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Comparing Complete Remission After Treatment With Selumetinib/Placebo in Patient With Differentiated Thyroid Cancer (ASTRA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01843062
Recruitment Status : Terminated (Study was terminated based on the findings of primary analysis at 18 months post-RAI treatment. Patients pending 3 year follow up had end of study phone call.)
First Posted : April 30, 2013
Results First Posted : April 22, 2019
Last Update Posted : August 28, 2019
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Differentiated Thyroid Cancer
Interventions Drug: Selumetinib
Drug: Placebo
Drug: Radioactive Iodine Therapy
Enrollment 233
Recruitment Details Study conducted between 27 Aug 2013 and 06 Mar 2019. 42 centres in 8 countries randomised patients in the study. A primary analysis was performed for the 18 months post-radioactive iodine (RAI) treatment period with a data cut-off of 18 May 2018. All primary and secondary outcome measures were reported at the time of the primary analysis.
Pre-assignment Details Eligible patients with differentiated thyroid cancer at high risk of primary treatment failure were randomly assigned (ratio 2:1), to receive selumetinib in combination with adjuvant RAI therapy or placebo and adjuvant RAI therapy for a period of approximately 5 weeks.
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description Patients received selumetinib (75 milligrams [mg], orally twice daily [BD]), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 millicuries (mCi). To stimulate iodide uptake, patients received a recombinant human thyroid stimulating hormone (rhTSH) injection for each of the 2 days immediately prior to RAI therapy. Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Period Title: Overall Study
Started 155 78
Intention to Treat (ITT) Analysis Set 155 78
Safety Analysis Set 154 77
BRAF/NRAS Mutation Positive Analysis Set [1] 91 51
Ongoing at Primary Analysis Data Cut-off 134 71
Completed [2] 133 69
Not Completed 22 9
Reason Not Completed
Protocol Violation             1             0
New treatment following progression             2             0
Pregnancy             1             0
Adverse Event             2             0
Incorrect randomisation             1             0
Withdrawal by Subject             12             3
Death             1             2
Lost to Follow-up             2             4
[1]
BRAF/NRAS positive = mutations in BRAF/NRAS oncogenes had been detected
[2]
Completed the end of study visit or end of study phone call
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI Total
Hide Arm/Group Description Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy. Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy. Total of all reporting groups
Overall Number of Baseline Participants 155 78 233
Hide Baseline Analysis Population Description
The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 155 participants 78 participants 233 participants
46.2  (14.20) 47.9  (14.67) 46.8  (14.35)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 155 participants 78 participants 233 participants
Female
92
  59.4%
40
  51.3%
132
  56.7%
Male
63
  40.6%
38
  48.7%
101
  43.3%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 155 participants 78 participants 233 participants
Hispanic or Latino
27
  17.4%
14
  17.9%
41
  17.6%
Not Hispanic or Latino
128
  82.6%
64
  82.1%
192
  82.4%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 155 participants 78 participants 233 participants
White
145
  93.5%
73
  93.6%
218
  93.6%
Black or African American
3
   1.9%
1
   1.3%
4
   1.7%
Asian
3
   1.9%
3
   3.8%
6
   2.6%
Other
4
   2.6%
1
   1.3%
5
   2.1%
1.Primary Outcome
Title Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set
Hide Description

Patients were defined to be in complete remission if all of the following criteria were demonstrated:

  1. Serum thyroglobulin (Tg) levels <1 nanograms / millilitre (ng/mL) during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis.
  2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review.
  3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review.
  4. No histopathological evidence of thyroid cancer on fine needle aspiration (FNA)/biopsy when performed, as assessed by investigator site review.
  5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment.
Time Frame At 18 months post-RAI treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description:
Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Overall Number of Participants Analyzed 155 78
Measure Type: Number
Unit of Measure: Percentage of participants
40.0 38.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Selumetinib 75 mg BD + RAI, Placebo + RAI
Comments Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8205
Comments The primary endpoint was to be considered statistically significant if the 2-sided p-value was less than 0.05. P-value and confidence intervals (CIs) were calculated using profile likelihood.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.61 to 1.87
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive
Hide Description

Patients were defined to be in complete remission if all of the following criteria were demonstrated:

