NAPORAFENIB for Melanoma (BRAFV600 or NRAS mutant)

Inclusion criteria

• {"criterion_text":"- Male or female must be ≥ 12 years\n- For adolescent participants only (12-17 years): body weight > 40kg\n- Histologically confirmed unresectable or metastatic cutaneous melanoma\n- Documentation of BRAFV600 or NRAS mutation in tumor tissue prior to study treatment as determined by local assay or as determined by central pre-screening assessment performed at a Novartis designated laboratory\n- Previously treated for unresectable or metastatic melanoma: Participants with NRAS mutation: Participants must have received prior systemic therapy for unresectable or metastatic melanoma with checkpoint inhibitors (CPI), either an anti-PD-1/PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally directed anti-neoplastic agents Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant therapy with a checkpoint inhibitor Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systematic therapy A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed. Additional agents administered with a CPI are permitted. To rule out pseudo-progression, participants must have documented confirmed progressive disease as per iRECIST v1.1 while on/after treatment with checkpoint inhibitor therapy. Confirmation is not required for patients who remained on treatment >6 months Participants with BRAFV600 mutant disease: Participants must have received prior systemic therapy for unresectable or metastatic melanoma with a checkpoint inhibitor (CPI), either an anti-PD-1/ anti-PD-L1 as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally directed anti-neoplastic agents. Additionally, participants must have received targeted therapy with a RAFi as a single agent or in combination with a MEKi (+/- CPI allowed) as the last prior therapy Prior checkpoint inhibitor therapy in the unresectable or metastatic setting is not required for participants who have progressed on or within 6 months of adjuvant checkpoint inhibitors Prior therapy with T-VEC (talimogene laherparepvec) is allowed and will not be counted as a prior line of systemic therapy A maximum of two prior lines of CPI-containing systemic immunotherapy for unresectable or metastatic melanoma are allowed. Additional agents with CPI are permitted A maximum of one line of targeted therapy is allowed, and it must be the most recent line of therapy If a participant discontinued targeted therapy for reasons other than disease progression, a switch to another targeted therapy regimen is allowed Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy\n- Participants must have a site of disease amenable to repeated biopsies and must be willing to undergo a new tumor biopsy at baseline and during treatment according to the treating institution’s own guidelines and requirements for such procedures. For screening biopsy, exceptions may be made for patients who have recently undergone a fresh tumor biopsy out of the screening window and have received no intervening therapy, after discussion with the Novartis medical monitor. Bone metastases are not acceptable as a site for biopsy"}

Exclusion criteria

• {"criterion_text":"- All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable\n- Insufficient bone marrow, hepatic or renal function at the screening visit\n- Abnormal ECG as determined by the mean of a triplicate ECG and assessed locally\n- Cardiac disease or cardiac repolarization abnormality\n- Presence of ≥ CTCAE grade 2 toxicity (except alopecia) due to prior anti-cancer therapy. Grade 2 endocrinopathies being treated with replacement therapy and that are no longer symptomatic\n- History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)"}

Primary endpoints

• {"endpoint_text":"- Confirmed ORR using RECIST v1.1, per local assessment","definition_or_measurement_approach":"Objective Response Rate (ORR) confirmed by RECIST v1.1 assessed per local assessment (as stated: \"Confirmed ORR using RECIST v1.1, per local assessment\")."}

Secondary endpoints

• {"endpoint_text":"- Safety: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) including changes in laboratory values, vital signs and cardiac assessment","definition_or_measurement_approach":"Safety assessed by incidence and severity of AEs and SAEs, including laboratory values, vital signs and cardiac assessments."}
• {"endpoint_text":"- Tolerability: Dose interruptions, reductions, and permanent discontinuations of study treatments","definition_or_measurement_approach":"Tolerability measured by recording dose interruptions, dose reductions, and permanent discontinuations of study treatments."}
• {"endpoint_text":"- DoR, PFS and DCR using RECIST v1.1, per local assessment","definition_or_measurement_approach":"Duration of Response (DoR), Progression Free Survival (PFS) and Disease Control Rate (DCR) assessed using RECIST v1.1 per local assessment."}
• {"endpoint_text":"- DoR, PFS, DCR and ORR, assessed using RECIST v1.1, per central assessment for all participants (selection and expansion) for the combination arms that moved to expansion","definition_or_measurement_approach":"For combination arms that expand, DoR, PFS, DCR and ORR will be evaluated centrally using RECIST v1.1 for all participants (selection and expansion)."}
• {"endpoint_text":"- Overall survival (OS)","definition_or_measurement_approach":"Overall survival measured as time from randomisation/enrolment to death from any cause (OS endpoint stated but no additional measurement detail provided in the record)."}
• {"endpoint_text":"- Serum/plasma concentration and pharmacokinetic parameters of each combination regimen","definition_or_measurement_approach":"Pharmacokinetics assessed by serum/plasma concentration measurements and calculation of PK parameters for each combination regimen."}

Belgium

Earliest CTIS Part Ii Submission Date

10-05-2024

Latest Decision Or Authorization Date

13-06-2024

Processing Time Days

34

Number Of Sites

2

Number Of Participants

7

Germany

Earliest CTIS Part Ii Submission Date

10-05-2024

Latest Decision Or Authorization Date

13-06-2024

Processing Time Days

34

Number Of Sites

2

Number Of Participants

9

Italy

Earliest CTIS Part Ii Submission Date

10-05-2024

Latest Decision Or Authorization Date

17-06-2024

Processing Time Days

38

Number Of Sites

1

Number Of Participants

7

France

Earliest CTIS Part Ii Submission Date

12-06-2024

Latest Decision Or Authorization Date

09-07-2024

Processing Time Days

27

Number Of Sites

6

Number Of Participants

30

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

sponsorDuties: 1

Name

IQVIA Limited

Responsibilities

sponsorDuties: 3

Name

Parexel International (IRL) Limited

Responsibilities

sponsorDuties: 12

Name

Icon Laboratory Services Inc.

Responsibilities

sponsorDuties: 4

Third parties

• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"15: Imaging","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"3","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Phardis S.r.l.","duties_or_roles":"15: Local equipment storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"15: ECG analysis/ review","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"4","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Movianto Belgium","duties_or_roles":"15: Drug return and destruction","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"1","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"12","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"15: TMF archive Activation sites activities","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Icon Laboratory Services Inc.","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Diagnostic Services Limited","duties_or_roles":"4","organisation_type":"Laboratory/Research/Testing facility"}