Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

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

Nivolumab

Immunomodulating Agents

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then treatment will be left at the investigator choice and continued until the 2nd progression.

encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks followed, after a week of pause, by nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections, followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression. Then patients will be rechallenged with encorafenib 450 mg QD + binimetinib 45 mg BID orally continuously until the 2nd progression.

nivolumab 3 mg/kg q3w + ipilimumab 1 mg/kg q3w for 4 injections followed by nivolumab 480 mg IV q4w until completion of 2 years total treatment or progression.

Nivolumab + Ipilimumab

encorafenib 450 mg QD + binimetinib 45 mg BID orally for 12 weeks

Encorafenib + Binimetinib

Caroline Robert

This is a multicenter, 2-arm open-label, randomized comparative phase II study. The objective of this trial is to prospectively evaluate whether a sequential approach with an induction period of 12 weeks with encorafenib + binimetinib followed by combination immunotherapy with nivolumab + ipilimumab improves progression free survival compared to combination immunotherapy nivolumab + ipilimumab alone in patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.

Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib

Combination of Targeted Therapy (Encorafenib and Binimetinib) Followed by Combination of Immunotherapy (Ipilimumab and Nivolumab) vs Immediate Combination of Immunotherapy in Patients With Unresectable or Metastatic Melanoma With BRAF V600 Mutation : an EORTC Randomized Phase II Study (EBIN)

All publications must comply with the terms specified in the EORTC Policy 009 "Release of Results and Publication Policy".

PRS is defined as the time from the date of randomization until the first date of progression, or until date of death (whatever the cause), whichever occurs first. Progression will be assessed according to the RECIST criteria (version 1.1)

OS is defined as the time from the date of randomization to the date of death, whatever the cause.

CR will be assessed according to the RECIST criteria (version 1.1)

Time to CR is defined as the time from the date of randomization until the occurrence of first CR.

Duration of CR will be measured from the time measurement criteria for CR are first met until the first date that recurrence is objectively documented.

Best overall response will be assessed according to the RECIST criteria (version 1.1)

Time to best response is defined as the time from the date of randomization until the occurrence of the best response (CR or PR, whichever comes first). CR and PR will be assessed according to the RECIST criteria (version 1.1)

Best response duration will be measured from the time measurement criteria for CR/PR (whichever is first recorded) are first met until the first date that recurrent or progressive disease is objectively documented. CR and PR will be assessed according to the RECIST criteria (version 1.1)

This study will use the International Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, for adverse event reporting.

PFS2 is defined as the time from randomization to second objective disease progression, or death from any cause, whichever first. The second objective disease progression will be assessed according to the RECIST criteria (version 1.1)

European Organisation for Research and Treatment of Cancer - EORTC

Mitogens

Oral encorafenib 450mg once daily and oral binimetinib 45mg twice daily for 8 weeks pre-operative and for up to 44 weeks post-operative.

Immediate surgery followed by Investigator's choice of standard adjuvant therapy to commence within 12 weeks of surgery and to continue for up to 52 weeks.

Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor, which suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF kinase (V600E, D and K).

Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. Binimetinib inhibits activation of MEK by BRAF and inhibits MEK kinase activity

Standard Adjuvant Treatment

Lisa Bax

Sophie Twelves

Pippa Corrie

A two-arm, randomised trial investigating the response of encorafenib and binimetinib compared to standard adjuvant therapy.

A phase II, multi-centre, open label, randomised trial.

The trial will assess the delivery, response rate, treatment compliance, efficacy and safety of encorafenib and binimetinib compared to standard adjuvant therapy in patients with BRAFV600 mutant clinically detected AJCC stage III(B/C/D) or oligometastatic stage IV Melanoma.

Neoadjuvant and adjuvant administration schedule

Perioperative Encobini in BRAFV600 Mutant Stage III (B/C/D) or Oligometastatic Stage IV Melanoma

Perioperative Encorafinib+Binimetinib in BRAFV600 Mutant Clinically Detected AJCC Stage III (B/C/D) or Oligometastatic Stage IV Melanoma

% of patients with a complete response using Haemotoxylin and Eosin staining of tumour removed at surgery.

Incidence of missed treatment doses assessed from number of tablets returned.

% of patients with a complete response using CT scan tumour measurement assessment (RECIST) from start of treatment until 8 weeks.

Rate of patients with drug related toxicities reported from start of study until end of treatment

Incidence of lymphoedema toxicity using circumferential limb measurement and questionnaires for an average of 12 months.

Number of patients deceased from start of treatment for an average of 12 months.

Quality of life assessed by Functional Assessment of Cancer Therapy - Melanoma (FACT-M) questionnaire for an average of 12 months.