  1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis.
  2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review.
  3. No confirmed radiological evidence of thyroid cancer, as assessed by blinded independent central review.
  4. No histopathological evidence of thyroid cancer FNA/biopsy when performed, as assessed by investigator site review.
  5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment.
Time Frame At 18 months post-RAI treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The BRAF/NRAS mutation positive analysis set included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description:
Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Overall Number of Participants Analyzed 91 51
Measure Type: Number
Unit of Measure: Percentage of participants
37.4 41.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Selumetinib 75 mg BD + RAI, Placebo + RAI
Comments Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6549
Comments P-value and CIs were calculated using profile likelihood.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.42 to 1.73
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set
Hide Description

Patients were defined to be in clinical remission if all of the following criteria were demonstrated:

  1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis.
  2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review.
  3. No evidence of thyroid cancer on diagnostic whole body scan (WBS), as assessed by blinded independent central review.
  4. No histopathological evidence of thyroid cancer on FNA/biopsy when performed to clarify equivocal ultrasound findings, as assessed by investigator site review.
  5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment.
Time Frame At 18 months post-RAI treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT analysis set included all randomised patients. Patients who were randomised but did not subsequently go on to receive selumetinib/placebo were included in the ITT analysis set.
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description:
Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Overall Number of Participants Analyzed 155 78
Measure Type: Number
Unit of Measure: Percentage of participants
40.0 38.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Selumetinib 75 mg BD + RAI, Placebo + RAI
Comments Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.8205
Comments P-value and CIs were calculated using profile likelihood.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.61 to 1.87
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive
Hide Description

Patients were defined to be in clinical remission if all of the following criteria were demonstrated:

  1. Serum Tg levels <1 ng/mL during rhTSH stimulation, in the absence of interfering Tg antibodies, as assessed by standardised central laboratory analysis.
  2. No confirmed evidence of thyroid cancer on neck ultrasound, as assessed by investigator site review.
  3. No evidence of thyroid cancer on diagnostic WBS, as assessed by blinded independent central review.
  4. No histopathological evidence of thyroid cancer on FNA/biopsy when performed to clarify equivocal ultrasound findings, as assessed by investigator site review.
  5. No further thyroid cancer therapy was administered in the first 18 months following the initial RAI treatment.
Time Frame At 18 months post-RAI treatment
Hide Outcome Measure Data
Hide Analysis Population Description
The BRAF/NRAS mutation positive analysis set included only those patients from the ITT population whose tumour samples were mutation positive for the oncogenes BRAF or NRAS.
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description:
Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
Overall Number of Participants Analyzed 91 51
Measure Type: Number
Unit of Measure: Percentage of participants
37.4 41.2
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Selumetinib 75 mg BD + RAI, Placebo + RAI
Comments Selumetinib in combination with RAI was compared with placebo in combination with RAI. The analysis was performed using a logistic regression model including treatment as the only covariate. An odds ratio >1 favours selumetinib in combination with RAI.
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6549
Comments P-value and CIs were calculated using profile likelihood.
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.85
Confidence Interval (2-Sided) 95%
0.42 to 1.73
Estimation Comments [Not Specified]
Time Frame Includes adverse events (AEs) with an onset date on or after the date of first dose and up to and including 30 days following the date of last dose of selumetinib/placebo. Overall timeframe for collection of AEs was up to 66 days from the first dose.
Adverse Event Reporting Description All-Cause Mortality is reported for the ITT analysis set for the overall study period. Serious and Other (non-serious) AE data is reported for the safety analysis set (including all patients who received at least 1 dose of randomised treatment) for the 5-week treatment period plus 30-day follow-up phase.
 
Arm/Group Title Selumetinib 75 mg BD + RAI Placebo + RAI
Hide Arm/Group Description Patients received selumetinib (75 mg, orally BD), for a period of approximately 5 weeks. Selumetinib was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy. Patients received placebo capsules (to match selumetinib, orally BD), for a period of approximately 5 weeks. Placebo was to be started approximately 4 weeks prior to the planned day of RAI therapy administered as a single oral dose of 100 mCi. To stimulate iodide uptake, patients received a rhTSH injection for each of the 2 days immediately prior to RAI therapy.
All-Cause Mortality
Selumetinib 75 mg BD + RAI Placebo + RAI
Affected / at Risk (%) Affected / at Risk (%)
Total   1/155 (0.65%)      2/78 (2.56%)    
Hide Serious Adverse Events
Selumetinib 75 mg BD + RAI Placebo + RAI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   7/154 (4.55%)      0/77 (0.00%)    
Gastrointestinal disorders     
Gastric haemorrhage † 1  1/154 (0.65%)  1 0/77 (0.00%)  0
Immune system disorders     
Drug hypersensitivity † 1  1/154 (0.65%)  1 0/77 (0.00%)  0
Infections and infestations     
Cellulitis † 1  1/154 (0.65%)  1 0/77 (0.00%)  0
Metabolism and nutrition disorders     
Hypercalcaemia † 1  1/154 (0.65%)  1 0/77 (0.00%)  0
Nervous system disorders     
Syncope † 1  1/154 (0.65%)  1 0/77 (0.00%)  0
Skin and subcutaneous tissue disorders     
Dermatitis acneiform † 1  2/154 (1.30%)  2 0/77 (0.00%)  0
1
Term from vocabulary, MedDRA 21.1
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Selumetinib 75 mg BD + RAI Placebo + RAI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   141/154 (91.56%)      43/77 (55.84%)    
Eye disorders     
Periorbital oedema † 1  8/154 (5.19%)  8 0/77 (0.00%)  0
Vision blurred † 1  16/154 (10.39%)  16 5/77 (6.49%)  5
Gastrointestinal disorders     
Constipation † 1  15/154 (9.74%)  15 3/77 (3.90%)  3
Diarrhoea † 1  68/154 (44.16%)  78 12/77 (15.58%)  13
Dry mouth † 1  15/154 (9.74%)  15 3/77 (3.90%)  3
Dyspepsia † 1  8/154 (5.19%)  8 1/77 (1.30%)  1
Nausea † 1  44/154 (28.57%)  44 8/77 (10.39%)  10
Stomatitis † 1  17/154 (11.04%)  18 4/77 (5.19%)  4
Vomiting † 1  14/154 (9.09%)  14 0/77 (0.00%)  0
General disorders     
Face oedema † 1  9/154 (5.84%)  9 0/77 (0.00%)  0
Fatigue † 1  44/154 (28.57%)  44 13/77 (16.88%)  13
Oedema peripheral † 1  30/154 (19.48%)  32 4/77 (5.19%)  4
Investigations     
Blood creatine phosphokinase increased † 1  31/154 (20.13%)  31 1/77 (1.30%)  1
Weight decreased † 1  0/154 (0.00%)  0 4/77 (5.19%)  4
Musculoskeletal and connective tissue disorders     
Muscle spasms † 1  1/154 (0.65%)  1 4/77 (5.19%)  4
Nervous system disorders     
Dysgeusia † 1  6/154 (3.90%)  6 4/77 (5.19%)  4
Headache † 1  8/154 (5.19%)  8 10/77 (12.99%)  11
Paraesthesia † 1  4/154 (2.60%)  4 4/77 (5.19%)  4
Respiratory, thoracic and mediastinal disorders     
Cough † 1  3/154 (1.95%)  3 4/77 (5.19%)  4
Skin and subcutaneous tissue disorders     
Rash follicular † 1  13/154 (8.44%)  13 0/77 (0.00%)  0
Rash macular † 1  12/154 (7.79%)  12 2/77 (2.60%)  2
Acne † 1  13/154 (8.44%)  13 2/77 (2.60%)  2
Dermatitis acneiform † 1  67/154 (43.51%)  70 4/77 (5.19%)  4
Dry skin † 1  12/154 (7.79%)  12 4/77 (5.19%)  4
Pruritus † 1  21/154 (13.64%)  21 3/77 (3.90%)  3
Rash maculo-papular † 1  19/154 (12.34%)  19 4/77 (5.19%)  4
Vascular disorders     
Hypertension † 1  20/154 (12.99%)  23 3/77 (3.90%)  3
1
Term from vocabulary, MedDRA 21.1
†
Indicates events were collected by systematic assessment
The study was terminated early (based on the findings of the primary analysis at 18 months post-RAI treatment) and all randomised patients who had not yet completed their 3-year follow-up visit were instead to have an end of study phone call.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
If the Study is part of a multi-centre clinical trial, the Institution or Investigator agree not to independently publish results of, or make presentations related to, the Study until first occurrence of one of the following: multi-centre primary Publication is published; no multi-centre primary Publication is submitted within 2 years after conclusion, abandonment or termination of the Study at all sites; or Sponsor confirms in writing there will be no multi-centre primary Publication.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Clinical Lead
Organization: AstraZeneca
Phone: +1 302 885 1180
EMail: ClinicalTrialTransparency@astrazeneca.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01843062    
Other Study ID Numbers: D1532C00065
2013-000423-14 ( EudraCT Number )
First Submitted: March 14, 2013
First Posted: April 30, 2013
Results First Submitted: March 27, 2019
Results First Posted: April 22, 2019
Last Update Posted: August 28, 2019