Treatment of BRAF ( B-Rapidly Accelerated Fibrosarcoma) Mutated Papillary Craniopharyngioma (Swecranio)

Neoadjuvant and Postoperative Treatment With Dabrafenib and Trametinib in BRAF Mutated Papillary Craniopharyngioma

Subjects with papillary craniopharyngioma harboring a BRAF mutation will be treated with a BRAF + MEK inhibitor (dabrafenib + trametinib) after informed consent. Study participants will be administered oral dabrafenib and trametinib until maximal tumor volume reduction assessed by MRI. Progression free survival, cognition, ophthalmologic status, hypothalamic status and quality of life will be assessed 1 year after initiation of study treatment

Study Overview

• Status: Recruiting
• Conditions: Craniopharyngioma
• Intervention / Treatment: Drug: Oral dabrafenib and trametinib

Detailed Description

Background. Papillary craniopharyngioma harbours a BRAF mutation in 90% of cases. Treatment with BRAF + MEK (mitogen activated protein kinase ) inhibitors (dabrafenib + trametinib) may prevent patients from undergoing surgery with a high risk of serious side effects, or provide an additional treatment option when further surgery is not advised.

Study intervention Subjects with newly diagnosed craniopharyngioma where radical surgery is not considered adequate or patients with recurrence of craniopharyngioma where further surgery is not considered possible without serious sequelae will be asked for informed consent Study participants are treated continuously with dabrafenib and trametinib orally, until maximal tumor shrinkage. Evaluation is done by MRI to measure tumor volume, as well as assessment of performance status, quality of life, cognition, ophthalmologic status, performance status and hypothalamic status.

Study type The study is a Phase II, single armed, open label and multicenter study Study drugs are Dabrafenib (Tafinlar) and trametinib (Mekinist) Primary outcome To evaluate tumor response in the form of reduced tumor volume on MRI in patients with papillary craniopharyngioma during treatment with dabrafenib and trametinib.

Secondary outcomes

To evaluate dabrafenib and trametinib treatment for the following aspects:

• response according to RECIST Duration of response for patients treated without subsequent surgery
• how many patients become operable after neoadjuvant treatment
• progression-free survival after 1 and 2 years
• quality of life during and after treatment The effect of treatment on vision, cognition and hypothalamic effects Exploratory outcomes Levels of circulating BRAF Trial population 25 patients Trial duration Participants are treated with the study treatment for at least one year if the treatment is well tolerated, to maximum tumor reduction, or longer according to the investigators´s assessment. Treatment is discontinued in case of progression, unacceptable toxicity or at the request of the patient.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Eva Marie Erfurth, MD. PhD.; Phone Number: +4646172363; Email: eva_marie.erfurth@med.lu.se
• Study Contact Backup: Name: Sara Kinhult, MD. PhD.; Phone Number: +4646177587; Email: sara.kinhult@skane.se

Study Locations

• Sweden
  • Lund, Sweden, 22185
    • Recruiting
    • Department of Endocrinology
    • Contact: Eva Marie Erfurth, MD, PhD; Phone Number: +4646172363; Email: eva_marie.erfurth@med.lu.se
    • Contact: Sara Kinhult, MD, PhD; Phone Number: +46 46177587; Email: sara.kinhult@skane.se
    • Principal Investigator: Eva Marie Erfurth, MD, PhD
    • Sub-Investigator: Kinhult Sara, MD, PhD
    • Sub-Investigator: Ekman Bertil, MD, PhD
    • Sub-Investigator: Dalhlqvist Per, MD, PhD
    • Sub-Investigator: Ragnarsson Oscar, MD, PhD
    • Sub-Investigator: Siesjö Peter, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Histologically verified papillary craniopharyngioma.
2. BRAF mutated V600E (valine 600 glutamine), verified immunohistochemically and by molecular genetic analysis
3. Newly diagnosed tumor, or recurrence after previous surgery, where surgery is not considered to be able to be performed radically without the risk of serious or permanent sequelae.
4. Age over 18 years
5. Functional status according to ECOG (Eastern Cooperative Oncology Group performance status) 0-2

6. Adequate organ function:

   neutrophils> 1.5 x 109 platelets> 100 x 109 creatinine <1.5 x ULN (upper limit of normal) or creatinine clearance <45 ml / min bilirubin <1.5 x ULN ASAT (aspartate aminotransferase) / ALAT (alanine aminotransferase) <2.5 x ULN

7. Ability to understand and give informed consent.
8. Previous cancer, which does not require current treatment is allowed.
9. The patient agrees to use an adequate method to avoid pregnancy.

Exclusion Criteria:

1. Ongoing treatment in another drug study or other experimental treatment.
2. Previous treatment with BRAF or MEK inhibitors.
3. Hypersensitivity to study drugs.
4. Ongoing treatment with non-authorized drugs, (strong inducers of CYP2C8 or CYP3A4). If the patient is on unauthorized drugs, they must be discontinued at least 14 days before inclusion.
5. Known cardiovascular disease where treatment with MEK inhibitors is considered inappropriate, eg severe heart failure, prolongation of QT time, uncontrolled arrhythmia, recent (<6 months) cardiac infarction, uncontrolled hypertension.
6. Active bleeding; intracranial hemorrhage last 4 weeks before inclusion.
7. Thromboembolic disease last 6 months and unstable anticoagulant treatment less than 4 weeks before inclusion.
8. Women who are pregnant or breastfeeding.
9. Previous central serous retinopathy or retinal vein occlusion.
10. Previous uveitis or iritis last 4 weeks before inclusion.
11. Surgery within the last 3 weeks.
12. For postoperative patients; radiation therapy within the last 3 months.

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: Dabrafenib and trametinib; Dabrafenib 75 mg twice daily and trametinib 2 mg once daily	Drug: Oral dabrafenib and trametinib; Neoadjuvant or postoperative treatment of patients with verified BRAF mutated papillary craniopharyngioma

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response	To evaluate tumor response measured as maximally reduced tumor volume on MRI during treatment with dabrafenib and trametinib. Maximally reduced volume is defined as the time point where no further reduction of tumor volume can be observed	1 month to 5 years (sliding timepoints)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response ratio	Response ratio according to RECIST	1 year after initiation of study treatment
Response duration	Duration of response for patients treated without subsequent surgery	From time of study drug discontinuation to time of observed increased tumor volume assessed up to 1 year
Operability after neoadjuvant trial treatment	Number of patients which become operable after neoadjuvant treatment	1 year after initiation of study treatment
Progression-free survival 1 year	Defined as unchanged or diminished tumor volume	1 year
Progression-free survival 2 years	Defined as unchanged or diminished tumor volume	2 years
QOL after treatment	Quality of life assessed by EQ5D5L (EuroQual 5 dimensions 5 levels) at 1 year after start of study treatment and compared to baseline	1 year
QOL after treatment	Quality of life assessed by EORTC QLQ30 (European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire 30) at 1 year after start of study treatment and compared to baseline	1 year
Cognitive status after treatment	Cognitive status assessed by CNS (central nervous system) Vital Signs 1 year after initiation of treatment and compared to baseline	1 year
Opthalmologic status after treatment	Opthalmologic status assessed as compound measure of visual acuity and visual field defects 1 year after initiation of treatment and compared to baseline	1 year
Hypothalamic status after treatment	Hypothalamic status assessed as compound measure of pituitary and hypothalamic status 1 year after initiation of treatment and compared to baseline	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of circulating mutated BRAF	BRAF assessed by plasma analysis and compared to baseline levels	1 week after initiation of trial treatment
Levels of circulating mutated BRAF	BRAF assessed by plasma analysis and compared to baseline levels	2 weeks after initiation of trial treatment
Levels of circulating mutated BRAF	BRAF assessed by plasma analysis and compared to baseline levels	6 months after initiation trial treatment
Levels of circulating mutated BRAF	BRAF assessed by plasma analysis and compared to baseline levels	12 months after initiation trial treatment
Levels of circulating of mutated BRAF	BRAF assessed by plasma analysis and compared to baseline levels	3 months after end of trial treatment

Collaborators and Investigators

• Sponsor: Eva Marie Erfurth, MD, PhD
• Collaborators: Novartis
• Investigators: Study Chair: Peter Siesjö, MD. PhD., Department of Neurosurgery, SUS, Lund Sweden; Study Chair: Sara Kinhult, MD. PhD, Department of Oncology, SUS, Lund Sweden; Principal Investigator: Eva Marie Erfurth, MD. PhD, Department of Endocrinology, SUS, Lund, Sweden

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2023
• Primary Completion (Estimated): September 10, 2027
• Study Completion (Estimated): April 10, 2028

Study Registration Dates

• First Submitted: April 20, 2022
• First Submitted That Met QC Criteria: August 30, 2022
• First Posted (Actual): September 1, 2022

Study Record Updates

• Last Update Posted (Estimated): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Trametinib; BRAF mutation; Neoadjuvant; Postoperative; Dabrafenib
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Musculoskeletal Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Bone Diseases; Bone Neoplasms; Craniopharyngioma; Adamantinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: ver 1-21

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No