Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Rare Diseases

Melanoma

Neoplasm Metastasis

Brain Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Channel Blockers

Trametinib

Dabrafenib

Gallopamil

Protein Kinase Inhibitors

Enzyme Inhibitors

Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Dabrafenib will be provided as 50 mg and 75 mg capsules

Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Novartis Pharmaceuticals

This is a multi-cohort, open label, Phase II study with Dabrafenib (GSK2118436) and Trametinib (GSK1120212) combination therapy in subject with BRAF mutation-positive melanoma that has metastasized to the brain. This study will evaluate the safety and efficacy of 4 cohorts. Cohorts will consist of; V600 E, D, K, R mutations, metastases to the brain, symptomatic and asymptomatic, with or without prior local (brain) therapy, with or without prior local (brain) therapy, and range of ECOG scores from 0-2.

Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

BRF117277: A Phase II, Open-Label, Multicentre Study of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. No hypothesis testing completed for cohort A, B,C and D

Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort A, B,C and D

Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime. This is based on investigator-assessed response. No hypothesis testing completed for cohort A,B,C and D

the number of subjects with a confirmed overall Complete response (CR) or Partial response (PR) by investigator assessment using the Response evaluation criteria in solid tumors (RECIST 1.1 criteria). To determine the overall response, all target and non-target lesions will be assessed using modified RECIST 1.1 criteria.

Duration of intracranial, extracranial and overall response, are defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression. No hypothesis testing completed for cohort A,B,C and D

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Overall survival (OS) is defined as the time from the first dose until death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Cohort A

Cohort B

Cohort C

Cohort D

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population.

Intracranial Response (IR) Rate in Cohort A

All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Intracranial Response Rate of Cohorts B, C and D

Intracranial

Extra cranial

Overall rate

Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort

Extracranial Response Rate (ER) for Each Cohort

Overall Response (OR) for Each Cohort

Duration of intracranial

Duration of extracranial

Duration of Overall Response

Duration of Intracranial, Extracranial and Overall Response for Each Cohort

Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment

Overall Survival (OS) for Each Cohort

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antibodies

Antibodies, Monoclonal

Immunoglobulins

For the phase Ib study, HLX208 is administered orally at two dose levels of 600mg BID or 900 mg BID. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks.

For the phase II study, HLX208 is administered orally with the RP2D dose. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks.

HLX208 is a BRAF V600E inhibitor ,and HLX10 is an anti-PD-1 monoclonal antibody.

HLX208+HLX10

Shun Lu, Dr.

An open-label, multicenter phase Ib/II clinical study to evaluate safety, tolerability, pharmacokinetics, and efficacy of HLX208 (BRAF V600E Inhibitor) combined with HLX10 （anti-PD-1 monoclonal antibody）in advanced NSCLC patients with BRAF V600 mutation.

This is an open-label, multicenter phase Ib/II clinical study to evaluate safety, tolerability, pharmacokinetics, and efficacy of HLX208 (BRAF V600E Inhibitor) combined with HLX10 （anti-PD-1 monoclonal antibody）in advanced NSCLC patients with BRAF V600 mutation.

For the phase Ib study, HLX208 is administered orally at two dose levels of 600mg BID or 900 mg BID. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks.

For the phase II study, HLX208 is administered orally with the RP2D dose. And HLX10 is administered intravenously at a fixed dose of 300mg every 3 weeks.

A Phase Ib/II Clinical Trial to Evaluate the Safety and Efficacy of HLX208+HLX10 in NSCLC With BRAF V600E Mutation

A Phase Ib/II Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of HLX208 （BRAF V600E Inhibitor） Combined With Serplulimab（HLX10, Anti-PD-1 Antibody） in Advanced NSCLC Patients With BRAF V600E Mutation.

Association of efficacy with biomarkers including PD-L1 expression, BRAF V600E mutation abundance, MSI status and TMB status.

The maximum tolerated dose of HLX208 combined with HLX10.

The proportion of patients experiencing dose limiting toxicity (DLT) events.

Objective response rate assessed by the investigator per RECIST 1.1.

The proportion of patients experiencing SAE.

Area under the concentration-time curve from time 0 to the last concentration measurable time point.

Area under the concentration-time curve from time 0 to infinity.

Area under the steady-state concentration-time curve

Shanghai Henlius Biotech

patients on adjuvant treatment with dabrafenib + trametinib

There is no treatment allocation. Patients administered dabrafenib by prescription that have started before inclusion of the patient into the study will be enrolled.

dabrafenib

There is no treatment allocation. Patients administered trametinib by prescription that have started before inclusion of the patient into the study will be enrolled.

trametinib

Non-interventional (observational) cohort prospective real life study with primary and secondary data collection from patients on adjuvant treatment with dabrafenib + trametinib in patients with completely resected high-risk stage III (stage IIIA \[lymph node \> 1mm\], IIIB, IIIC and IIID according to AJCC 8th edition) melanoma in Turkey.

The prospective registration of completely resected high-risk stage III melanoma patients treated with dabrafenib and trametinib in the adjuvant setting will be based on collaboration with centers of excellence on melanoma patients treatment. Pre-identified centers (up to 12) considered as the most advanced according to their knowledge and experience, will take part in the patients recruitment.

Adjuvant Dabrafenib and Trametinib Treatment in Patients With Completely Resected High-risk Stage III Melanoma.

A Real-life Study to Evaluate the Use of Adjuvant Treatment With Dabrafenib and Trametinib in Routine Practice in Patients With Completely Resected High-risk Stage III Melanoma

RFS is the length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer.

Total duration of treatment defined as median time on adjuvant dabrafenib + trametinib treatment (from start to end of treatment/permanent treatment discontinuation).

Collection of number of patients on treatment

Rate of permanent study drug discontinuation due to any reason will be collected

Rate of permanent drug discontinuation due to pyrexia and other AEs will be collected

Collection of incidence and severity of Adverse Events

Collection of procedures of the management of Adverse Events (AEs)

death, relapse, AEs, withdrawal of consent, other

Average dose of dabrafenib and trametinib used during the treatment including dose reductions.

collection of the proportion of patients with dabrafenib and trametinib dose reduction during treatment

Collection of the reason for dabrafenib and trametinib dose reduction

Collection of the type of relapse: local, regional or distant

Antipyretics

Anti-Inflammatory Agents

Antirheumatic Agents

Fibrinolytic Agents

Analgesics

Platelet Aggregation Inhibitors

Aspirin

Primary IIIB-IV BRAF V600E mutated advanced non-small cell lung cancer in a population of patients with advanced lung cancer proposed to be treated with Trametinib， Dabrafenib and Asprin

Treatment drug: Dabrafenib 150 mg BID, Trametinib 2 mg QD, Aspirin 100 mg/tablet, 1 tablet/time, QD

Combind asprin with Trametinib and Dabrafenib

He Yong, MD

The purpose of this study is to observe the safety and efficacy of Aspirin combined with Trametinib and Dalafenib in the treatment of advanced BRAF V600E mutated non-small cell lung cancer (NSCLC)

lung cancer is the leading cause of morbidity and mortality in China, and non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. The incidence of V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in NSCLC is 1.5% to 3.5%, and BRAF V600 accounts for about 30-50% of all BRAF mutations, among them, V600E mutation is the most common . NSCLC patients with BRAF V600 mutation have poor prognosis and shorter overall survival (OS). In terms of drug therapy for these patients didn't get a better clinical benefits of chemotherapy and immunotherapy, and the progression free survival (PFS) of chemotherapy is only 1.5\~4.2 months . The PFS of patients with BRAF-mutated NSCLC treated with immune checkpoint inhibitors was only 3.1 to 5.3 months . In recent years, the application of targeted therapy has brought new hope for patients with lung cancer BRAF mutation. In three cohorts of the Phase II clinical trial BRF113928, the BRAF inhibitor darafenib, was demonstrated has a significant efficacy as a single agent in treated patients with BRAF V600E mutation (cohort A), combined with mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor trametinib in treated patients (cohort B), and combined with trametinib in treated patients (cohort C), respectively. Objective response rates (ORR) were 33.0%, 63.2%, and 64.0%, and PFS were 5.5, 9.7, and 14.6 months, respectively. BRF113928 research shows that Dabrafenib combined with Trametinib had good efficacy in the treatment of BRAFV600 mutant NSCLC patients, regardless of whether it was used as first-line therapy or back-line therapy, and was superior to BRAF single-agent targeted therapy. In terms of safety, the most common adverse event (AE) of Dabrafenib combined with Trametinib was fever. In cohort B and cohort C, the incidence of fever of all grades was 46% and 64%, respectively, but most of them were grade , while the incidence of grade 3-4 AE was relatively low, 2% and 11%. In general, it is safe and controllable . The main management methods for fever AE caused by Dabrafenib combined with Trametinib as follows: after the first occurrence of fever syndrome, the patient should stop taking both drugs and immediately start oral antipyretic therapy. After the fever, it is still recommended to continue the drug for 3 days before stopping the fever treatment. The selection and usage of related antipyretic drugs should be comprehensively evaluated by doctors, and the options include non-steroidal anti-inflammatory drugs, acetaminophen, and anethene. At present, the latest NCCN and CSCO both regard Dabrafenib combined with Trametinib as the preferred first-line treatment for BRAF V600E mutated advanced NSCLC patients . In March 2023, Dabrafenib combined with Trametinib entered the national medical insurance directory, reducing the economic burden of patients. However, drug resistance to targeted drugs is inevitable. Studies have shown that the resistance mechanism of BRAF/MEK inhibitors is mainly mediated by the PI3K-Akt-mtor and RAS-RAF-MEK pathways, such as cell cycle related gene changes, PI3K-AKT pathway activation, NRAS/KRAS mutations, etc. Drug resistance mechanism of Dabrafenib combined with Trametinib is complicated, there are few opportunities to use targeted drugs, also lack of clear recommendation for follow-up treatment guidelines, usually systemic treatment such as immunotherapy and chemotherapy are adopted. How to overcome the resistance mechanism, delay drug resistance, and further prolong the PFS and OS of patients of Dabrafenib combined with Trametinib still need more exploration.

Previous epidemiological studies have suggested that aspirin may reduce the incidence of certain cancers, including lung cancer. A study from the United States included 365 patients with advanced non-small cell lung cancer treated with Osimertinib, 77 of whom were taking aspirin while taking Osimertinib. The results showed that the median PFS of patients treated with aspirin was 21.3 months, which was significantly longer than the median PFS of 11.6 months of patients treated with Osimertinib alone. However, the median OS of patients treated with aspirin was lower than that of patients treated with Osimertinib alone, which was 32.3 months. Combined with aspirin could significantly reduce the risk of death of patients by 44%, suggesting that EGFR-TKI combined with aspirin could improve the patients' PFS and reduce the risk of death and bleeding events. And the same as the targeted drugs, Dabrafenib who joint Trametinib whether can combine with aspirin? How safe is it? Can the combination of aspirin with Dabrafenib and Trametinib improve the PFS and OS of patients? Aspirin has antipyretic and analgesic effects, while one of the most common adverse reactions of Dabrafenib combined with Trametinib is fever. Can the combination of Dabrafenib combined with Trametinib reduce the occurrence of adverse events of fever? At present, in the field of lung cancer, there is no literature report on aspirin combined with Dabrafenib and Trametinib in the treatment of BRAF V600E mutated advanced NSCLC. In order to solve the above problem, further improve the BRAF V600E mutations in NSCLC patients with long-term survival, we proposed the observational phase II study to evaluate the efficacy and safety of aspirin combined with Dabrafenib and Trametinib in advanced NSCLC with BRAF V600E mutation.

Primary Objectives: To determine the progression-free survival time (PFS) of aspirin combined with Dabrafenib and Trametinib;

Secondary Objectives:

A, To determine the 3 year Overall Survival (OS) in the aspirin combined with Dabrafenib and Trametinib; B, To observe the Objective Response Rate (ORR) of aspirin combined with Dabrafenib and Trametinib; C, To observe the Disease Control Rate (DCR) in aspirin combined with Dabrafenib and Trametinib; D, To observe the fever-reducing rate of aspirin combined with Dabrafenib and DabrafenibTrametinib E, To observe the risk of coronary events in patients with aspirin combined with Dabrafenib and Trametinib.

Subjects were treated with aspirin in combination with trametinib and dalafenib. The subject will be observed on the drug for 36 months, unless the subject develops tumor progression (deterioration) or a toxic reaction that is difficult to tolerate.

Treatment drug: Dabrafenib 150 mg BID, Trametinib 2 mg QD, Aspirin 100 mg/tablet, 1 tablet/time, QD.

Dabrafenib or trametinib should be interrupted or adjusted in time if a participant developed toxicity during treatment. In case of severe drug toxicity, the participant must discontinue the drug.. If the subject develops therapeutic toxicity of Asprin during the administration, the investigator shall interrupt or adjust the dose of aspirin in a timely manner. If serious drug toxicity occurs, the subject must stop taking the drug.