Rate of monthly recruitment achieved during the last 6 months of the trial recruitment period

Pierre Fabre Medicament

CCTU- Cancer Theme

Chief Investigator

Hormones

Sacituzumab govitecan

Axitinib

Talazoparib

Protein Kinase Inhibitors

Enzyme Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Immunoconjugates

Immunologic Factors

This arm of the Strata PATH trial will assess the clinical benefit of Lorbrena® (lorlatinib) in ALK and ROS1 gene fusion positive solid tumors, as detected by Strata testing, with the exception of NSCLC.

lorlatinib

This arm of the Strata PATH trial will assess the clinical benefit of Braftovi® (encorafenib) + Mektovi® (binimetinib) in BRAF p.v600X mutated solid tumors, as detected by Strata testing, with the exception of melanoma and colorectal cancer.

encorafenib + binimetinib

This arm of the Strata PATH trial will assess the clinical benefit of Talzenna® (talazoparib) in patients with advanced solid tumors harboring deep deletions or deleterious mutations with LOH in BRCA1/2 and PALB2, as detected by Strata testing, excluding HER2 negative breast cancer.

talazoparib

This arm of the Strata PATH trial will assess the clinical benefit of Trodelvy® (sacituzumab govitecan) in patients with advanced solid tumors and are Trop2 Treatment Response Score High (Trop2 TRS-H), as detected by Strata testing, excluding triple negative breast cancer, hormone receptor positive/ human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer, metastatic urothelial cancer, non-small cell lung (NSCLC) cancer, small cell lung cancer (SCLC), head and neck cancer, colorectal cancer (CRC), and endometrial cancer.

sacituzumab govitecan

This arm of the Strata PATH trial will assess the clinical benefit of Inlyta® (axitinib) in patients with advanced solid tumors and are Angiogensis Inhibitor Treatment Response Score High (Angio TRS-H), as detected by Strata testing, excluding renal cell carcinoma, alveolar soft part sarcoma, and solitary fibrous tumors.

axitinib

Kat Kwiatkowski, PhD

StrataPATH™ is a non-randomized, open-label trial designed to explore efficacy and safety of multiple FDA-approved and commercially available cancer therapies in new, biomarker-guided patient populations.

StrataPATH is a non-randomized, open-label trial designed to explore efficacy and safety of multiple FDA-approved and commercially available cancer therapies in new, biomarker-guided patient populations. Aiming to increase clinical benefit for patients, this study will leverage technology advancements, scientific literature, and Strata's real-world evidence to define novel, highly responsive pan-tumor molecular indications for FDA-approved therapies in both the advanced and micro-metastatic settings. Strata will rapidly identify participants who have efficacy signals for possible expansion into adaptive or randomized studies. Enrollment in each drug/biomarker cohort is competitive. Cohorts may be added, changed, or discontinued over the course of the study

Strata PATH™ (Precision Indications for Approved Therapies)

Strata PATH™ (Precision Indications for Approved Therapies): A Study Evaluating the Clinical Activity and Safety of Approved Drugs Within Biomarker-Guided Patients With Solid Tumors

RECIST criteria will be used to assess the clinical activity of cancer treatments in participants with pre-specified biomarker profiles.

DoR will be used to assess the duration of response of cancer treatments in participants with pre-specified biomarker profiles.

TTD will be used to assess the duration of response of cancer treatments in participants with pre-specified biomarker profiles.

TTnT will be used to assess the duration of response of cancer treatments in participants with pre-specified biomarker profiles.

Molecular response calculated as a ratio of mean VAF on treatment at 6 months compared to baseline VAF will be used to assess the clinical activity of cancer treatments in participants with pre-specified biomarker profiles.

Evaluate overall survival (OS) for participants who received a cancer treatment with pre-specified biomarker profiles

Monitor and summarize any unexpected safety events in participants who received a biomarker-guided cancer treatment

Evaluate ctDNA response rate at additional timepoints for participants who received cancer treatment with pre-specified biomarker profiles

Merck Sharp & Dohme LLC

Pfizer

Gilead Sciences

Strata Oncology

Digestive System Diseases

Liver Diseases

Gastrointestinal Diseases

Moderate hepatic impairment (Child-Pugh Class B)

The doses administered to patients with normal hepatic function will be the same as the recommended commercialised doses

A smaller dose than the dose approved for patients with normal hepatic function has been defined

Petr Arenberger

Encorafenib in combination with binimetinib have been approved in USA, Europe, Australia, Japan and Switzerland for the treatment of adult patients with unresectable or metastatic melanoma with BRAF V600 mutation.

The main objective of this study is to find a safe and effective dose of encorafenib in combination with binimetinib for patients who have BRAF-mutant metastatic or unresectable melanoma with hepatic dysfunction (i.e. moderate or severe impairment).

