Clinical trial NCT05525273: Treatment of BRAF ( B-Rapidly Accelerated Fibrosarcoma) Mutated Papillary Craniopharyngioma
Official title: Neoadjuvant and Postoperative Treatment With Dabrafenib and Trametinib in BRAF Mutated Papillary Craniopharyngioma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Craniopharyngioma
Keywords: BRAF mutation
Dabrafenib
Trametinib
Neoadjuvant
Postoperative
Lead sponsor: Skane University Hospital
Sponsor class: OTHER
Collaborators: name: Novartis
First posted: 2022-09-01
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase 1, single arm, open label, multicenter.
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Tumor response
timeFrame: 1 month to 5 years (sliding timepoints)
Secondary outcomes:
measure: Response ratio
timeFrame: 1 year after initiation of study treatment
measure: Response duration
timeFrame: From time of study drug discontinuation to time of observed increased tumor volume assessed up to 1 year
measure: Operability after neoadjuvant trial treatment
timeFrame: 1 year after initiation of study treatment
measure: Progression-free survival 1 year
timeFrame: 1 year
measure: Progression-free survival 2 years
timeFrame: 2 years
measure: QOL after treatment
timeFrame: 1 year
measure: QOL after treatment
timeFrame: 1 year
measure: Cognitive status after treatment
timeFrame: 1 year
measure: Opthalmologic status after treatment
timeFrame: 1 year
measure: Hypothalamic status after treatment
timeFrame: 1 year
Other outcomes:
measure: Levels of circulating mutated BRAF
timeFrame: 1 week after initiation of trial treatment
measure: Levels of circulating mutated BRAF
timeFrame: 2 weeks after initiation of trial treatment
measure: Levels of circulating mutated BRAF
timeFrame: 6 months after initiation trial treatment
measure: Levels of circulating mutated BRAF
timeFrame: 12 months after initiation trial treatment
measure: Levels of circulating of mutated BRAF
timeFrame: 3 months after end of trial treatment
Locations:
city: Lund
country: Sweden
facility: Department of Endocrinology
Study officials:
affiliation: Department of Neurosurgery, SUS, Lund Sweden
name: Peter Siesjö, MD. PhD.
role: STUDY_CHAIR
affiliation: Department of Oncology, SUS, Lund Sweden
name: Sara Kinhult, MD. PhD
role: STUDY_CHAIR
affiliation: Department of Endocrinology, SUS, Lund, Sweden
name: Eva Marie Erfurth, MD. PhD
role: PRINCIPAL_INVESTIGATOR
References: