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

Study Overview
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Brief Summary
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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.

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

Conditions
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Uveal Melanoma

Intervention / Treatment
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* Drug: LXS196
* Drug: LXS196 and HDM201


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HDM2 inhibitor, Uveal melanoma, Metastatic uveal melanoma, Phase I, LXS196, PKC inhibitor, HDM201, dose escalation