Study of Efficacy and Safety of LXH254 Combinations in Patients With Previously Treated Unresectable or Metastatic Melanoma

• ClinicalTrials.gov Identifier: NCT04417621
• Recruitment Status: Active, not recruiting
• First Posted: June 4, 2020
• Last Update Posted: October 23, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 3, 2020
• First Posted Date: June 4, 2020
• Last Update Posted Date: October 23, 2023
• Actual Study Start Date: October 30, 2020
• Estimated Primary Completion Date: April 26, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 3, 2020)

Overall Response Rate [ Time Frame: 35 months ]

Confirmed ORR using RECIST v1.1, per local assessment

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 3, 2020)

• Duration of Reposnse (DOR) [ Time Frame: 4 years ]
  Local and central assessment
• Progression Free Survival (PFS) [ Time Frame: 4 years ]
• Disease Control Rate (DCR) [ Time Frame: 3 years ]
  Using RECIST v1.1, per local and central assessment
• Overall Survival (OS) [ Time Frame: 4 years ]
• Derived PK parameter (Cmax) for LXH254 & LTT462 [ Time Frame: Up to 5 months ]
• Derived PK parameter (Cmax) for LXH254 & trametinib [ Time Frame: Up to 5 months ]
• Derived PK parameter (Cmax) for LXH254 & ribociclib [ Time Frame: Up to 5 months ]
• Derived PK parameter (AUC) for LXH254 & LTT462 [ Time Frame: Up to 5 months ]
• Derived PK parameter (AUC) for LXH254 & trametinib [ Time Frame: Up to 5 months ]
• Derived PK parameter (AUC) for LXH254 & ribociclib [ Time Frame: Up to 5 months ]
• Incidence of adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: 35 months ]
  Number of participants with Adverse Events (AEs) and SAEs as a measure of safety and tolerability
• Dose Interruptions [ Time Frame: 35 months ]
  Tolerability measured by the number of subjects who have interruptions of study treatment and reason for interruptions
• Dose reductions [ Time Frame: 35 months ]
  Tolerability measured by the number of subjects who have reductions of study treatment and reason for reductions

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Brief Summary: The primary purpose of this study is to evaluate the efficacy of LXH254 combinations in previously treated unresectable or metastatic melanoma
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• Drug: LXH254
  LXH254 will be supplied as tablet for oral use.
• Drug: LTT462
  LTT462 will be supplied as hard gelatin capsule for oral use.
• Drug: Trametinib
  Trametinib will be supplied as film-coated tablet for oral use
• Drug: Ribociclib
  Ribociclib will be supplied in tablets and hard gelatin capsules.

Study Arms

• Experimental: LXH254 + LTT462
  Interventions:

  • Drug: LXH254
  • Drug: LTT462
• Experimental: LXH254 + trametinib
  Intervention: Drug: Trametinib
• Experimental: LXH254 + ribociclib
  Intervention: Drug: Ribociclib

• Publications *: 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: June 20, 2022): 134
• Original Estimated Enrollment (submitted: June 3, 2020): 320
• Estimated Study Completion Date: April 26, 2024
• Estimated Primary Completion Date: April 26, 2024 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years to 120 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Belgium, France, Germany, Israel, Italy, Netherlands, Norway, Switzerland, United Kingdom, United States
• Removed Location Countries: Austria

Administrative Information

• NCT Number: NCT04417621
• Other Study ID Numbers: CLXH254C12201; 2020-000873-26 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: October 2023