NEO- and Adjuvant Targeted Therapy in Braf-mutated Anaplastic Cancer of the Thyroid (NEO-ATACT Study) (NEO-ATACT)

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.

Study Overview

• Status: Recruiting
• Conditions: Anaplastic Thyroid Cancer
• Intervention / Treatment: Drug: dabrafenib/trametinib

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ellen Kapiteijn, MD, PhD; Phone Number: 0031-71-5263486; Email: h.w.kapiteijn@lumc.nl
• Study Contact Backup: Name: Saskia Luelmo, MD; Phone Number: 0031-71-5263464; Email: S.A.C.Luelmo@lumc.nl

Study Locations

• Netherlands
  • Zuid-Holland
    • Leiden, Zuid-Holland, Netherlands, 2300RC
      • Recruiting
      • Ellen Kapiteijn
      • Contact: Ellen Kapiteijn, MD, PhD; Phone Number: +31715263486; Email: h.w.kapiteijn@lumc.nl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: neo-adjuvant and adjuvant braf/mek-inhibition; Participants will undergo neo-adjuvant treatment with dabrafenib/trametinib. After 6 weeks of BRAF/MEK inhibitors, participants will undergo an evaluation of resectability. If the tumor is resectable, patients undergo tumor resection. If not resectable, neo-adjuvant treatment continues for another 6 weeks followed by a new evaluation. All resected patients receive adjuvant dabrafenib/trametinib up to a total treatment duration of 52 weeks. If resection is not possible, patients will continue on dabrafenib/trametinib.

Drug: dabrafenib/trametinib; braf/mek-inhibition

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
primary endpoint of the study will be R0 resection rate (efficacy).	primary endpoint of the study will be R0 resection rate (efficacy).	after 6-12 weeks braf/mek-inhibition

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neo-adjuvant and adjuvant treatment related toxicity of dabrafenib/trametinib (according to CTCAE v. 5.0)	Neo-adjuvant and adjuvant treatment related toxicity of dabrafenib/trametinib (according to CTCAE v. 5.0) during 1 year of treatment with braf/mek-inhibition	during 1 year of treatment with braf/mek-inhibition
30-day postoperative surgical complications	30-day postoperative surgical complications (within 30 days after surgery)	within 30 days after surgery
Histopathological response after neo-adjuvant treatment	Histopathological response after neo-adjuvant treatment: complete response (<10% tumor cells), partial response (between more than 10% and up to 50% tumor cells), or no response (still more than 50% tumor cells)	6-12 weeks neo-adjuvant braf/mek-inhibition
Locoregional-free survival	Locoregional-free survival	at 2 years
Distant metastasis-free survival	Distant metastasis-free survival	at 2 years
Overall survival	Overall survival	at 2 years

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Novartis
• Investigators: Principal Investigator: Ellen Kapiteijn, MD, PhD, Leiden University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2023
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: June 29, 2023
• First Submitted That Met QC Criteria: October 5, 2023
• First Posted (Actual): October 12, 2023

Study Record Updates

• Last Update Posted (Actual): October 12, 2023
• Last Update Submitted That Met QC Criteria: October 5, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Thyroid Carcinoma, Anaplastic; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: NEOAC

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No