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.

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).