A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma

• ClinicalTrials.gov Identifier: NCT02974725
• Recruitment Status: Terminated
• First Posted: November 28, 2016
• Last Update Posted: May 17, 2024
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: November 23, 2016
• First Posted Date: November 28, 2016
• Last Update Posted Date: May 17, 2024
• Actual Study Start Date: February 24, 2017
• Actual Primary Completion Date: April 24, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 4, 2020)

• Number of participants with Adverse Events (AEs) as a measure of safety and tolerability [ Time Frame: up to 5 years ]
• Dose limiting toxicities (DLTs) (dose escalation only) [ Time Frame: up to 3 years ]
• Tolerability measured by the number of subjects who have interruptions/reductions of study treatment and reason for interruptions/reductions [ Time Frame: up to 5 years ]
• Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity [ Time Frame: Up to 5 years ]

Original Primary Outcome Measures (submitted: November 23, 2016)

• Number of participants with Adverse Events (AEs) as a measure of safety and tolerability [ Time Frame: 12 months ]
• Dose limiting toxicities (DLTs) (dose escalation only) [ Time Frame: 1 cycle (28 days) ]

Current Secondary Outcome Measures (submitted: October 3, 2023)

• Overall Response Rate (ORR) [ Time Frame: Up to 5 years ]
• Duration of response (DOR) [ Time Frame: Up to 5 years ]
• Disease Control Rate (DCR) [ Time Frame: Up to 5 years ]
• Progression Free Survival (PFS) [ Time Frame: Up to 5 years ]
• Overall Survival (OS) - (dose expansion part only) [ Time Frame: Up to 5 years ]
• Derived PK parameter (Cmax) for LXH254 & LTT462: [ Time Frame: Up to 5 years ]
• Derived PK parameter (AUC) for LXH254 & LTT462 [ Time Frame: Up to 5 years ]
• Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples [ Time Frame: up to 5 years ]
• Derived PK parameter (Cmax) for LXH254 & trametinib [ Time Frame: up to 5 years ]
• Derived PK parameter (AUC) for LXH254 & trametinib [ Time Frame: Up to 5 years ]
• Derived PK parameter (Cmax) for LXH254 & ribociclib [ Time Frame: Up to 5 years ]
• Derived PK parameter (AUC) for LXH254 & ribociclib [ Time Frame: Up to 5 years ]

Original Secondary Outcome Measures (submitted: November 23, 2016)

• Overall Response Rate (ORR) [ Time Frame: Up to 12 months ]
• Duration of response (DOR) [ Time Frame: Up to 12 months ]
• Disease Control Rate (DCR) [ Time Frame: Up to 12 months ]
• Progression Free Survival (PFS) [ Time Frame: Up to 12 months ]
• Overall Survival (OS) - (dose expansion part only) [ Time Frame: Up to 12 months ]
• Plasma concentrations of LXH254 [ Time Frame: Up to Month 5 ]
• Plasma concentrations of LTT462 [ Time Frame: Up to Month 5 ]
• Derived PK parameter (Cmax) for LXH254 & LTT462: [ Time Frame: Up to Month 5 ]
• Derived PK parameter (AUC) for LXH254 & LTT462 [ Time Frame: Up to Month 5 ]
• Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples [ Time Frame: baseline, month 12 ]

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

Descriptive Information

• Brief Title: A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma
• Official Title: A Phase Ib, Open-label, Multicenter Study of Oral LXH254-centric Combinations in Adult Patients With Advanced or Metastatic KRAS or BRAF Mutant Non-Small Cell Lung Cancer or NRAS Mutant Melanoma
• Brief Summary: To characterize safety and tolerability and identify a recommended dose and regimen for the LXH254 in combination with LTT462 or trametinib or ribociclib.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Non-Small Cell Lung Cancer
• Melanoma

Intervention

• Drug: LXH254
  LXH254 will be supplied as tablet for oral use.
• Drug: LTT462
  LTT462 will be supplied as hard gelatin capsule for oral use.
• Drug: Trametinib
  Trametinib will be supplied as film-coated tablet for oral use
• Drug: Ribociclib
  Ribociclib will be supplied in tablets and hard gelatin capsules.

Study Arms

• Experimental: LXH254+LTT462
  Interventions:

  • Drug: LXH254
  • Drug: LTT462
• Experimental: LXH254+Trametinib
  Interventions:

  • Drug: LXH254
  • Drug: Trametinib
• Experimental: LXH254+Ribociclib
  Interventions:

  • Drug: LXH254
  • Drug: Ribociclib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 15, 2024): 241
• Original Estimated Enrollment (submitted: November 23, 2016): 100
• Actual Study Completion Date: April 24, 2024
• Actual Primary Completion Date: April 24, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patients must have advanced or metastatic NSCLC or cutaneous melanoma
• Presence of KRAS or BRAF mutation (NSCLC) or NRAS mutation (cutaneous melanoma) in tumor tissue
• All patients participating in this clinical trial must have progressed following standard therapy or, in the opinion of the Investigator, no effective standard therapy exists, is tolerated, appropriate or is considered equivalent to study treatment.
• ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2

Exclusion Criteria:

-Dose expansion - KRAS or NRAS mutant patients groups: Prior treatment with a RAFi (including any BRAFi and pan-RAFi), MEKi and/or ERKi. (Patients with KRAS mutant NSCLC with prior G12C inhibitor treatments are also excluded in the LXH254+trametinib expansion part). BRAF mutant patients group: Prior treatment with any EGFR, ALK, ROS1, KRAS, RAF (both BRAFV600 selective and pan-RAF), MEK1/2 and/or ERK1/2 inhibitors (for patients with BRAF V600 mutant NSCLC, prior treatments with BRAF and MEK1/2 inhibitors are allowed).

Patients who have received more than 3 lines of anti-cancer therapy are excluded.

• 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 (PPI) which cannot be discontinued 3 days prior to the start study treatment and for the duration of the study.
• Patients with Gilbert's syndrome or other heritable diseases of bile processing.

Other protocol-defined inclusion/exclusion criteria 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: Australia, Belgium, France, Germany, Israel, Italy, Korea, Republic of, Poland, Spain, Sweden, United States

Administrative Information

• NCT Number: NCT02974725
• Other Study ID Numbers: CLXH254X2102; 2016-004293-18 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

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: May 2024