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

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ClinicalTrials.gov Identifier: NCT02601378
Recruitment Status : Recruiting
First Posted : November 10, 2015
Last Update Posted : August 28, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 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 : November 1, 2019
Estimated Study Completion Date : November 1, 2019


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




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 ]


Information from the National Library of Medicine

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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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02601378


Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
United States, New York
Novartis Investigative Site Recruiting
New York, New York, United States, 10032
Australia, New South Wales
Novartis Investigative Site Recruiting
Westmead, New South Wales, Australia, 2145
France
Novartis Investigative Site Recruiting
Paris, France, 75231
Netherlands
Novartis Investigative Site Recruiting
Leiden, Netherlands, 2300 RC
Norway
Novartis Investigative Site Recruiting
Oslo, Norway, NO-0424
Spain
Novartis Investigative Site Recruiting
Madrid, Spain, 28050
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02601378     History of Changes
Other Study ID Numbers: CLXS196X2101
First Posted: November 10, 2015    Key Record Dates
Last Update Posted: August 28, 2018
Last Verified: August 2018
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