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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Apr 2021 → ongoing

Decision date (initial)

2024-06-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2024-511934-11-00

EudraCT number

2020-000873-26

ClinicalTrials.gov

NCT04417621

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Safety

To evaluate the efficacy of each combination arm based on Objective Response Rate (ORR) as confirmed by RECIST 1.1, per local assessments

Secondary objectives 4

1. To characterize the safety and tolerability of each combination arm through the incidence and severity of AEs including changes in laboratory values, vital signs, cardiac assessment, dose interruptions, reduction and permanent discontinuations of study treatments.
2. To further evaluate the efficacy of each combination arm by duration of response (DOR), progression free survival (PFS) and disease control rate (DCR) using RECIST v1.1, per local assessment. Additionally, for the treatment combination arm(s) that expanded, DoR, PFS, DCR and ORR will be evaluated using RECIST v1.1 per central assessment.
3. To evaluate the overall survival (OS) of each combination arm.
4. To characterize the pharmacokinetics of each combination regimen through serum/plasma concentration and pharmacokinetic parameters of each combination regimen.

Conditions and MedDRA coding

Previously treated unresectable or metastatic BRAFV600 or NRAS mutant melanoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Male or female must be ≥ 12 years
2. For adolescent participants only (12-17 years): body weight > 40kg
3. Histologically confirmed unresectable or metastatic cutaneous melanoma
4. 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
5. 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
6. 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 6

1. All primary central nervous system (CNS) tumors or symptomatic CNS metastases that are neurologically unstable
2. Insufficient bone marrow, hepatic or renal function at the screening visit
3. Abnormal ECG as determined by the mean of a triplicate ECG and assessed locally
4. Cardiac disease or cardiac repolarization abnormality
5. 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
6. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Confirmed ORR using RECIST v1.1, per local assessment

Secondary endpoints 6

1. Safety: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs) including changes in laboratory values, vital signs and cardiac assessment
2. Tolerability: Dose interruptions, reductions, and permanent discontinuations of study treatments
3. DoR, PFS and DCR using RECIST v1.1, per local assessment
4. 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
5. Overall survival (OS)
6. Serum/plasma concentration and pharmacokinetic parameters of each combination regimen

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 9

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 12

Locations

4 EU/EEA countries · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Temporary halts 4 · Art. 38 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications