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

• Register: ClinicalTrials.gov
• Last refreshed on: 10 October 2022
• Main ID: NCT02601378
• Date of registration: 06/11/2015
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharmaceuticals
• Public title: A Phase I Study of LXS196 in Patients With Metastatic Uveal Melanoma.
• Scientific title: A Phase I, Multi-center, Open-label, Study of LXS196, an Oral Protein Kinase C Inhibitor, in Patients With Metastatic Uveal Melanoma
• Date of first enrolment: February 1, 2016
• Target sample size: 107
• Recruitment status: Terminated
• URL: https://clinicaltrials.gov/show/NCT02601378
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

Australia, France, Netherlands, Norway, Spain, United States

Contacts

• Name: Novartis Pharmaceuticals
• Affiliation: Novartis Pharmaceuticals

Key inclusion & exclusion criteria

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).



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Uveal Melanoma

Intervention(s)

Drug: LXS196

Drug: LXS196 and HDM201

Primary Outcome(s)

Incidence of dose limiting toxicities (DLTs) (Dose escalation only) [Time Frame: Cycle 1 in dose escalation]

Dose interruptions, reductions and dose intensity [Time Frame: Continuously throughout the study until 30 days after treatment discontinuation]

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) [Time Frame: Continuously throughout the study until 30 days after treatment discontinuation]

Secondary Outcome(s)

LXS196 plasma protein content as a single agent [Time Frame: Cycle 1, 2, 3 and 4 Day 1]

Plasma PK parameters of HDM201: AUC [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1]

Plasma PK parameters of LXS196 in combination with HDM201: Tmax [Time Frame: 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 [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1]

Progression free survival (PFS) per RECIST version 1.1 criteria [Time Frame: 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 HDM201 concentration-time profiles [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1]

Plasma PK parameters of HDM201: Cmax [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1]

LXS196 plasma protein binding as a single agent [Time Frame: Cycle 1 Day 1, 2, 15, 16]

Plasma LXS196 concentration-time profiles in combination with HDM201 [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma PK parameters of LXS196 as a single agent: t1/2 [Time Frame: 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 [Time Frame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma PK parameters of LXS196 in combination with HDM201: Cmax [Time Frame: 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 [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma LXS196 concentration-time profiles as a single agent [Time Frame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma PK parameters of LXS196 as a single agent:AUC [Time Frame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma PK parameters of HDM201: Tmax [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1]

Plasma PK parameters of LXS196 as a single agent: Cmax [Time Frame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1]

Plasma PK parameters of HDM201: t1/2 [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1]

Plasma PK parameters of LXS196 in combination with HDM201: Racc [Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1]

Modulation of signaling molecules downstream of PKC [Time Frame: Baseline and Cycle 1 Day 15]

Overall response rate (ORR) per RECIST version 1.1 criteria [Time Frame: 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: Tmax [Time Frame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1]

Secondary ID(s)

CLXS196X2101

Source(s) of Monetary Support

Please refer to primary and secondary sponsors