Clinical trial NCT06079333: NEO- and Adjuvant Targeted Therapy in Braf-mutated Anaplastic Cancer of the Thyroid (NEO-ATACT Study)
Official title: NEO- and Adjuvant Targeted Therapy in Braf-mutated Anaplastic Cancer of the Thyroid (NEO-ATACT Study)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Anaplastic Thyroid Cancer
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2023-10-12
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: prospective, non-randomized, single center, open-label phase II study
Primary purpose: TREATMENT

Brief summary: Anaplastic thyroid cancer (ATC) is an almost invariable lethal cancer in humans.

Most patients present with a rapid progressive mass in the neck with progressive complaints like dyspnoea, dysphagia or pain. The risk of suffocation is the main reason for rapid surgical intervention, but we know from literature that an oncological resection with clear margins is seldomly achieved. Some patients deteriorate that fast after surgery that radiation therapy and/or chemotherapy is not feasible anymore. Patients with BRAF-mutated ATC already have shown to benefit from targeted BRAF/MEK inhibition. This study aims to increase the number of patients that undergo a successful R0 tumor resection after neo-adjuvant BRAF/MEK inhibitor treatment.

Detailed description: Unmet need ATC is a very serious condition and is, apart from a few exclusive cases, always lethal. Many patients suffer uncontrollable loco-regional disease with even so uncontrollable complaints of airway obstruction, oesophagus obstruction, pain and neck movement impairment. One of the only shown beneficial treatment is complete surgical resection with clear surgical margins combined with radiotherapy and systemic treatment. However, in less than 10-15% of the patients the pathologist reports clear surgical margins. Thereby it is noticeable that surgery often results in serious morbidity, due to an esophagectomy, laryngectomy or trachea resection all accompanied by an extensive reconstruction. All of these come with serious morbidity and seldomly lead to clear margins and better outcome.

Proposed solution A single center, phase II study for the evaluation of safety and efficacy of neo-adjuvant and adjuvant dabrafenib/trametinib treatment in BRAF mutated ATC patients. By introducing neo-adjuvant treatment the hypothesis is that better selection is done for patients who are eligible for complete surgery and that surgery results more often in clear surgical margins after neo-adjuvant treatment. Second benefit of treating patients with combined loco-regional and systemic agents before surgery is that micro/macrometastases (being there in at least 30% of the patients at diagnosis) are already being treated directly after diagnosis. Lastly, adjuvant treatment with dabrafenib/trametinib will hopefully result in reduction of local and distant recurrences after surgery.

Eligibility criteria: Inclusion 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.

Exclusion Criteria:

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.

Primary outcomes:
measure: primary endpoint of the study will be R0 resection rate (efficacy).
timeFrame: after 6-12 weeks braf/mek-inhibition
Secondary outcomes:
measure: Neo-adjuvant and adjuvant treatment related toxicity of dabrafenib/trametinib (according to CTCAE v. 5.0)
timeFrame: during 1 year of treatment with braf/mek-inhibition
measure: 30-day postoperative surgical complications
timeFrame: within 30 days after surgery
measure: Histopathological response after neo-adjuvant treatment
timeFrame: 6-12 weeks neo-adjuvant braf/mek-inhibition
measure: Locoregional-free survival
timeFrame: at 2 years
measure: Distant metastasis-free survival
timeFrame: at 2 years
measure: Overall survival
timeFrame: at 2 years
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Ellen Kapiteijn
state: Zuid-Holland
Study officials:
affiliation: Leiden University Medical Center
name: Ellen Kapiteijn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: