Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

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

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Trametinib

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Single arm study with dabrafenib + trametinib combination therapy

Dabrafenib + Trametinib

Neyns Bart, MD, PhD

Patients with BRAF V600 mutant advanced melanoma benefit from treatment with a BRAF-inhibitor (e.g. dabrafenib, vemurafenib) and from combination of a BRAF- and MEK-inhibitor (e.g. dabrafenib and trametinib). Following initial tumor regression, progression is diagnosed in a majority of patients treated with BRAF-inhibitor mono-therapy within the first 12-months of therapy. Various molecular mechanisms that underlie the development of resistance to treatment with a BRAF-inhibitor have been reported. These mechanisms do not include secondary mutations in the BRAF-gene and therefore resistance to BRAF-inhibition could potentially be reversible when selective pressure by BRAF-inhibition is withheld for a sufficient period of time of melanoma progression. This clinical trial protocol addresses the potential renewed anti-tumor activity of combined BRAF- and MEK inhibition with the combination of dabrafenib and trametinib in patients with unresectable AJCC stage III or - IV BRAF V600 mutant melanoma who are documented with progression of disease at least 12 weeks following the last day of dosing of a BRAFinhibitor containing treatment regimen.

Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients

A Phase II Clinical Trial on the Combination of Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients With Advanced BRAF V600 Mutant Melanoma

To explore if tumor specific cfDNA levels can be used as a monitoring tool to detect early progression of disease

Universitair Ziekenhuis Brussel

Bart Neyns, MD PhD

Nivolumab

Pembrolizumab

Immune Checkpoint Inhibitors

Immunomodulating Agents

Ipilimumab

Antineoplastic Agents, Immunological

Patients receiving ipilimumab + nivolumab

Ipilimumab + nivolumab

Dabrafenib + trametinib

Novartis Pharmaceuticals

This was a retrospective cohort study using the PharMetrics database. The analysis was conducted using the most recent 5 years of data from the database, January 1, 2015, to October 30, 2020. Included patients were followed for outcome evaluation from the index date (first prescription of treatment, immunotherapy \[IO\], or targeted therapy \[TT\] following diagnosis of non-metastatic malignant melanoma and evidence of first lymph node resection), until the first occurrence or end of continuous eligibility or end of the study period.

Retrospective Assessment of Adverse Events-related Healthcare Resource Utilization and Costs of Immune Checkpoint Inhibitor and Targeted Therapy for Adjuvant Treatment of Melanoma

Respiratory Tract (Lung and Bronchial) Diseases

Carcinoma, Non-Small-Cell Lung

Carcinoma

Carcinoma, Bronchogenic

Bronchial Neoplasms

Lung Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Dabrafenib 150mg BID + Trametinib 2mg QD/（2 cycles）

Capmatinib

Li Zhang, MD

This is a Phase II, two parallel group study assessing the efficacy and safety of neoadjuvant and adjuvant targeted therapy in patients with stage IB-IIIA NSCLC harboring BRAF V600 or MET exon14 mutations.

This is a Phase II, two parallel group study assessing the efficacy and safety of neoadjuvant and adjuvant targeted therapy in patients with stage IB-IIIA NSCLC harboring BRAF V600 or MET exon14 mutations. Eligible patients with BRAF V600 mutations will receive dabrafenib 150mg bid plus trametinib 2mg qd for 8 weeks before a surgical resection (neoadjuvant), and followed by up to 4 cycles of adjuvant chemotherapy, if receive adjuvant chemotherapy, up to four cycles, chemo regimen according to investigators' choice, and up to 2 years of adjuvant targeted therapy with dabrafenib plus trametinib. For patients with MET exon14 mutations, they will receive capmatinib 400mg bid for 8 weeks before surgery (neoadjuvant), followed by up to 4 cycles of adjuvant chemotherapy, about adjuvant chemotherapy same as BRAF V600 group, and up to 2 years of adjuvant targeted therapy with capmatinib post-surgery. During treatment, patients will visit their physicians regularly for disease and safety assessment. After the end of treatment, survival follow-up will be conducted every 3 months for up to 3 years. Approximately 40 evaluable patients will be enrolled in the study (20 patients in each cohort).

Neoadjuvant and Adjuvant Targeted Treatment in NSCLC With BRAF V600 or MET Exon 14 Mutations

A Phase II, Two Parallel Group Study of Neoadjuvant and Adjuvant Targeted Treatment in NSCLC With BRAF V600 or MET Exon 14 Mutations

pCR rate is defined as the percentage of participants with no residual viable tumor cells.

MPR rate is defined as the percentage of participants with ≤10% residual viable tumor cells.

EFS is defined as the time from intervention to the first documented disease progression per RECIST v1.1 that precludes surgery, local or distant disease recurrence, or death from any cause, whichever occurs first.

DFS defined as the time from the end of surgery until recurrence or death due to any cause, DFS rate at 12, 24, 36 and 60 months.

OS defined as the time between the date of enrollment and the date of death due to any cause.

Sun Yat-sen University

Director

Gland and Hormone Related Diseases

Symptoms and General Pathology

Thyroid Neoplasms

Thyroid Diseases

Disease Progression

Thyroid Carcinoma, Anaplastic

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Neoplasms, Glandular and Epithelial

Anaplastic Thyroid Cancer

Mitogens

Taxane

Patients with BRAF-positive anaplastic thyroid cancer who were previously treated with dabrafenib and trametinib (with a clinical or objective response at the start of treatment) and later with tumor progression during anti-BRAF therapy with the transition to at least one line of chemotherapy (treatment with taxane-containing regimens is mandatory) followed by progression on it.

