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

• ClinicalTrials.gov Identifier: NCT02601378
• Recruitment Status: Active, not recruiting
• First Posted: November 10, 2015
• Last Update Posted: February 27, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

This study is 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 (Clinical Trial)
• 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: February 1, 2016
• Estimated Primary Completion Date: June 29, 2021
• Estimated Study Completion Date: June 30, 2021

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

Outcome Measures

Primary Outcome Measures :

1. Incidence of dose limiting toxicities (DLTs) (Dose escalation only) [ Time Frame: Cycle 1 in dose escalation ]
   cycle = 28 days
2. 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 ]
3. Dose interruptions, reductions and dose intensity [ Time Frame: Continuously throughout the study until 30 days after treatment discontinuation ]

Secondary Outcome Measures :

1. 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 ]
2. 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 ]
3. Modulation of signaling molecules downstream of PKC [ Time Frame: Baseline and Cycle 1 Day 15 ]
4. 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 ]
5. 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 ]
6. 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 ]
7. 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 ]
8. 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 ]
9. 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 ]
10. Plasma HDM201 concentration-time profiles [ Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1 ]
11. Plasma PK parameters of HDM201: AUC [ Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1 ]
12. Plasma PK parameters of HDM201: Cmax [ Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1 ]
13. Plasma PK parameters of HDM201: Tmax [ Time Frame: Cycle 1 Day 1, 2, 3, 8; Cycle 2, 3, 4, 5 and 6 Day 1 ]
14. 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 ]
15. 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 ]
16. 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 ]
17. 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 ]
18. 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 ]
19. 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 ]
20. 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 ]
21. LXS196 plasma protein binding as a single agent [ Time Frame: Cycle 1 Day 1, 2, 15, 16 ]
22. LXS196 plasma protein content as a single agent [ Time Frame: Cycle 1, 2, 3 and 4 Day 1 ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, New York

Novartis Investigative Site

New York, New York, United States, 10032

Australia, New South Wales

Novartis Investigative Site

Westmead, New South Wales, Australia, 2145

France

Novartis Investigative Site

Paris, France, 75231

Netherlands

Novartis Investigative Site

Leiden, Netherlands, 2300 RC

Norway

Novartis Investigative Site

Oslo, Norway, NO-0424

Spain

Novartis Investigative Site

Madrid, Spain, 28050

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02601378
• Other Study ID Numbers: CLXS196X2101
• First Posted: November 10, 2015
• Last Update Posted: February 27, 2020
• Last Verified: February 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Uveal melanoma; Metastatic uveal melanoma; Phase I; LXS196; PKC inhibitor; HDM201; HDM2 inhibitor; dose escalation

Additional relevant MeSH terms:

Melanoma; Uveal Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Eye Neoplasms; Neoplasms by Site; Eye Diseases; Uveal Diseases