This is an open label, multicentre, phase I study to evaluate the impact of moderate and severe hepatic impairment (HI) on the pharmacokinetics and safety of encorafenib in combination with binimetinib, in adult patients with unresectable or metastatic BRAF V600-mutant melanoma.

For each participant, the treatment period will be split in 2 phases:

* a HI assessment phase assessing the impact of hepatic impairment after a single dose (Day 1) and after repeated doses (Day 15).
* a post-HI assessment phase: after completing the HI assessment phase, participants may continue treatment in the post-HI assessment phase until disease progression or unacceptable toxicity.

Participants with hepatic impairment will be enrolled sequentially according to their severity. The study will start first in participants with normal hepatic function and moderate hepatic impairment respectively.

Participants will be assigned to one of the following 3 study groups:

* Group with normal hepatic function: 4 participants
* Group with moderate hepatic impairment (Child-Pugh Class B): 4 participants
* Group with severe impairment (Child-Pugh Class C): 4 participants

An Internal Review Committee (IRC) will review the safety and PK data of encorafenib in combination with binimetinib for group with normal hepatic function and group with moderate hepatic impairment and make a recommendation prior to start group with severe impairment enrolment. The Sponsor will determine whether it is safe and feasible to proceed with group with severe impairment.

Participants will receive treatment doses according to their assigned group.

Participants with hepatic impairment will be enrolled sequentially according to their severity.

Hepatic Impairment Study of Encorafenib in Combination With Binimetinib in BRAF Melanoma

'An Open Label, Multicentre, Phase I Study to Evaluate the Impact of Moderate and Severe Hepatic Impairments on the Pharmacokinetics and Safety of Encorafenib in Combination With Binimetinib in Adult Patients With Unresectable or Metastatic BRAF V600-mutant Solid Tumors'.

Maximum Observed Plasma Concentration of encorafenib expressed as total and unbound concentrations

Area Under the Plasma Concentration versus Time Curve from Time 0 to Time of Last Quantifiable Concentration of encorafenib expressed as total and unbound concentrations

Area Under the Plasma Concentration versus Time Curve from Time 0 to Infinity of encorafenib expressed as total and unbound concentrations

Time to Reach Maximum Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032)

Minimum Observed Plasma Concentration of encorafenib and its metabolite (LHY746) and binimetinib and its active metabolite (AR00426032) expressed as total and unbound concentrations

Terminal Phase Plasma Half-life of encorafenib and binimetinib and their metabolite

Apparent Total Body Clearance of encorafenib and binimetinib and their metabolites as total and unbound concentrations

Apparent Volume of Distribution at Terminal Phase of encorafenib and binimetinib and their metabolites as total and unbound concentrations

Metabolic Ratio of Cmax of LHY746 to Cmax of encorafenib, Metabolic Ratio of Cmax of AR00426032 to Cmax of binimetinib Corrected for Molecular Weights

Metabolic Ratio of AUC of LHY746 to AUC of encorafenib, Metabolic Ratio of AUC of AR00426032 to AUC of binimetinib Corrected for Molecular Weights

Symptoms and General Pathology

Neoplasm Metastasis

Neoplastic Processes

Neo adjuvant BRAF/MEK inhibition (encorafenib/binimetinib).

Patients receive encorafenib 450 mg once daily for a period of 8 weeks. Patients receive 45 mg binimetinib twice daily for a period of 8 weeks. After the neo-adjuvant therapie, patients will receive encorafenib 450 mg once daily fand binimetinib 45mg twice daily for 44 weeks.

In the open label phase II study, the combination of BRAF/MEK inhibition with encorafenib/binimetinib in the neo-adjuvant setting will be investigated.

Furthermore, efficacy of adjuvant BRAF/MEK inhibition with encorafenib/binimetinib, for 44 weeks will be evaluated.

HW Kapiteijn, phd

Ellen Kapiteijn, phd

Daan Rauwerdink, drs

Phase 2 open-label single arm intervention study administering encorafenib/binimetinib in neo-adjuvant setting followed by surgery and subsequent adjuvant encorafenib/binimetinib in in-transit melanoma patients without lymph node and distant metastases.

Phase 2 open-label single arm intervention study administering encorafenib/binimetinib in neo-adjuvant setting followed by surgery and subsequent adjuvant encorafenib/binimetinib in patients diagnosed solely with in-transit metastatic melanoma.

Primary objective is to determine the efficacy of neo-adjuvant encorafenib/binimetinib as measured by pathological response rate (partial-, complete- and no response). In the biopsy at week 0 the viability will be judged and will be graded according to the amount of tumor necrosis: \>50% tumor necrosis with \<50% viable tumor cells, \<50% necrosis with \>50% viable tumor cells and 100% necrosis without viable tumor cells. Partial response is defined as a decrease of at least 50% of the viable tumor cells and complete response as 100% decrease of tumor cells, whereas no response is defined as more than 50% of viable tumor cells present.