Evaluate the Efficacy and Safety of Aspirin in Combination With Trametinib and Dabrafenib

An Observational Phase II Study to Evaluate the Efficacy and Safety of Aspirin in Combination With Trametinib and Dabrafenib in Advanced Non-small Cell Lung Cancer Patients With BRAF V600E Mutation

Univariate analysis of the relationship between lung cancer and treatment regimens: DFS and OS were used to compare whether there was a statistical difference (P-value less than or equal to 0.05) in the overall survival curve between the experimental and control groups by log-rank test; Multifactor analysis: PFS and OS will use a COX-proportional hazard model to estimate the hazards ratio and explore other factors that influence efficacy.

Security analysis data sets will be used for analysis. descriptive statistics, adverse events (AE), laboratory test results (blood biochemistry, liver and kidney function, coagulation and stool routine, etc.) and important vital signs (such as blood pressure) were mainly used to summarize and analyze the list.

Progression-free survival (PFS) was calculated in 36 patients treated with aspirin combined with Dabrafenib and Trametinib

Refers to the proportion of patients with fever from the beginning of treatment to the end of follow-up.

3 year Overall Survival (OS) was calculated in 36 patients treated with aspirin combined with Dabrafenib and Trametinib

The Objective Response Rate (ORR) was calculated in 36 patients treated with aspirin combined with Dabrafenib and Trametinib. ORR will be analyzed using tests, and logistic regression methods will be used to explore other factors that influence the outcome.

The Disease Control Rate (DCR) was calculated in 36 patients treated with aspirin combined with Dabrafenib and Trametinib. DCR will be analyzed using tests, and logistic regression methods will be used to explore other factors that influence the outcome.

Risk of coronary events was calculated in 36 patients treated with aspirin combined with Dabrafenib and TrametinibTrametinib

Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Director of Department of Respiratory Diseases

Encorafenib hard capsule will be orally self-administered. A fixed-flat dose of 300 mg (4 x 75 mg) Per Oral (PO) encorafenib will be administered once-daily (QD).

Encorafenib

Li Zhang, MD

This is a phase 1, multicenter, open-label, single-arm study to investigate the safety and tolerability of encorafenib 300 mg once daily (QD) monotherapy in adult Chinese participants with B-RAF Proto-oncogene, Serine/threonine Kinase V600E (BRAF V600E) mutant advanced solid tumors (unresectable metastatic melanoma or metastatic non-small cell lung cancer (NSCLC)), who are BRAF-inhibitor treatment-naïve and have failed the previous therapy(ies) in the metastatic setting or are not eligible to standard therapy. Participants will be eligible for the study based on identification of a BRAF V600E mutation in tumor tissue by a local National Medical Products Administration (NMPA) approved assay obtained prior to screening.

Phase 1 Safety Study of Encorafenib in Chinese Patients With Advanced Metastatic BRAF V600E Mutant Solid Tumors

Multicenter, Open-label, Phase 1 Study Investigating the Safety and Tolerability of Encorafenib Monotherapy in BRAF V600E-mutated Chinese Patients With Advanced Metastatic Solid Tumors

Incidence, nature and severity of treatment emergent adverse events (TEAEs) graded as per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03, TEAEs leading to dose interruption, reduction and discontinuation, treatment-emergent serious adverse events (SAEs) and deaths will be reported.

Clinically notable shift from baseline in blood hematology parameters data \[Hemoglobin (Low/High); Leukocytes (Low/ High); Neutrophils (Low); Platelets (Low/High); Lymphocytes (Low/High)\] will be graded using NCI CTCAE Version 4.03. Clinically notable shift is defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. Number of participants with at least one clinically notable shift during study will be reported.

Clinically notable shift from baseline in blood clinical chemistry parameter values \[Phosphate (Low); Alanine Aminotransferase (High); Albumin (Low); Alkaline Phosphatase (High); Aspartate Aminotransferase (High); Bilirubin (High); Calcium Corrected (Low/High); Creatinine (High); Glucose (Low/High); Magnesium (Low/High); Potassium (Low/High); Sodium (Low/High)\] will be graded using NCI-CTCAE, Version 4.03. Clinically notable shift is defined as a worsening from baseline by at least 2 grades, or to grade 3 or above. Number of participants with at least one clinically notable shift during study will be reported.

Clinically notable shift from baseline in coagulation parameters parameter values \[activated partial thromboplastin time (seconds), international normalized ratio (INR) or prothrombin time (seconds)\] will be graded using NCI-CTCAE, Version 4.03. Number of participants with abnormal levels or notable shift during study will be reported.

Quantitative assessment of appearance, color, specific gravity, blood, glucose, leukocytes, ketones, pH and protein at each visit and changes from baseline (for quantitative parameters) will be calculated and tabulated. Microscopy findings (normal/abnormal and clinical significance) will be recorded. Number of participants with abnormal/ clinical significant changes during study will be reported.

Clinically notable elevated values: Systolic blood pressure (BP): ≥ 160 mmHg and an increase ≥ 20 mmHg from baseline; Diastolic BP: ≥ 100 mmHg and an increase ≥ 15 mmHg from baseline; Heart rate : ≥ 120 beats/min (bpm) with increase from baseline of ≥ 15 bpm; Weight (kg) increase from baseline of ≥ 10%; Body temperature(°C) ≥ 37.5°C). Clinically notable low values: Systolic BP: ≤ 90 mmHg with decrease from baseline of ≥ 20 mmHg; Diastolic BP: ≤ 50 mmHg with decrease from baseline of ≥ 15 mmHg; Heart rate: ≤ 50 bpm with decrease from baseline of ≥ 15 bpm; Weight: ≥ 20% decrease from baseline; Body temperature \[°C\]: ≤ 36 °C. Number of participants with TEAEs related to notable changes to the vital signs after the start of study drug will be reported.

12-lead ECGs will be obtained using an internationally recognized 12-lead cardiograph. Clinically notable ECG values: QT \[millisecond (ms)\] and QT interval (ms) corrected for heart rate using Fridericia's formula (QTcF) intervals (ms): increase from baseline \> 30 ms; increase from baseline \> 60 ms, new \> 450 ms, new \> 480 ms, new \> 500 ms. Heart rate (beats/min): increase from baseline \> 25% to a value \> 100 bpm, decrease from baseline \> 25% and to a value \< 50 bpm. Number of participants with TEAEs related to abnormal or notable changes to ECG parameters after the start of study drug will be reported.

Adverse event of special interest (AESI) are as follows: acute renal failure, cutaneous non-squamous cell carcinoma, cutaneous squamous cell carcinoma, melanomas, palmar-plantar erythrodysaesthesia syndrome, photosensitivity, rash, severe cutaneous adverse reactions, facial paresis, tachycardia, haemorrhage, hepatic failure, liver function test abnormalities, myopathy and uveitis-type events. Number and percentage of participants with at least one event of any AESI and of each category of AESI will be reported in participants.

Pierre Fabre Medicament

The first cohort of 15 subjects will receive oral dabrafenib 150 mg twice daily orally for 7 to 14 days prior to surgery in Cohort A; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

The second cohort of 15 subjects will receive dabrafenib 150 mg twice daily combined with trametinib 2 mg once daily (Cohort B) orally for 7 to 14 days prior to surgery; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

Dabrafenib will be provided for oral administration as 50 mg and 75 mg capsules. Dabrafenib will be dosed orally with approximately 200 mL of water, twice a day. Dabrafenib should be administered under fasting conditions.

Dabrafenib 150 mg

Trametinib study treatment will be provided as 0.5 mg and 2.0 mg tablets. should be taken orally with approximately 200 mL of water under fasting conditions, either one hour before or two hours after a meal.

Trametinib 2.0 mg

GSK Clinical Trials

This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites

An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib were collected on day of surgical resection of the brain metastasis(es), Two samples were collected before surgery and 2 samples after surgery with one hour gap in between. Upon collection blood was placed on wet ice. Plasma was isolated within 60 minutes of collection and frozen at -20 degree celsius.

Concentrations of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and possibly other drug-related species were quantified in the pharmacokinetic tissue sample by an investigative Liquid chromatography- mass spectrometry (LC-MS)/MS method. The spatial distribution of dabrafenib, its metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib and possibly other drug-related species in the tissue samples were determined using an investigative matrix assisted laser desorption ionization (MALDI) analysis method. Parenchymal brain metastases and extracranial metastases using MALDI imaging was not determined for all participants (completed by GSK for the first two participants enrolled)

Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), were planned but not collected.

Concentrations of dabrafenib, its metabolites hydroxy-, carboxy- and desmethyl-dabrafenib) and trametinib in CSF (in participants who agree for optional collection of CSF at the time of brain tumor resection). Optional collection of CSF was obtained in the operating room on the day of brain metastasis resection. CSF samples for only one participant were collected and analyzed.

Changes in MAPK pathway markers in paired extracranial biopsies taken pre-treatment, during craniotomy, and at disease progression, and changes in markers between post-operative intracranial and extracranial biopsies was planned but not performed as the study was terminated due to low enrollment.

