Neoplasms

All Conditions

Gland and Hormone Related Diseases

Carcinoma

Thyroid Neoplasms

Thyroid Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Micronutrients

Anti-Infective Agents

Trametinib

Dabrafenib

Iodine

Cadexomer iodine

Protein Kinase Inhibitors

Enzyme Inhibitors

Patients with progressive, metastatic or locally advanced, unresectable radioiodine (RAI)-refractory thyroid cancer of follicular cell origin with mutation involving MAPK signalling pathway, including BRAFV600E mutation or RAS mutation.

Participants will receive systemic therapy in the form of oral tablet dabrafenib 150mg twice a day \& oral tablet trametinib 2mg once a day for 1 or 4 weeks.

Pre- \& post-systemic therapy assessment of tumor iodine absorption is done using I-124 PET CT scan. Participants are prepared for this scan with intramuscular injection of thyrogen 0.9mg on 2 consequent days, followed by I-124 PET-CT scan over the next 3 days for tumoral lesional dosimetry.

Participants are then started on systemic therapy for 1 week, followed by I-124 PET-CT scan. If at least one tumor site can attain adequate dosimetry, RAI (I-131) treatment under thyrogen stimulation will be considered. Systemic therapy will be stopped 3 days after I-131.

If after 1 week of systemic therapy, tumors do not reach dosimetry criteria, participants will be continued on systemic therapy for a total of 4 weeks duration, followed by I-124 PET-CT scan. If tumor can attain adequate dosimetry, I-131 treatment will be considered.

dabrafenib and trametinib

Samantha, Peiling Yang, MBBS, MRCP

Kelvin, Siu Hoong Loke, MBBS, MRCP

Progressive and metastatic thyroid cancer patients, who no longer respond to radioactive iodine (RAI), are currently treated with long term tyrosine kinase inhibitors to control tumor growth. The investigators will study the effect of short term oral anti-cancer drug combination, called dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), in improving thyroid cancer RAI absorption that can potentially lead to tumor shrinkage response. To assess for suitability, participant's thyroid cancer tissue taken at the time of surgery will be tested for DNA changes, such as BRAFV600E, RAS, or MEK mutations.

Based on experimental studies, the response to these medications could occur within 1 week of treatment. So in the study, the investigators will find out whether participant's cancer would respond to 1 week of treatment with these medications rather than the 1 month duration of treatment in previous re-differentiation clinical trials. After 1 week of treatment with dabrafenib and trametinib, iodine absorption I-124 PET-CT scan will predict if the cancer will respond to RAI. If iodine absorption is insufficient on the scan, treatment with dabrafenib and trametinib will be continued for a total of 4 weeks. Then iodine absorption response of participant's cancer will be assessed on I-124 PET-CT scan again. If the iodine absorption is good at 1 week or 4 weeks, the investigators will treat the participant with thyroid cancer using RAI.

The 1-week treatment regime can potentially save cost, avoid drug toxicity with prolonged treatment, and prevent drug resistance that can occur with longer treatment period.

Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Re-differentiation Therapy

Phase II Clinical Trial in Radioactive Iodine-Refractory Advanced Thyroid Carcinoma Evaluating BRAF & MEK Blockade Therapy for Re-differentiation- Applying a Novel Time-Dependent Concept

The primary endpoint can be considered attained in both groups of participants:

* those that attain target lesional dosimetry after 1 week of therapy
* those that attain target lesional dosimetry after 4 weeks of therapy

Singapore General Hospital

National University Hospital, Singapore

Skin and Connective Tissue Diseases

Rare Diseases

Melanoma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

BGB324 capsules, 200 mg once daily + pembrolizumab 2 mg/kg IV every 3. week

Treatment until disease progression, or unacceptable toxicity

BGB324 capsules: Dose finding part of the study will determine if 100 mg once daily should be used for main part of the study or if 200 mg once daily once daily should be used.

Dabrafenib capsules: 150 mg twice daily Trametinib tablets: 2 mg once daily

Treatment until disease progression, or unacceptable toxicity

Pembrolizumab 2 mg/kg IV every 3. week

Treatment until disease progression, or unacceptable toxicity

Dabrafenib capsules:150 mg twice daily Trametinib tablets: 2 mg once daily

Treatment until disease progression, or unacceptable toxicity

BGB324+pembrolizumab

BGB324+dabrafenib and trametinib

pembrolizumab

Oddbjørn Straume, MD PhD

The purpose of the study is to assess the safety and efficacy of BGB324 given together with standard treatment, pembrolizumab or dabrafenib and trametinib, compared to standard treatment alone,

This is an investigator initiated randomized randomized clinical phase 1b/2 clinical trial comparing safety and efficacy of the Axl inhibitor BGB324 in combination with pembrolizumab or dabrafenib+trametinib with that of pembrolizumab or dabrafenib+trametinib alone. Patients with non-resectable stage III or stage IV melanoma will be stratified based on BRAF mutation and tumor load to start dabrafenib+trametinib (BRAF mutation and high tumor load) or pembrolizumab (BRAF wild type or BRAF mutation and low tumor load) in first line. The patients will be randomized 2:1 to receive BGB324 in combination with pembrolizumab or dabrafenib+trametinib or to receive pembrolizumab or dabrafenib+trametinib alone. A 3+3 dose escalation will be performed for the combination of BGB324 and dabrafenib+trametinib. There is a major focus on predictive markers of treatment response evaluated in blood samples and biopsies.

BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib in Metastatic Melanoma

A Phase Ib/II Randomised Open Label Study of BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib Compared to Pembrolizumab or Dabrafenib/Trametinib Alone, in Patients With Advanced Non-resectable (Stage IIIc) or Metastatic (Stage IV) Melanoma

From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 5 years

through study completion, an average of 1 year

through study completion, an average of 2 year

BerGenBio ASA

Haukeland University Hospital

Dabrafenib and trametinib treatment under routine conditions according to the applying SmPC.

Dabrafenib and Trametinib

Adjuvant therapy with dabrafenib plus trametinib in melanoma was approved in 2018 by the EMA (EUropean Medicines Agency).

The purpose of this non-interventional study is to assess the usage of adjuvant dabrafenib and trametinib in clinical practice, where the patient population may differ from study population.

Melanoma is a disease of significant metastatic potential if not detected very early. Oncogenic mutations in BRAF (B-Raf proto-oncogene, serine/threonine kinase) are found in approximately 40% of melanomas and result in constitutive activation of the MAPK (Mitogen-Activated Protein Kinase) pathway.

Treatment with the BRAF inhibitor dabrafenib plus the MEK (Mitogen-activated protein kinase kinase) inhibitor trametinib showed improved overall survival in patients with unresectable or metastatic BRAF V600E/K-mutant melanoma (COMBI-d and COMBI-v studies). In an adjuvant setting treatment with dabrafenib and trametinib significantly reduced the risk of melanoma recurrence in patients with high-risk, stage III BRAF V600-mutant melanoma, with improvements in OS (Overall Survival), DMFS (Distant Metastasis Free Survival), and FFR (Freedom From Relaps) (COMBI-AD study). Based on these results, adjuvant dabrafenib plus trametinib therapy was approved in 2018 by the EMA.

Compared to the metastatic situation, issues of compliance and treatment adherence may be more relevant in adjuvant treatments, as patients are free of disease and potentially cured even without adjuvant treatment. As the routine administration of drugs including dosing, treatment interruptions, and early termination in clinical practice may vary from procedures defined in clinical trials, this study aims to assess the usage of adjuvant dabrafenib and trametinib in the routine clinical setting.

BRAF-/MEK-Inhibition With Dabrafenib and Trametinib in Melanoma Patients

BRAF-/MEK-Inhibition With Dabrafenib and Trametinib in Melanoma Patients in the Adjuvant Setting: a Non-interventional Observatory Study

Median time on adjuvant dabrafenib + trametinib treatment defined as the interval between start of treatment and permanent discontinuation of treatment.

Rate of permanent study drug discontinuation due to any reason.

Rate of permanent study drug discontinuation due to adverse drug reactions (ADRs).

Occurrence of pyrexia and related symptoms, listing the grade, number of episodes, and time to resolution.

Type of adverse drug reaction (ADR) management applied for pyrexia and correlation with occurrence/persistence of pyrexia.

ADRs persisting/emerging up to 3 months post-treatment.

Assessment of health-related quality of life (HRQoL), measured by the European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC-QLQ-C30).

The EORTC QLQ-C30 consists of the folowing scales, with each dimension specifying five levels of severity \[not at all (level 1), a little (level 2), quite a bit (level 3), very much (level 4)\]:

* functional scales (Physical, Role, Cognitive, Emotional, Social Functioning)
* symptom scales (Fatigue, Pain and Nausea/Vomiting)
* single item scales (Dyspnoea, Insomnia, Appetite Loss, Constipation, Diarrhoea and Financial Difficulties).

Additionally the Global Health Status and QoL scales are incorporated, specifying on a scale from 1 (very poor) to 7 (excellent).

Relapse free survival (RFS) time and rate

Distant metastasis free survival (DMFS) time.

Distant metastasis free survival (DMFS) rate.

Correlation between time on treatment and efficacy endpoints (RFS, DMFS, OS).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Re-differentiation Therapy	NCT04554680	Thyroid Cancer	dabrafenib and ...	21 Years - 99 Years	National University Hospital, Singapore
BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib in Metastatic Melanoma	NCT02872259	Melanoma	BGB324+pembroli... BGB324+dabrafen... pembrolizumab dabrafenib and ...	18 Years -	Haukeland University Hospital
Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Re-differentiation Therapy	NCT04554680	Thyroid Cancer	dabrafenib and ...	21 Years - 99 Years	National University Hospital, Singapore
BRAF-/MEK-Inhibition With Dabrafenib and Trametinib in Melanoma Patients	NCT03944356	Melanoma	Dabrafenib and ...	18 Years -	EuMelaReg gGmbH
BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib in Metastatic Melanoma	NCT02872259	Melanoma	BGB324+pembroli... BGB324+dabrafen... pembrolizumab dabrafenib and ...	18 Years -	Haukeland University Hospital
BGB324 in Combination With Pembrolizumab or Dabrafenib/Trametinib in Metastatic Melanoma	NCT02872259	Melanoma	BGB324+pembroli... BGB324+dabrafen... pembrolizumab dabrafenib and ...	18 Years -	Haukeland University Hospital
Clinical Trial in RAI-Refractory Thyroid Carcinoma Evaluating BRAF & MEK Blockade for Re-differentiation Therapy	NCT04554680	Thyroid Cancer	dabrafenib and ...	21 Years - 99 Years	National University Hospital, Singapore

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