| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Radio Iodine Refractory Thyroid Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| This is a 35 patient pilot study (n=25 patients in the in BRAF wild type arm and n=10 patients in the BRAFV600E mutant arm) testing the hypothesis that the inhibition of MEK can restore iodine incorporation in BRAF wild type (WT) and a combined inhibition of BRAF and MEK can restore iodine incorporation in BRAFV600E mutant (MUT), radioiodine-refractory (RAIR) thyroid cancer |
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| E.2.2 | Secondary objectives of the trial |
1) To evaluate changes in thyroglobulin levels in treated patients.
2) To evaluate the safety/tolerability of trametinib and dabrafenib/trametinib combination therapy.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients must have histologically or cytologically confirmed progressive radioiodine refractory metastatic thyroid carcinoma of follicular origin (including papillary and its respective variants).
• Confirmation in a certified laboratory of the mutation status of BRAF gene (primary tumor, recurrent tumor, or metastasis) .
• Patients for whom a systemic treatment with sorafenib or lenvatinib or a chemotherapy is not considered and/or who refused to take either of these drugs within the next 6 months.
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 15 mm with CT scan, MRI, or calipers by clinical exam. Tumors in previously irradiated fields may be considered measureable if there is evidence of tumor progression after radiation treatment.
• RAI-refractory disease on structural imaging, defined as any one of the following:
1) A metastatic lesion that is not radioiodine-avid on a diagnostic or therapeutic radioiodine scan performed less than 1 year prior to enrollment in the current study, or
2) Morphologically progressive or stable disease despite adequate RIT at least 6 month prior to enrollment in the current study
There are no size limitations for the index lesion used to satisfy this entry criterion.
• No recent treatment for thyroid cancer as defined as:
1) No prior 131I therapy is allowed < 6 months prior to initiation of therapy on this protocol. A diagnostic study using < 400 MBq of 131I is not considered 131I therapy.
2) No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol. (Previous treatment with radiation for any indication is allowed if the investigator judges that the previous radiation does not significantly compromise patient safety on this protocol.)
3) No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy on this protocol.
• Age ≥ 18 years.
• ECOG performance status ≤ 2 (or Karnofsky ≥60%, see Appendix D).
• Life expectancy of greater than 3 months.
• Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• All prior treatment-related toxicities must be CTCAE v4.0 grade ≤ 1 (except alopecia). Grade 2 prior treatment related toxicities may be allowed after discussion with the Principal Investigator.
• Patients must have normal organ and bone marrow function as defined below:
• Absolute neutrophil count (ANC) > 1.5x109/L
• Hemoglobin ≥ 9 g/dL
• Platelets ≥ 100 x 109/L
• Albumin ≥ 2.5 g/dL
• Total bilirubin ≤ 1.5x institutional ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x institutional ULN unless it is related to the primary disease
• creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) ≥ 50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min
• Negative pregnancy test within 7 days prior to starting the study premenopausal women. Women of non-childbearing potential may be included without pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year.
• Fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. Effective methods of contraception are defined as those, which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
• Ability to understand and the willingness to sign a written informed consent document.
• Patients must agree to undergo to research biopsy of a malignant lesion if the mutation status cannot be proven through archival tissue specimen.
• Availability of archival tumor tissue from the thyroid cancer primary or metastasis (a tissue block or a minimum of 30 unstained slides would be required. Patients with less archival tissue available may still be eligible for the study after discussion with the Principal Investigator). This does not apply to patients who undergo a biopsy. |
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| E.4 | Principal exclusion criteria |
• Concomitant malignancies or previous malignancies within the last 3 years. Exception: Patients who have been disease-free for 3 years, patients with a history of completely resected non-melanoma skin cancer, and/or patients with indolent secondary malignancies, are eligible.
• Use of other investigational drugs within 28 days preceding the first dose of drug treatment during this study.
• Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
• Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib and/or to dabrafenib .
• History or evidence of cardiovascular risk including any of the following:
• History or evidence of current, clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to the initiation of therapy on this protocol are eligible).
• History of acute coronary syndromes (specifically, myocardial infarction and unstable angina), severe/unstable angina, coronary angioplasty, or stenting within 6 months prior to the initiation of therapy on this protocol.
• History of symptomatic congestive heart failure within 6 months prior to the initiation of therapy on this protocol.
• History of cerebrovascular attack or transient ischemic attack within 6 months prior to the initiation of therapy on this protocol.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant, lactating, or breast feeding women.
• Patients unable to follow a low iodine diet or requiring medication with high content in iodide (amiodarone).
• Patients who received iodinated intravenous contrast as part of a radiographic procedure within 3 months of study registration. Those that have had iodinated intravenous contrast within this time frame may still be eligible if a urinary iodine analysis reveals that the excess iodine has been adequately cleared after the last intravenous contrast administration.
• Unwillingness or inability to comply with study and follow-up procedures. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
To determine the proportion of patients with BRAF WT RAIR thyroid cancer in which trametinib and the proportion of patients with BRAF MUT (N-, H-, K-RAS mutant, RET/PTC rearrangement) RAIR thyroid cancer in which the combination-therapy of dabrafenib and trametinib can increase tumoral iodine incorporation sufficiently.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| the time point for evaluation of the primary endpoint is about three weeks after initiation of treatment with trametinib or with combination trametinib and dabrafenib |
|
| E.5.2 | Secondary end point(s) |
1) To evaluate changes in thyroglobulin levels in treated patients.
2) To evaluate the safety/tolerability of trametinib and dabrafenib/trametinib combination therapy.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| the time point for second endpoint is six months after drug treatment |
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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 | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Enhancing Radioiodine Incorporation into Radio Iodine Refractory Thyroid Cancers with MAPK Inhibition |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| patients with BRAF wild type: trametinib and patients with BRAFV600E mutant:trametinb + dabrafenib |
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| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | No |
| 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
|
| the end of the trial is after completion of treatment with trametinib or with combination trametinib and dabrafenib after SPECT Imaging. The trial will be closed even if the last subject did not unable to realize the last visit. |
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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 | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
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