Differentiated Thyroid Cancer
Conditions
Keywords
Selumetinib, Differentiated Thyroid Cancer , AZD6244
Brief summary
The study is designed to evaluate the clinical efficacy, safety and tolerability of selumetinib with radioactive iodine therapy in patients with differentiated thyroid cancer.
Detailed description
A Randomised, Double Blind Study to Compare the Complete Remission Rate Following a 5-Week Course of Selumetinib or Placebo and Single Dose Adjuvant Radioactive Iodine Therapy in Patients with Differentiated Thyroid Cancer.
Interventions
DRUGSelumetinib
3 capsules of 25 mg strength orally twice a day for approximately 5 weeks treatment period
DRUGPlacebo
3 capsules ( to match Selumetinib capsules) orally twice a day for approximately 5 weeks treatment period
A single oral radioactive iodine dose of 100 mCI(3.7 GBq) 131I (+/-10% at the time of administration)to be administered 30 days after randomization. Additionaly, Thyrogen (Recombinant human TSH) will be used to stimulate iodine uptake according to the manufacturer's recommendation(0.9 mg intramuscular injection once a day for the 2 days prior to the dose of radioactive iodine)
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
Differentiated thyroid cancer Tumor \>4 cm, or Gross extra-thyroid extension, or 1 lymph node \>1 cm, or 5 or more lymph nodes of any size Previous thyroidectomy Must be able to receive radioactive iodine therapy Must be able to receive Thyroid Stimulating Hormone suppression
Exclusion criteria
Metastaic disease Anaplastic thyroid cancer, medullary thyroid cancer or Hurthle cell carcinoma Presence of anti-Tg antibodies Previous treatment with any radiation Unresolved toxicity ≥ common terminology criteria for adverse event Grade 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | At 18 months post-RAI treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | At 18 months post-RAI treatment | 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. |
| Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | At 18 months post-RAI treatment | 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. |
| Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | At 18 months post-RAI treatment | 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. |
Countries
Brazil, Denmark, France, Germany, Italy, Poland, Sweden, United States
Participant flow
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.
Participants by arm
| Arm | Count |
|---|---|
| Selumetinib 75 mg BD + RAI 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. | 155 |
| Placebo + RAI 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. | 78 |
| Total | 233 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 1 | 2 |
| Overall Study | Incorrect randomisation | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | New treatment following progression | 2 | 0 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 12 | 3 |
Baseline characteristics
| Characteristic | Total | Selumetinib 75 mg BD + RAI | Placebo + RAI |
|---|---|---|---|
| Age, Continuous | 46.8 Years STANDARD_DEVIATION 14.35 | 46.2 Years STANDARD_DEVIATION 14.2 | 47.9 Years STANDARD_DEVIATION 14.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 41 Participants | 27 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 192 Participants | 128 Participants | 64 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 6 Participants | 3 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 4 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 218 Participants | 145 Participants | 73 Participants |
| Sex: Female, Male Female | 132 Participants | 92 Participants | 40 Participants |
| Sex: Female, Male Male | 101 Participants | 63 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 155 | 2 / 78 |
| other Total, other adverse events | 141 / 154 | 43 / 77 |
| serious Total, serious adverse events | 7 / 154 | 0 / 77 |
Outcome results
Primary
Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + RAI | Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | 40.0 Percentage of participants |
| Placebo + RAI | Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | 38.5 Percentage of participants |
Comparison: 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.p-value: 0.820595% CI: [0.61, 1.87]Regression, Logistic
Secondary
Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + RAI | Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | 40.0 Percentage of participants |
| Placebo + RAI | Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; ITT Analysis Set | 38.5 Percentage of participants |
Comparison: 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.p-value: 0.820595% CI: [0.61, 1.87]Regression, Logistic
Secondary
Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + RAI | Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | 37.4 Percentage of participants |
| Placebo + RAI | Clinical Remission Rate (Expressed as Percentage of Patients in Clinical Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | 41.2 Percentage of participants |
Comparison: 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.p-value: 0.654995% CI: [0.42, 1.73]Regression, Logistic
Secondary
Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive
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
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Selumetinib 75 mg BD + RAI | Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | 37.4 Percentage of participants |
| Placebo + RAI | Complete Remission Rate (Expressed as Percentage of Patients in Complete Remission) at 18 Months Post-RAI Treatment; Subgroup Analysis BRAF/NRAS Mutation Positive | 41.2 Percentage of participants |
Comparison: 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.p-value: 0.654995% CI: [0.42, 1.73]Regression, Logistic