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

Anti-Infective Agents

Antirheumatic Agents

Antibodies

Immune Checkpoint Inhibitors

Hydroxychloroquine

Immunoglobulins

Antimalarials

Antiprotozoal Agents

Antiparasitic Agents

Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy.

Upfront treatment with dabrafenib 150 mg twice daily, trametinib 2 mg once daily and hydroxychloroquine 200 mg twice daily upfront until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.

Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy.

Upfront treatment with dabrafenib 150 mg twice daily, trametinib 2 mg once daily until disease progression. At disease progression, add-on of hydroxychloroquine 200 mg twice daily. Treatment until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment

Upfront treatment with dabrafenib, trametinib and hydroxychloroquine in phase 1 and Arm A phase 2.

Upfront treatment with dabrafenib and trametinib in Arm B phase 2 with add-on of hydroxychloroquine at progression of disease

Upfront treatment with dabrafenib, trametinib and hydroxychloroquine in phase 1 and Arm A phase 2. Add-on at progression of disease in Arm B phase 2

Bart Neyns, Phd,Md

This phase 1/2 trial addresses the efficacy and safety of the combination of dabrafenib, trametinib and the oral autophagy inhibitor hydroxychloroquine in patients with unresectable AJCC (American Joint Committee on Cancer) stage III or stage IV BRAF (v-Raf murine sarcoma viral oncogene homolog B) V600 mutant melanoma who are documented with progression of disease following treatment with a BRAF with or without MEK (MAPK/Erk kinase) inhibitor and treatment with an immune checkpoint inhibitor. The investigators hypothesize hydroxychloroquine will be able to overcome or prevent autophagy-driven resistance to dabrafenib and trametinib. The investigators will also investigate the value of plasma BRAF V600 mutant circulating tumor DNA (ctDNA) as a predictive or prognostic marker.

Lead-in phase 1 safety trial followed by asymmetrically randomized open- label, double-arm, two-stage, multicenter, phase 2 clinical trial.

Patients are eligible if they are diagnosed with BRAF V600 mutant unresectable AJCC (American Joint Committee on Cancer) stage III or IV melanoma and are documented with progression of disease following treatment with a BRAF with or without MEK inhibitor and treatment with an immune checkpoint inhibitor (at least an anti-PD1 \[programmed cell death 1\] antibody). Patients will be considered for study participation not earlier than 12 weeks after the last dosing of the prior BRAF with or without MEK inhibitor therapy and 4 weeks after the last dosing of immune checkpoint inhibitor therapy.

Phase 1

Patients will be screened and if found eligible treated with the combination of standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) with the autophagy inhibitor hydroxychloroquine (200 mg twice daily). Treatment will continue until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment. Throughout their study participation, patients will be continuously monitored for safety and evaluated for tumor response every 8 weeks or sooner if there is clinical suspicion of progressive disease.

Six patients will be included for this phase 1 trial with incidence of adverse events as primary endpoint and ORR (objective response rate), PFS (progression-free survival), OS (overall survival, per RECIST v1.1 \[Response Evaluation Criteria for Solid Tumors\]) and value of ctDNA (circulating tumor DNA) as secondary endpoints.

Phase 2

Patients will be screened and if found eligible asymmetrically randomized to treatment with the combination of standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) with the autophagy inhibitor hydroxychloroquine (200 mg twice daily) (arm A, investigational arm) or treatment with standard dosing of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) (arm B, contemporary control arm). Stratification will occur according to baseline lactate dehydrogenase level. Treatment will continue until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment. However, at disease progression in arm B (dabrafenib plus trametinib), hydroxychloroquine (200 mg twice daily) will be added to the standard treatment and treatment will be continued until disease progression, unacceptable treatment related toxicity or patient's refusal to continue study treatment.

Throughout their study participation, patients will be continuously monitored for safety and evaluated for tumor response every 8 weeks or sooner if there is clinical suspicion of progressive disease.

Primary endpoint is ORR (objective response rate) in arm A, secondary endpoints are ORR (objective response rate) in arm B and PFS (progression-free survival), OS (overall survival), incidence of adverse events and value of ctDNA (circulating tumor DNA) in both arms.

Dabrafenib/Trametinib/Hydroxychloroquine for Advanced Pretreated BRAF V600 Mutant Melanoma

A lead-in Phase I Followed by a Phase II Clinical Trial on the Combination of Dabrafenib, Trametinib and the Autophagy Inhibitor Hydroxychloroquine in BRAF/MEK Inhibitor-pretreated Patients With Advanced BRAF V600 Mutant Melanoma

Adverse events graded by the Common Terminology Criteria of Adverse Events version 4 (CTCAE v4)

Objective response rate (ORR; defined as the percentage of subjects with a confirmed complete response \[CR\] or partial response \[PR\] at any time per Response Evaluation Criteria in Solid Tumors \[RECIST\], version 1.1 \[Eisenhauer 2009\]).

