Clinical trial NCT04417621: Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma
Official title: A Randomized, Open-label, Multi-arm, Two-part, Phase II Study to Assess Efficacy and Safety of Multiple LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic BRAFV600 or NRAS Mutant Melanoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Melanoma
Keywords: LXH254
Melanoma
NRAS
BRAF
LTT462
Trametinib
Ribocliclib
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2020-06-04
Enrollment: 134
Sex: ALL
Minimum age (years): 12
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to evaluate the efficacy of LXH254 combinations in previously treated unresectable or metastatic melanoma


Eligibility criteria: Inclusion Criteria:

Male or female must be ≥ 12 years For adolescents only (12-17 years): body weight \> 40kg Histologically confirmed unresectable or metastatic cutaneous melanoma

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.
* A maximum of two prior lines of systemic CPI-containing immunotherapy for unresectable or metastatic melanoma are allowed. Additional agents administered with CPI are permitted.
* To rule out pseudo-progression, participants must have documented confirmed progressive disease as per RECIST v1.1 while on/after treatment with checkpoint inhibitor therapy. Confirmation is not required for patients who remained on treatment for \>6 months.
* Participants with BRAFV600 mutant disease:
* 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. 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.
* A maximum of two prior lines of systemic CPI-containing 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.
* Participants must have documented progressive disease as per RECIST v1.1 while on/after treatment with targeted therapy.

Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment within the stated timeframes:

* ≤ 4 weeks for radiation therapy or ≤ 2 weeks for limited field radiation for palliation prior to the first dose of study treatment.
* ≤ 2 weeks for small molecule therapeutics.
* ≤ 4 weeks for any immunotherapy treatment including immune checkpoint inhibitors.
* ≤ 4 weeks for chemotherapy agents, locally directed anti-neoplastic agents, or other investigational agents.
* ≤ 6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin c.

Participants participating in additional parallel investigational drug or medical device studies.

All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable 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).

Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.

Other protocol-defined exclusion criteria may apply

Primary outcomes:
measure: Overall Response Rate
timeFrame: 35 months
Secondary outcomes:
measure: Duration of Reposnse (DOR)
timeFrame: 4 years
measure: Progression Free Survival (PFS)
timeFrame: 4 years
measure: Disease Control Rate (DCR)
timeFrame: 3 years
measure: Overall Survival (OS)
timeFrame: 4 years
measure: Derived PK parameter (Cmax) for LXH254 & LTT462
timeFrame: Up to 5 months
measure: Derived PK parameter (Cmax) for LXH254 & trametinib
timeFrame: Up to 5 months
measure: Derived PK parameter (Cmax) for LXH254 & ribociclib
timeFrame: Up to 5 months
measure: Derived PK parameter (AUC) for LXH254 & LTT462
timeFrame: Up to 5 months
measure: Derived PK parameter (AUC) for LXH254 & trametinib
timeFrame: Up to 5 months
measure: Derived PK parameter (AUC) for LXH254 & ribociclib
timeFrame: Up to 5 months
measure: Incidence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: 35 months
measure: Dose Interruptions
timeFrame: 35 months
measure: Dose reductions
timeFrame: 35 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic Mayo Rochester
state: Minnesota
city: New York
country: United States
facility: NYU Laura and Isaac Perlmutter Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering
state: New York
city: Pittsburgh
country: United States
facility: University of Pittsburgh Med Center
state: Pennsylvania
city: Houston
country: United States
facility: Univ of TX MD Anderson Cancer Cntr
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: North Sydney
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Wooloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Subiaco
country: Australia
facility: Novartis Investigative Site
state: Western Australia
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Tuebingen
country: Germany
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
References:
citation: Moschos SJ. War against NRAS-Mutant Melanoma Using Targeted Therapies Remains Challenging. Clin Cancer Res. 2022 Jul 15;28(14):2977-2979. doi: 10.1158/1078-0432.CCR-22-1256.