Study of efficacy and safety of LXH254 combinations in patients with previously treated unresectable or metastatic melanoma

Phase 1

• Conditions: previously treated unresectable or metastatic BRAFV600 or NRAS mutant melanoma; MedDRA version: 21.1Level: PTClassification code 10027480Term: Metastatic malignant melanomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10027150Term: Melanoma malignantSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-000873-26-BE
• Lead Sponsor: ovartis Pharma AG

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-01-04
• Last Update Posted: 18 June 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 320

Inclusion Criteria

- Male or female must be = 18 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 an anti-PD-1/PD-L1 checkpoint inhibitor (CPI) as a single agent or in combination with anti-CTLA-4, investigational agents, chemotherapy or locally directed antineoplastic agents. No additional systemic treatment is allowed for unresectable or metastatic melanoma
- 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 RECIST 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), 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. No additional systemic treatment is allowed for advanced or metastatic melanoma
-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 systematic 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.
Other protocol-defined inclusion criteria may apply.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 265
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 55

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 or = 5 half-life (whichever is shorter) for small molecule therapeutics.
· = 4 weeks for any immunotherapy treatment including immune checkpoint inhibitors.
· = 4 weeks for chemotherapy agents, locally directed antineoplastic 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).
- Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
- 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 inclusion/exclusion criteria may apply

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the anti-tumor efficacy of LXH254 in combination with novel agents including LTT462, trametinib, ribociclib in participants with previously treated unresectable or metastatic, BRAFV600 or NRAS mutant melanoma as measured by objective response rate.;Secondary Objective: - To characterize the safety and tolerability of each combination arm<br>- To further evaluate the efficacy of each combination arm<br>- To evaluate the OS of each combination arm<br>- To characterize the pharmacokinetics of each combination regimen;Primary end point(s): Confirmed objective response rate (ORR) using RECIST v1.1, per local assessment;Timepoint(s) of evaluation of this end point: Patient has at least 8 months or has progressed, died, discontinued study or started new anti-neoplastic therapy earlier.