Progression-free survival (PFS; defined as the time from treatment initiation until the earliest date of disease progression or death due to any cause)

Overall survival (OS; defined as the time from treatment initiation until the date of death due to any cause).

Copy number of BRAF V600 mutant ctDNA as measured by quantitative Polymerase Chain Reaction (qPCR)

Objective response rate 1 (ORR 1; defined as the percentage of subjects with a confirmed complete response \[CR\] or partial response \[PR\] prior to the addition of hydroxychloroquine at any time per Response Evaluation Criteria in Solid Tumors \[RECIST\], version 1.1 \[Eisenhauer 2009\]).

Objective response rate 2 (ORR 2; defined as the percentage of subjects with a confirmed complete response \[CR\] or partial response \[PR\] following the addition of hydroxychloroquine at any time per Response Evaluation Criteria in Solid Tumors \[RECIST\], version 1.1 \[Eisenhauer 2009\]).

Progression-free survival (PFS; defined as the time from randomization until the earliest date of disease progression or death due to any cause)

Overall survival (OS; defined as the time from randomization until the date of death due to any cause).

Progression-free survival 1 (PFS 1; defined as the time from randomization until the earliest date of disease progression or death due to any cause whilst treated with dabrafenib and trametinib)

Progression-free survival 2 (PFS 2; defined as the time from addition of hydroxychloroquine to dabrafenib and trametinib until the earliest date of disease progression or death due to any cause)

Overall survival 1 (OS 1; defined as the time from randomization until death due to any cause whilst treated with dabrafenib and trametinib)

Overall survival 2 (OS 2; defined as the time from addition of hydroxychloroquine to dabrafenib and trametinib until death due to any cause)

Overall survival 3 (OS 3; defined as the time from randomization until death).

Copy number of BRAF V600 mutant ctDNA as measured by quantitative Polymerase Chain Reaction (qPCR) in plasma

University Hospital, Ghent

Gland and Hormone Related Diseases

Symptoms and General Pathology

Thyroid Neoplasms

Thyroid Diseases

Disease Progression

Thyroid Carcinoma, Anaplastic

Carcinoma

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.

Saint Petersburg State University, Russia

Oncologist

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Bortezomib

Re-challenge with bortezomib as second line therapy in myeloma patients relapsed after a previous bortezomib-based treatment

Pellegrino Musto, MD

This observational, non-interventional, retrospective, multicenter, national study focuses on collecting information about the effectiveness and safety of bortezomib re-use at first relapse in MM patients already treated in their first line with a bortezomib-based regimen, re-challenged with the same drug according to current clinical practice and/or Italian SIE/SIES/GITMO, IMWG and/or NCCN Guidelines/Treatment Recommendations.

Data will be collected retrospectively from approximately 25 haematologic/oncologic sites in Italy. Approximately, data of up to 100 patients will be collected.

Bortezomib as First Salvage Therapy for Myeloma Patients Previously Exposed to Bortezomib as Initial Treatment.

REal Life, Retrospective Study of BOrtezomib Use as secoND Treatment for Myeloma Patients Previously Exposed to Bortezomib-based Therapies as First Line

International Myeloma Study Group Criteria

Types (haematological and non hematological) and degree (Common terminology criteria adverse criteria)

IRCCS Centro di Riferimento Oncologico della Basilicata

Scientific Director

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antibodies, Monoclonal

Rechallenge with an anti-EGFR monoclonal antibody in patients with metastatic colorectal cancer

Aziz ZAANAN, MD, PhD

Pierre LAURENT-PUIG, MD, PhD

Julien TAIEB, MD, PhD

Some data have suggested a clinical survival benefit related to the reintroduction of anti-EGFRs therapy in patients with metastatic colorectal cancer (mCRC). Based on resistance mechanisms related to the development of resistant clones, the investigators could assume that patients who benefited most from the reintroduction of anti-EGFRs were those who, through interval chemotherapy, had no longer mutated RAS clone in plasma that appeared during the progression with the first anti-EGFR treatment. Conversely, those who did not benefit from this therapy were probably patients who had mutated RAS clones circulating at the time of reintroduction of anti-EGFRs. To support this hypothesis, investigators propose to evaluate the correlation between the eventual presence of RAS mutations in circulating blood and the efficacy of an anti-EGFR therapy reintroduction in patients with mCRC.

