E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
BRAF-mutated anaplastic thyroid cancer |
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E.1.1.1 | Medical condition in easily understood language |
Anaplastic thyroid cancer with BRAF mutation |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043745 |
E.1.2 | Term | Thyroid neoplasm malignant |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
This study aims to increase the number of patients that undergo a successful R0 tumor resection after neo-adjuvant BRAF/MEK inhibitor treatment. |
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E.2.2 | Secondary objectives of the trial |
To evaluatue: - Neo-adjuvant and adjuvant treatment related toxicity of dabrafenib/trametinib (according to CTCAE v. 5.0) - 30-day postoperative surgical complications - Histopathological response on neo-adjuvant treatment - Locoregional-free survival - Distant metastasis-free survival - Overall survival - Whether neo-adjuvant and adjuvant treatment with dabrafenib/trametinib influences quality of life |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order to be eligible to participate in this study, a subject must meet all of the following criteria: 1. Informed consent. 2. Age over 18 years old. 3. World Health Organization (WHO) Performance Status 0 or I. 4. Histologically confirmed ATC (centrally reviewed). 5. Confirmed presence of BRAFV600E/K mutation in primary tumor tissue. 6. No distant metastases (M0). 7. Free or secured airway. 8. Able to swallow pills. 9. Patients must have undergone complete disease staging including: PET-CT scan and CT-neck/thorax/abdomen. 10. No prior anticancer systemic treatment (including chemotherapy, immunotherapy, oncolytic viral therapy, other systemic therapies). 11. No prior radiotherapy to site of interest. 12. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥ 6.5 mmol/L, AST ≤ 2.5 x ULN, ALT ≤ 2.5 x ULN, Total bilirubin ≤ 1.5 X ULN, INR and PTT in normal range, LDH < 2xULN. Serum creatinine ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration rate > 50 mL/min/1.73m2. 13. Absence of additional severe and/or uncontrolled concurrent disease.
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E.4 | Principal exclusion criteria |
A potential subject who meets any of the following criteria will be excluded from participation in this study: 1. No informed consent. 2. History of cancer within 2 years from diagnosis of ATC (exception: basal cell skin cancer, in situ carcinoma). 3. Poorly differentiated transformation of previous differentiated thyroid cancer. 4. Presence of distant metastases. 5. Underlying medical conditions that, in the Investigator's opinion, will make the administration of study treatment hazardous or obscure the interpretation of toxicity determination or adverse events. 6. History of congestive heart failure, active cardiac conditions, including unstable coronary syndromes, significant arrhythmias and severe valvular disease must be evaluated for risks of undergoing general anesthesia. 7. Pregnancy or nursing.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint of the study will be R0 resection rate (efficacy) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- In the interim analysis after inclusion of 7 patients, >12 weeks after start neo-adjuvant therapy - In the final analysis after inclusion of 20 patients (if study not ended prematurely), >12 weeks after start neo-adjuvant therapy |
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E.5.2 | Secondary end point(s) |
a. Treatment limiting acute toxicity, grade 3-4 according to CTCAE version 5.0 b. 30 day postoperative surgical complications c. Histopathological response d. Locoregional control at 3 months, 6 months, 1 year and 2 years e. Distant metastases at 3 months, 6 months, 1 year and 2 years f. Overall survival g. Quality of life at baseline, 3 months, 6 months and 1 year
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After inclusion of the last patient: a. After treatment, >52 weeks after start neo-adjuvant therapy b. >30 days after surgical resection c. >30 days after surgical resection d. >3 months, 6 months, 1 year and 2 years after start neo-adjuvant therapy e. >3 months, 6 months, 1 year and 2 years after start neo-adjuvant therapy f. After last follow-up, >5 years after start neo-adjuvant therapy g. >3 months, 6 months, 1 year and 2 years after start neo-adjuvant therapy |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study is defined as the last patient’s last visit. An interim safety analysis will be done after 7 patients. In case of zero patients with a surgical resection the study will be terminated prematurely. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |