Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations

• ClinicalTrials.gov Identifier: NCT02607813
• Recruitment Status: Terminated
• First Posted: November 18, 2015
• Last Update Posted: December 21, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 5, 2015
• First Posted Date: November 18, 2015
• Last Update Posted Date: December 21, 2022
• Actual Study Start Date: January 18, 2016
• Actual Primary Completion Date: February 18, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 6, 2016)

• Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity. [ Time Frame: From Cycle 1 Day 1 until 30 days for LXH254 single agent and 150 days for LXH254 in combination with PDR001 post study treatment (expected duration approximately 12 months) ]
  cycle = 28 days
• Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 single agent only) [ Time Frame: 28 days ]
  cycle = 28 days
• Incidence and nature of dose limiting toxicities (DLTs) (dose escalation and LXH254 in combination with PDR001 only) [ Time Frame: 56 days ]
  cycle =28 days

Original Primary Outcome Measures (submitted: November 17, 2015)

• Safety and tolerability as assessed by incidence and severity of adverse events (AEs), dose interruptions, reductions, and dose intensity. [ Time Frame: From Cycle 1 Day 1 until 30 days post study treatment (expected duration approximately 12 months) ]
  cycle = 28 days
• Incidence and nature of dose limiting toxicities (DLTs) (dose escalation only) [ Time Frame: 28 days ]
  cycle = 28 days

Current Secondary Outcome Measures (submitted: July 6, 2016)

• Overall response rate (ORR) [ Time Frame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Disease control rate (DCR) [ Time Frame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Duration of response (DoR) [ Time Frame: Every 2 cycles after starting study treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Progression-free survival (PFS) [ Time Frame: Every 2 cycles after starting study treatment until disease progression; expected duration approximately 12 months ]
  cycle = 28 days
• Overall survival (OS) - only for dose expansion [ Time Frame: From time of start treatment until the date of death; expected duration approximately 12 months ]
  cycle = 28 days
• Plasma concentrations of LXH254 [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Area Under the Curve (AUC) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: half-life (T1/2) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood [ Time Frame: Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months) ]
  cycle = 28 days
• Plasma concentrations of PDR001 [ Time Frame: Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1 ]
  cycle = 28 days
• Derived PK parameters of PDR001: Area Under the Curve (AUC) [ Time Frame: Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1 ]
  cycle = 28 days
• Derived PK parameters of PDR001: Peak Plasma Concentration (Cmax) [ Time Frame: Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1 ]
  cycle = 28 days
• Derived PK parameters of PDR001: Time to Peak Plasma Concentration (Tmax) [ Time Frame: Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1 ]
  cycle = 28 days
• Derived PK parameters of PDR001: half-life (T1/2) [ Time Frame: Cycle 1 days 1, 2, 8, and 15; Cycle 2 days 1; Cycle 3 Day 1, 2 and 8; Cycle 4 Day 1; Cycle 5 Day 1; Cycle 6 Day 1 ]
  cycle = 28 days

Original Secondary Outcome Measures (submitted: November 17, 2015)

• Overall response rate (ORR) [ Time Frame: Every 2 cycles after starting LXH254 treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Disease control rate (DCR) [ Time Frame: Every 2 cycles after starting LXH254 treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Duration of response (DoR) [ Time Frame: Every 2 cycles after starting LXH254 treatment until end of treatment; expected duration approximately 12 months ]
  cycle = 28 days
• Progression-free survival (PFS) [ Time Frame: Every 2 cycles after starting LXH254 treatment until disease progression; expected duration approximately 12 months ]
  cycle = 28 days
• Overall survival (OS) - only for dose expansion [ Time Frame: From time of start treatment until the date of death; expected duration approximately 12 months ]
  cycle = 28 days
• Plasma concentrations of LXH254 [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Area Under the Curve (AUC) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Peak Plasma Concentration (Cmax) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: Time to Peak Plasma Concentration (Tmax) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Derived PK parameters of LXH254: half-life (T1/2) [ Time Frame: Cycle 1 days 1, 2, 3, 8, 15, and 16; Cycle 2 days 1 and 15; Cycle 3 Day 1; Cycle 5 Day 1 ]
  cycle = 28 days
• Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor tissue and in blood [ Time Frame: Cycle 1 day 1, 2, 3, 15, and 16; upon disease progression (expected duration approximately 12 months) ]
  cycle = 28 days

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase I Study of LXH254 in Patients With Advanced Solid Tumors Haboring MAPK Pathway Alterations
• Official Title: A Phase I Dose Finding Study of Oral LXH254 in Adult Patients With Advanced Solid Tumors Harboring MAPK Pathway Alterations
• Brief Summary: A Phase I Study of LXH254 in Patients With Advanced Solid Tumors That Harbor MAPK Pathway Alterations.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• NSCLC
• Ovarian Cancer
• Melanoma
• Other Solid Tumors

Intervention

• Drug: LXH254
  pan-RAF inhibitor
• Drug: PDR001
  Biological: PDR001 anti-PD1 antibody

Study Arms

• Experimental: Dose escalation LXH254
  Intervention: Drug: LXH254
• Experimental: Dose expansion LXH254: Group 1
  Intervention: Drug: LXH254
• Experimental: Dose expansion LXH254: Group 2
  Intervention: Drug: LXH254
• Experimental: Dose expansion LXH254: Group 3
  Intervention: Drug: LXH254
• Experimental: Dose expansion: LXH254 + PDR001
  Interventions:

  • Drug: LXH254
  • Drug: PDR001
• Experimental: Dose escalation LXH254 + PDR001
  Interventions:

  • Drug: LXH254
  • Drug: PDR001

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 16, 2021): 142
• Original Estimated Enrollment (submitted: November 17, 2015): 81
• Actual Study Completion Date: February 19, 2022
• Actual Primary Completion Date: February 18, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• All patients participating in this clinical trial must have progressed following standard therapy, or for whom, in the opinion of the Investigator, no effective standard therapy exists, is tolerated or appropriate.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
• Presence of at least one measurable lesion according to RECIST v1.1.
• Documented MAPK alteration

Additional inclusion criteria for the Dose Expansion part: LXH254 in combination with PDR001:

• Patients with confirmed KRAS-mutated NSCLC
• Patients with confirmed NRAS-mutated melanoma (cutaneous melanoma only)

Exclusion Criteria:

- Prior treatment with a BRAFi, MEKi and/or pan-RAF inihibitors for patients to be enrolled in the dose expansion part.

Exceptions may be made after documented agreement between Novartis and Investigator.

• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
• Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures.
• Patients receiving proton pump inhibitors which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
• Pregnant or nursing (lactating) women

Additional exclusion criteria for LXH254 in combination with PDR001

• History of severe hypersensitivity reactions, which in the opinion of the investigator may cause in increased risk of serious infusion reaction.
• Known human immunodeficiency virus (HIV).
• Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection.
• Active, known or suspected autoimmune disease.
• Active infection requiring systemic antibiotic therapy
• Patients requiring systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or equivalent) which cannot be discontinued at least 7 days prior to first dose of study treatment.
• Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.

Other inclusion/exclusion criteria as per protocol may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Italy, Japan, Korea, Republic of, Netherlands, Spain, Switzerland, United States

Administrative Information

• NCT Number: NCT02607813
• Other Study ID Numbers: CLXH254X2101; 2015-003421-33 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: March 2022