Secondary objectives are to assess efficacy of adjuvant BRAF/MEK inhibition, measured as local recurrence free survival (LRFS), distant metastases-free survival (DFMS), recurrence free survival (local and/or distant recurrence, RFS) and overall survival (OS). Additionally, the toxicity of the administered regimen will be assessed by analyzing the frequency- and type of adverse events, and occurrences of therapy interruption, dose reduction and or therapy cessation. Moreover, an exploration of drug measurements and ctDNA in blood and additional research of biopsies / resections will be done.

(Neo)Adjuvant BRAF/MEK Inhibition in pN1c Melanoma

Open Label Phase 2 Study Neo-Adjuvant BRAF/MEK Inhibition Followed by Surgery and Adjuvant BRAF/MEK Inhibition in In-transit Melanoma Metastases (NASAM)

Primary outcome is to determine the efficacy of neo-adjuvant eEncorafenib/bBinimetinib as measured by pathological response rate (partial-, complete- and no response). In the biopsy at week 0 the viability will be judged and will be graded according to the amount of tumor necrosis: \>50% tumor necrosis with \<50% viable tumor cells, \<50% necrosis with \>50% viable tumor cells and 100% necrosis without viable tumor cells. Partial response is defined as a decrease of at least 50% of the viable tumor cells, and complete response is defined as more than 90% a decrease of more than 90% of the tumor cells, whereas no response is defined as more than 50% of viable tumor cells present.

analyzing the frequency- and type of adverse events, and occurrences of therapy interruption, dose reduction and or therapycessation. Adverse events severity will be graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 5.0. Adverse events associated with BRAF/MEK inhibition will be termed as treatment related or potentially treatment related, adverse events which are not known class effects of BRAF/MEK inhibitors will be described as adverse events not treatment related. Adverse event assessment will take place from therapy initiation up to completion of adjuvant treatment (week 44) and 30 das after.

To assess efficacy of adjuvant BRAF/MEK inhibition by analyzing the surgical site clinically (bimonthly) and radiologically (every 4 months) during the adjuvant treatment.

Local disease recurrence is defined as pathologically confirmed metastasic melanoma in scar tissue and or recurrence of melanoma within 2cm of the surgical scar of primary melanoma of the previously removed melanoma.

Local disease recurrence will be measured from start of adjuvant therapy up to disease recurrence confirmation.

To assess efficacy of adjuvant BRAF/MEK inhibition by analyzing the surgical site clinically (bimonthly) and radiologically (every 4 months) during the adjuvant treatment.

Distant metastases free survival (DFMS) is defined as the moment of pathologically and or radiologically disease confirmation.

Distant metastatic disease includes, distant lymph nodes and organs. Distant metastatic free survival will be calculated using the start of therapy up to the moment of distant metastatic disease confirmation or last follow-up moment.

To assess efficacy of adjuvant BRAF/MEK inhibition by analyzing the surgical site clinically (bimonthly) and radiologically (every 4 months) during the adjuvant treatment.

Overall survival is defined as the moment of primary melanoma up to decease.

To assess efficacy of adjuvant BRAF/MEK inhibition by analyzing the surgical site clinically (bimonthly) and radiologically (every 4 months) during the adjuvant treatment.

The moment of start of adjuvant therapy up to decease or last follow-up moment.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy With Ipilimumab and Nivolumab Preceded or Not by a Targeted Therapy With Encorafenib and Binimetinib	NCT03235245	Unresectable St... Stage IV Melano...	Nivolumab + Ipi... Encorafenib + B...	18 Years -	European Organisation for Research and Treatment of Cancer - EORTC
Perioperative Encobini in BRAFV600 Mutant Stage III (B/C/D) or Oligometastatic Stage IV Melanoma	NCT05097378	Melanoma Cancer	Encorafenib + B... Standard Adjuva...	18 Years -	Cambridge University Hospitals NHS Foundation Trust
Strata PATH™ (Precision Indications for Approved Therapies)	NCT05097599	Cancer Advanced Solid ...	lorlatinib encorafenib + b... talazoparib sacituzumab gov... axitinib	18 Years -	Strata Oncology
Hepatic Impairment Study of Encorafenib in Combination With Binimetinib in BRAF Melanoma	NCT04759846	BRAF V600 Mutat... Unresectable Me... Metastatic Mela... Hepatic Impairm...	Encorafenib + B... Encorafenib + B... Encorafenib + B...	18 Years -	Pierre Fabre Medicament
(Neo)Adjuvant BRAF/MEK Inhibition in pN1c Melanoma	NCT05767879	Melanoma Stage ... In-Transit Meta...	Encorafenib + B...	18 Years -	Leiden University Medical Center

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