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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT02601378

Collaborator

(none)

107

Enrollment

Locations

Arms

71.2

Actual Duration (Months)

17.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Uveal Melanoma	Drug: LXS196 Drug: LXS196 and HDM201	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

107 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 1, 2016

Actual Primary Completion Date :

Jan 7, 2022

Actual Study Completion Date :

Jan 7, 2022

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicities (DLTs) (Dose escalation only) [Cycle 1 in dose escalation]
cycle = 28 days
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

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Columbia University Medical Center	New York	New York	United States	10032
2	Novartis Investigative Site	Westmead	New South Wales	Australia	2145
3	Novartis Investigative Site	Paris		France	75231
4	Novartis Investigative Site	Leiden		Netherlands	2300 RC
5	Novartis Investigative Site	Oslo		Norway	0379
6	Novartis Investigative Site	Madrid		Spain	28050