A Phase I Study of LXS196 in Patients With Metastatic Uveal Melanoma.

A Phase I, Multi-center, Open-label, Study of LXS196, an Oral Protein Kinase C Inhibitor, in Patients With Metastatic Uveal Melanoma

This study was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity of LXS196 as a single agent and in combination with HDM201 in patients with metastatic uveal melanoma.

Study Overview

• Status: Terminated
• Conditions: Uveal Melanoma
• Intervention / Treatment: Drug: LXS196; Drug: LXS196 and HDM201

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Novartis Investigative Site
• France
  • Paris, France, 75231
    • Novartis Investigative Site
• Netherlands
  • Leiden, Netherlands, 2300 RC
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0379
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28050
    • Novartis Investigative Site
• United States
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Male or female patients ≥18 years of age
• Diagnosis of uveal melanoma with histological or cytological confirmed metastatic disease. Disease must be treatment naive or have progressed (radiologically or clinically) on most recent therapy.
• Willingness to provide newly obtained tumor tissue at baseline and on treatment unless contraindicated by medical risk in the opinion of the treating physician.
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as >10 mm with CT scan.
• ECOG performance status ≤ 1

Key Exclusion Criteria:

• Malignant disease other than that being treated in this study.
• Symptomatic or untreated CNS metastases or spinal cord compression. Brain metastasis must be stable with verification by imaging .
• Impaired cardiac function or clinically significant cardiac diseases
• History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism (applicable to combination part only).
• Patients who are receiving treatment with medications that cannot be discontinued prior to study entry and that are considered to be any of the following:
• known and possible risk for QT prolongation
• known to be strong inducers or inhibitors of CYP3A4/5 (for single agent part); known to be moderate to strong inducers or inhibitors of CYP3A4/5 (for combination part)
• known to be inducers or inhibitors of P-gp
• known to be substrates of CYP3A4/5 and P-gp with a narrow therapeutic index
• Patients with abnormal laboratory values, defined as any of the following:
• AST or ALT > 3 times ULN, AST or ALT > 5 times ULN for patients with liver metastases.
• Total bilirubin > 1.5 x ULN, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN.
• Absolute neutrophil count (ANC) ≤ 1.5 x109/L.
• Platelets ≤ 100 x 109/L.
• Hemoglobin (Hgb) ≤ 90 g/L (9 g/dL).
• Creatinine > 1.5 x ULN
• Patients receiving live vaccines due to the expected bone marrow toxicity (applicable to combination part only).
• Patients treated with growth factors targeting the myeloid lineage (e.g. G-CSF, GM-CSF and M-CSF) within 2 weeks of starting study treatment. (applicable to combination part only).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LXS196 as a single agent; About 68 patients will be enrolled in dose escalation and expansion	Drug: LXS196; LXS196 as a single agent
Experimental: LXS196 in combination with HDM201; about 44 patients to be enrolled in dose escalation and expansion	Drug: LXS196 and HDM201; LXS196 in combination with HDM201

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of dose limiting toxicities (DLTs) (Dose escalation only)	cycle = 28 days	Cycle 1 in dose escalation
Incidence and severity of adverse events and serious adverse events, including changes in laboratory parameters, vital signs and ECGs graded as per NCI CTCAE version 4.03 (All patients)		Continuously throughout the study until 30 days after treatment discontinuation
Dose interruptions, reductions and dose intensity		Continuously throughout the study until 30 days after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall response rate (ORR) per RECIST version 1.1 criteria	From baseline, every 2 cycles until cycle 11, then every 3 cycles afterwards until disease progression or withdrawal of consent up to 12 months
Plasma LXS196 concentration-time profiles as a single agent	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Modulation of signaling molecules downstream of PKC	Baseline and Cycle 1 Day 15
Progression free survival (PFS) per RECIST version 1.1 criteria	From baseline, every 2 cycles until cycle 11, then every 3 cycles afterwards until disease progression or withdrawal of consent up to 12 months
Plasma PK parameters of LXS196 as a single agent:AUC	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 as a single agent: Cmax	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 as a single agent: Tmax	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 as a single agent: t1/2	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 as a single agent: Racc	Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
Plasma HDM201 concentration-time profiles	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
Plasma PK parameters of HDM201: AUC	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
Plasma PK parameters of HDM201: Cmax	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
Plasma PK parameters of HDM201: Tmax	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
Plasma PK parameters of HDM201: t1/2	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
Plasma LXS196 concentration-time profiles in combination with HDM201	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 in combination with HDM201:AUC	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 in combination with HDM201: Cmax	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 in combination with HDM201: Tmax	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 in combination with HDM201: t1/2	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
Plasma PK parameters of LXS196 in combination with HDM201: Racc	Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
LXS196 plasma protein binding as a single agent	Cycle 1 Day 1, 2, 15, 16
LXS196 plasma protein content as a single agent	Cycle 1, 2, 3 and 4 Day 1

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Study Results

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2016
• Primary Completion (Actual): January 7, 2022
• Study Completion (Actual): January 7, 2022

Study Registration Dates

• First Submitted: November 6, 2015
• First Submitted That Met QC Criteria: November 6, 2015
• First Posted (Estimate): November 10, 2015

Study Record Updates

• Last Update Posted (Actual): September 29, 2022
• Last Update Submitted That Met QC Criteria: September 27, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Phase I; HDM201; dose escalation; Uveal melanoma; Metastatic uveal melanoma; LXS196; PKC inhibitor; HDM2 inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Eye Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Uveal Diseases; Neuroendocrine Tumors; Nevi and Melanomas; Eye Neoplasms; Melanoma; Uveal Neoplasms
• Other Study ID Numbers: CLXS196X2101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No