Dabrafenib is an inhibitor of some mutated forms of BRAF kinases. Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. Dabrafenib and trametinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of dabrafenib 623 and trametinib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumors.

Ilya Sleptsov, MD

Ernest Dzhelialov

This pilot phase 2 study evaluates the effectiveness and safety of the Rechallenge concept in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy. Patients with BRAF-positive anaplastic thyroid cancer who were previously treated with dabrafenib and trametinib (with a clinical or objective response at the start of treatment) and later with tumor progression during anti-BRAF therapy and subsequent lines of chemotherapy are scheduled to undergo targeted therapy (repeated administration of dabrafenib and trametinib in standard doses) and evaluate the outcomes according to the primary and secondary endpoints.

The aim of the study was to demonstrate the efficacy and safety of the rechallenge concept in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy.

Scientific hypothesis: rechallenge in patients with BRAF-positive anaplastic thyroid cancer after progression on anti-BRAF therapy is effective and safe.

Trial design, materials and methods: this study is a pilot phase 2 study. This study is prospective and open-label.

Patients with BRAF-positive anaplastic thyroid cancer who were previously treated with dabrafenib and trametinib (with a clinical or objective response at the start of treatment) and later with tumor progression during anti-BRAF treatment with the transition to at least one line of chemotherapy (treatment with taxane-containing regimens is mandatory) followed by progression on it. Patients who meet the criteria and with no initial resistance to anti-BRAF therapy are scheduled to undergo targeted therapy (repeated administration of dabrafenib and trametinib in standard doses) and evaluate outcomes according to primary and secondary endpoints.

The control will be carried out by monitoring the initial state in dynamics. Before starting investigational therapy, data will be recorded for each patient in an individual registration card.

Before starting investigational therapy, clinical and laboratory parameters will be evaluated and computed tomography of the brain, neck, thoracic and abdominal cavities with intravenous contrast (baseline) will be performed.

Mutations in the BRAF V600 gene, microsatellite instability (MSI) and PD-L1 expression will be determined in the tumor material (first of all), and the following molecular genetic variants will be determined in the second place (planned): RET, NTRK, ALK, ROS1.

Investigational therapy includes dabrafenib 150 mg 2 times a day daily, trametinib 2 mg 1 time a day daily.

Duration of treatment: until progression or intolerable toxicity.

Follow-up period of patients:

* duration of the initial follow-up period: taking drugs for 10 days, followed by an assessment of the effect using tumor imaging methods;
* follow-up during active treatment in the framework of the study with tumor reduction after day 10 - continuation of targeted therapy until progression or intolerable toxicity;
* patient survival monitoring - documenting subsequent lines of antitumor treatment before the patient's death or loss of contact with him;
* patient safety monitoring is the period of research therapy, 30 and 90 days from the date of the final dose (provided there is no next line of antitumor treatment, during the next line, safety monitoring is discontinued).

Assessment of the response to treatment (assessment of clinical and laboratory parameters, computed tomography of the brain, neck, chest and abdominal cavity with intravenous contrast) will be carried out after 10 days, then - according to the decision of the research team. Based on the results of the control study, the response to treatment will be evaluated according to the RECIST 1.1 criteria. Patients who meet the criteria for progression will be excluded from the study.

When converting a tumor to resectability and planning surgical treatment, it is recommended to suspend taking the drug trametinib 5 days before surgery and resume taking it 3-5 days after. There is no correlation between dabrafenib and complications associated with surgical treatment, and no interruptions in treatment are required.

Study of the Rechallenge Concept in Patients With BRAF-positive Anaplastic Thyroid Cancer After Progression on Anti-BRAF Therapy

The proportion of participants with a partial or complete response to the therapy. It is determined according to the RECIST criteria.

The time from the date of initiation of treatment to the radiological progression or death of the patient for any reason.

Safety assessment will be assessed on the basis of adverse events (according to CTCAE 5.0)

The time from the start date of treatment to the death of the patient for any reason.

The proportion of participants with an initially unresectable or potentially resectable tumor who have moved to a resectable during treatment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients	NCT02296996	Malignant Melan...	Dabrafenib + Tr...	18 Years -	Universitair Ziekenhuis Brussel
Retrospective Assessment of Adverse Events-related Healthcare Resource Utilization and Costs of Immune Checkpoint Inhibitor and Targeted Therapy for Adjuvant Treatment of Melanoma	NCT05714371	Melanoma	Nivolumab Ipilimumab + ni... Pembrolizumab Dabrafenib + tr...	18 Years -	Novartis
Neoadjuvant and Adjuvant Targeted Treatment in NSCLC With BRAF V600 or MET Exon 14 Mutations	NCT06054191	NSCLC BRAF V600 Mutat... MET Exon 14 Mut...	Dabrafenib + Tr... Capmatinib	18 Years -	Sun Yat-sen University
Retrospective Assessment of Adverse Events-related Healthcare Resource Utilization and Costs of Immune Checkpoint Inhibitor and Targeted Therapy for Adjuvant Treatment of Melanoma	NCT05714371	Melanoma	Nivolumab Ipilimumab + ni... Pembrolizumab Dabrafenib + tr...	18 Years -	Novartis
Study of the Rechallenge Concept in Patients With BRAF-positive Anaplastic Thyroid Cancer After Progression on Anti-BRAF Therapy	NCT06362694	Anaplastic Thyr...	Dabrafenib + Tr...	18 Years -	Saint Petersburg State University, Russia
Dabrafenib and Trametinib for BRAF-inhibitor Pretreated Patients	NCT02296996	Malignant Melan...	Dabrafenib + Tr...	18 Years -	Universitair Ziekenhuis Brussel

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