Somatic mutations in KRAS exon 2 are considered as a predictive marker of lack of efficacy for anti-EGFR therapy (panitumumab or cetuximab) in patients with metastatic colorectal cancer. Recently, it has been shown that rare mutations of KRAS (exons 3 or 4) or NRAS (exons 2, 3 and 4) were also predictive for resistance to anti-EGFR antibodies. These data led to a further restriction of anti-EGFR therapy to the subgroup of patients without any RAS mutations.

Emerging RAS mutations in circulating tumor DNA (ctDNA) could be detected in patients with RAS non-mutated colorectal cancer treated with anti-EGFR. The appearance in blood of these rare RAS mutated clones during anti-EGFR therapy was associated with shorter progression free-survival. These results suggest that the growing and development of rare RAS mutated clone, which is probably pre-existing in the primary tumor, may constitute a mechanism of resistance for anti-EGFR therapy.

A phase II prospective study has evaluated the interest of reintroduction of cetuximab in 39 patients previously treated with irinotecan and cetuximab. For inclusion, patients should have had a clinical benefit (stable disease for at least 6 months or clinical response) with the previous line of cetuximab plus irinotecan therapy and then a progression disease for which underwent a new line of chemotherapy before the rechallenge of cetuximab plus irinotecan. The median number of line of chemotherapy before inclusion was 4, and the median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. In this study, the overall response rate was 53.8%, and the median progression free-survival was 6.6 months. No evaluation of circulating tumor DNA was performed in this study.

These data indicate that the colorectal cancer genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockage. It seems that efficacy of anti-EGFR reintroduction could be specifically observed in subgroup of patients who no longer have a RAS mutated clone following the interval chemotherapy.

The aim of this prospective non-interventional study is to evaluate the predictive impact of RAS mutations in circulating tumor DNA for efficacy of anti-EGFR reINTROduction (RASINTRO study) treatment in patients with metastatic colorectal cancer.

The primary endpoint will be the correlation between RAS mutations status in circulating tumor DNA and progression-free survival from the reintroduction of anti-EGFR therapy.

The blood sample for circulating tumor DNA assessment will be carried out in patients who agreed to participate in this observational study just before the first 3 cycles of chemotherapy. This study does not require any additional invasive procedures to those already scheduled for routine care. Indeed, blood sample will be collected from the Huber needle previously implanted in the port-a-cath for chemotherapy perfusion.

After DNA extraction from bood samples, RAS mutation testing will be performed using sequencing with a panel of genes (Ion AmpliSeq Colon and Lung Cancer Panel).

The data related to the patient (age at diagnosis, sex, weight, height, WHO performance status), tumor (tumor markers CEA and CA 19-9, histological type and tumor differentiation, tumor stage, and metastatic sites) and treatment (resection of the primary tumor, date of surgery, lines of chemotherapy, protocol regimen) will be collected anonymously. Monitoring data concern the efficacy of chemotherapy (tumor response, the date of disease progression/death).

Circulating tumor DNA

During the inclusion period, a blood sample will be taken just before the first 3 cycles of chemotherapy (C1, C2 and C3) and at tumor progression for mCRC patients treated in one of the participating AGEO centers. These samples will not require any additional invasive procedures since they will be made from the Huber needle previously implanted in the catheter for previously scheduled chemotherapy cycles.

The patient will sign an information letter and a specific informed consent for blood collection and biological studies. In case of specific refusal, the patient will not be included.

RAS Mutations in ctDNA and Anti-EGFR reINTROduction in mCRC (RASINTRO)

Predictive Impact of RAS Mutations in Circulating Tumor DNA for Efficacy of Anti-EGFR Reintroduction Treatment in Patients With Metastatic Colorectal Cancer

PFS will be evaluated according to the RAS mutations on circulating tumor DNA status

Tumor response will be evaluated according to the RAS mutations on circulating tumor DNA

OS will be evaluated according to the RAS mutations on circulating tumor DNA

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
Dabrafenib/Trametinib/Hydroxychloroquine for Advanced Pretreated BRAF V600 Mutant Melanoma	NCT03754179	Melanoma	Dabrafenib Trametinib Hydroxychloroqu...	18 Years -	Universitair Ziekenhuis Brussel
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
Bortezomib as First Salvage Therapy for Myeloma Patients Previously Exposed to Bortezomib as Initial Treatment.	NCT02797041	Multiple Myelom...	Bortezomib	18 Years -	IRCCS Centro di Riferimento Oncologico della Basilicata
RAS Mutations in ctDNA and Anti-EGFR reINTROduction in mCRC (RASINTRO)	NCT03259009	Metastatic Colo...		18 Years -	Association des Gastroentérologues Oncologues

Spots Global Cancer Trial Database for rechallenge

Every month we try and update this database with for rechallenge cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for rechallenge

Every month we try and update this database with for rechallenge cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for rechallenge cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.