Changes in the radiographic characteristics of the tumors were planned to be compared to (1) levels of dabrafenib, its metabolites and trametinib (where appropriate) in the brain metastases, plasma, and CSF, and (2) MAPK pathway activation status in tumors at the time of surgery. Results were planned to be compared to the analysis of early clinical responses in extracranial metastases, as determined by the Positron emission tomography (PET-CT) imaging. This analysis was planned but not performed as the study was terminated due to low enrollment

The change from Baseline to the pre-surgery intracranial disease assessment in the SLD of intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

The maximum change from Baseline in the SLD of unresected intracranial target lesions was planned to be calculated as a percentage change from the baseline SLD. It was planned to be reported for the V600E and V600K analysis populations for each cohort and also aggregately if appropriate. This analysis was planned but not performed as the study was terminated due to low enrollment.

Overall Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime as per modified Response Evaluation Criteria in Solid Tumors (RECIST). The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence and is determined programmatically based on the investigator's assessment of response at each time point. Overall Extracranial Response Rate was planned but not analyzed as the study was terminated due to low enrollment.

Overall survival, defined as the time from first dose of study treatment to death for any reason, was planned to summarize using Kaplan-Meier quartile estimates along with two sided 95% confidence intervals. But were not performed as the study was terminated due to low enrollment.

Vital sign measurements including temperature, respiratory rate, systolic and diastolic blood pressure, and pulse rate were planned to be performed but were neither summarized nor listed as the study was terminated.

A complete physical examination was planned which included assessments of the head, eyes, ears, nose, throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and extremities. Height and weight was also planned to be measured and recorded. A complete physical exam including a thorough genitourinary examination for female participants, inspection of the head and neck region, and digital rectal examination for both male and female participants was planned to be performed at Screening, and Month 12 or at discontinuation if discontinuation occurs prior to Month 12. If the participants had a genitourinary and rectal exam within 6 months of screening, these assessments need not to be repeated at screening. But data for physical examinations were not summarized and listed as the study was terminated.

112-lead ECGs were planned to be obtained at screening during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. At each assessment a 12-lead ECG was planned to be performed by qualified personnel at the site after at least a five-minute rest with the participants in a semi-recumbent or supine position. But data for 12-lead ECGs were not summarized and listed as the study was terminated.

ECHO include an evaluation for Left ventricular ejection fraction (LVEF) and both right- and left-sided valvular lesions. ECHO was planned to be performed at screening, Week 8 and every 16 weeks till discontinuation. data for ECHO was not summarized and listed as the study was terminated.

Laboratory assessments included parameters like Hematology, Standard Chemistry, Coagulation, Serum Pregnancy. Assessment of these parameters were planned to be performed by the central laboratory on screening, Day prior to surgery, Every 4 weeks after restart and Discontinuation, but were not analyzed as the study was terminated due to low enrollment.

AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AE were collected from the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment regardless of initiation of a new cancer therapy using Medical Dictionary for Regulatory Activities (MedDRA)

GlaxoSmithKline

AEs and SAEs were collected in Safety Set Population which comprised of all participants who received at least one dose of study treatment.

Participants in Cohort A received dabrafenib orally 150 milligram twice daily for 7 to 14 days prior to surgery.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain	NCT02039947	Melanoma and Br...	Dabrafenib Trametinib	18 Years -	Novartis
A Phase Ib/II Clinical Trial to Evaluate the Safety and Efficacy of HLX208+HLX10 in NSCLC With BRAF V600E Mutation	NCT05641493	Non Small Cell ...	HLX208+HLX10	18 Years - 80 Years	Shanghai Henlius Biotech
Adjuvant Dabrafenib and Trametinib Treatment in Patients With Completely Resected High-risk Stage III Melanoma.	NCT04961619	Melanoma	dabrafenib trametinib	18 Years -	Novartis
Evaluate the Efficacy and Safety of Aspirin in Combination With Trametinib and Dabrafenib	NCT05988697	NSCLC BRAF V600E Muta... Advanced Cancer Stage IIIB NSCL... Stage IV NSCLC	Combind asprin ...	18 Years - 75 Years	Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Phase 1 Safety Study of Encorafenib in Chinese Patients With Advanced Metastatic BRAF V600E Mutant Solid Tumors	NCT05003622	BRAF V600E Unre... BRAF V600E Meta... Melanoma	Encorafenib	18 Years -	Pierre Fabre Medicament
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for braf v600e mutation