Clinical trial NCT02601378: A Phase I Study of LXS196 in Patients With Metastatic Uveal Melanoma.
Official title: A Phase I, Multi-center, Open-label, Study of LXS196, an Oral Protein Kinase C Inhibitor, in Patients With Metastatic Uveal Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Uveal Melanoma
Keywords: Uveal melanoma
Metastatic uveal melanoma
Phase I
LXS196
PKC inhibitor
HDM201
HDM2 inhibitor
dose escalation
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-11-10
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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).

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs) (Dose escalation only)
timeFrame: Cycle 1 in dose escalation
measure: 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)
timeFrame: Continuously throughout the study until 30 days after treatment discontinuation
measure: Dose interruptions, reductions and dose intensity
timeFrame: Continuously throughout the study until 30 days after treatment discontinuation
Secondary outcomes:
measure: Overall response rate (ORR) per RECIST version 1.1 criteria
timeFrame: From baseline, every 2 cycles until cycle 11, then every 3 cycles afterwards until disease progression or withdrawal of consent up to 12 months
measure: Plasma LXS196 concentration-time profiles as a single agent
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Modulation of signaling molecules downstream of PKC
timeFrame: Baseline and Cycle 1 Day 15
measure: Progression free survival (PFS) per RECIST version 1.1 criteria
timeFrame: From baseline, every 2 cycles until cycle 11, then every 3 cycles afterwards until disease progression or withdrawal of consent up to 12 months
measure: Plasma PK parameters of LXS196 as a single agent:AUC
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 as a single agent: Cmax
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 as a single agent: Tmax
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 as a single agent: t1/2
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 as a single agent: Racc
timeFrame: Cycle 1 Day 1, 2, 3, 15; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma HDM201 concentration-time profiles
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
measure: Plasma PK parameters of HDM201: AUC
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
measure: Plasma PK parameters of HDM201: Cmax
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
measure: Plasma PK parameters of HDM201: Tmax
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
measure: Plasma PK parameters of HDM201: t1/2
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1
measure: Plasma LXS196 concentration-time profiles in combination with HDM201
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 in combination with HDM201:AUC
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 in combination with HDM201: Cmax
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 in combination with HDM201: Tmax
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 in combination with HDM201: t1/2
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: Plasma PK parameters of LXS196 in combination with HDM201: Racc
timeFrame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day1
measure: LXS196 plasma protein binding as a single agent
timeFrame: Cycle 1 Day 1, 2, 15, 16
measure: LXS196 plasma protein content as a single agent
timeFrame: Cycle 1, 2, 3 and 4 Day 1
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Westmead
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Paris
country: France
facility: Novartis Investigative Site
city: Leiden
country: Netherlands
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: