disease during cycle 1 | 1 |
| Withdrew: Adverse event | 1 |
| Withdrew: Withdrawal by subject | 4 |
| Withdrew: No disease evaluation per protocol | 1 |
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%.
| Participants | All Evaluable Participants |
|---|---|
| Objective Response Rate (ORR) | 1 |
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.
| weeks | All Evaluable Participants |
|---|---|
| Median Progression-Free Survival (PFS) | 32 (8.4 to 56) |
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.
| adverse events | All Evaluable Participants |
|---|---|
| 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 |
Overall Survival using the Kaplan-Meier method with associated confidence intervals. OS analysis was intended to be mostly exploratory and descriptive in nature.
| months | All Evaluable Participants |
|---|---|
| Overall Survival (OS) | NA (1 to NA) |
Collected over From first on treatment date to 30 days post last off treatment date, 7 years, 8 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| All Participants | — | 7/39 (17.9%) | 39/39 (100%) |
| Event | All Participants |
|---|---|
| Death NOSGeneral disorders | 2/39 |
| Atrial fibrillationCardiac disorders | 1/39 |
| DehydrationMetabolism and nutrition disorders | 1/39 |
| Memory impairmentNervous system disorders | 1/39 |
| SyncopeNervous system disorders | 1/39 |
| ConfusionPsychiatric disorders | 1/39 |
| PneumonitisRespiratory, thoracic and mediastinal disorders | 1/39 |
| HypotensionVascular disorders | 1/39 |
| Event | All Participants |
|---|---|
| FatigueGeneral disorders | 24/39 |
| DiarrheaGastrointestinal disorders | 21/39 |
| Rash maculo-papularSkin and subcutaneous tissue disorders | 15/39 |
| Edema limbsGeneral disorders | 14/39 |
| Rash acneiformSkin and subcutaneous tissue disorders | 12/39 |
| HyperglycemiaMetabolism and nutrition disorders | 11/39 |
| AnemiaBlood and lymphatic system disorders | 10/39 |
| NauseaGastrointestinal disorders | 9/39 |
| DyspneaRespiratory, thoracic and mediastinal disorders | 9/39 |
| Alanine aminotransferase increasedInvestigations | 8/39 |
All participants, unless specified differently in an Outcome Measure.
| Age, Categorical(Participants) | Arm I |
|---|---|
| <=18 years | 0 |
| Between 18 and 65 years | 21 |
| >=65 years | 18 |
| Age, Continuous(years) | Arm I |
|---|---|
| Median | 64 (37 to 86) |
| Gender(Participants) | Arm I |
|---|---|
| Female | 13 |
| Male | 26 |
| Region of Enrollment(participants) | Arm I |
|---|---|
| Canada | 5 |
| United States | 34 |
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