A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma

A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma

CLGX818X2101 is a first-time in-human, phase I study to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of daily administered LGX818 (daily, twice daily and/or every-other-day), a RAF kinase inhibitor. Patients with locally advanced or metastatic melanoma harboring the BRAF V600 mutation (during dose escalation phase and expansion phase) and patients with metastatic colorectal cancer harboring the BRAF V600 mutation (during the expansion phase) will be enrolled. The study consists of a dose escalation part were cohorts of patients will receive escalating oral doses of LGX818, followed by a safety dose expansion part were patients will be treated with oral dose of LGX818 given at the MTD or RP2D.

Study Overview

• Status: Completed
• Conditions: Melanoma and Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: LGX818

• Study Type: Interventional
• Enrollment (Actual): 107
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Western Sydney Local Health District
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital- Redbank Rd
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Centre
• France
  • Villejuif, France, 94805
    • Institut Gustave Roussy
  • Haute-garonne
    • Toulouse, Haute-garonne, France, 31059 Cedex 9
      • EDOG - Institut Claudius Regaud - PPDS
  • ILE DE France - VAL DE Marne (94)
    • Villejuif, ILE DE France - VAL DE Marne (94), France, 94800
      • Institut Gustave Roussy
  • VAL DE Marne
    • Villejuif, VAL DE Marne, France, 94800
      • Institut Gustave Roussy
  • Val-de-marne
    • Villejuif, Val-de-marne, France, 94805
      • Institut Gustave Roussy
    • Villejuif Cedex, Val-de-marne, France, 94805
      • Institut Gustave Roussy
• Japan
  • Tokyo
    • Chuo-ku, Tokyo, Japan, 104-0045
      • National Cancer Center Hospital
• Norway
  • Oslo, Norway, 00424
    • Oslo Myeloma Center - PPDS
• Spain
  • Badalona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron - PPDS
  • Barcelona, Spain, 08035
    • Hospital General Vall D'Hebron
  • Barcelona, Spain, 8035
    • Hospital Universitario Vall d'Hebron - PPDS
  • Madrid, Spain, 28050
    • Hospital Universitario HM Sanchinarro_CIOCC
  • Madrid, Spain, 28050
    • START MADRID_Hospital Universitario HM Sanchinarro - CIOCC
• Switzerland
  • Zürich, Switzerland, 8091
    • Universität Zürich
  • Graubünden (DE)
    • Chur, Graubünden (DE), Switzerland, 07000
      • Kantonsspital Graubunden
• United States
  • Florida
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

For the dose escalation phase:

1. Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]). For the dose expansion phase: (i) Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or (ii) confirmed diagnosis and non-resectable advanced metastatic colorectal cancer (mCRC) for which no further effective standard therapy exists.
2. Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation.
3. Evidence of measurable disease

Exclusion Criteria:

1. Previous therapy with a MEK inhibitor.
2. Symptomatic or untreated leptomeningeal disease.
3. Symptomatic or untreated brain metastasis.Patients previously treated for these conditions that are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging.
4. Known acute or chronic pancreatitis.
5. Clinically significant cardiac disease
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818
7. Previous or concurrent malignancy. Exceptions to this exclusion criteria include: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
8. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
9. History of thromboembolic or cerebrovascular events within the last 6 months

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LGX818 - Dose escalation	Drug: LGX818
Experimental: LGX818 - Dose Expansion at MTD or RP2D	Drug: LGX818

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase	DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: >=grade (G)3 neutropenia or thrombocytopenia for >7 days; G4 thrombocytopenia; febrile neutropenia; >=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (>=G3 for > 7 consecutive days or G4); >=G3 ALT or AST and >=G2 blood bilirubin; >=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for >7 consecutive days; >= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; >=G3 pancreatitis, rash/photosensitivity (G3 for > 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.	Up to 28 days
Number of Participants With DLT During Dose Expansion Phase	DLT= Adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within first 28 days of treatment with encorafenib and met any of following criteria: >=grade (G)3 neutropenia or thrombocytopenia for >7 days; G4 thrombocytopenia; febrile neutropenia; >=G3 serum creatinine, blood bilirubin; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and lipase and/or serum amylase (>=G3 for > 7 consecutive days or G4); >=G3 ALT or AST and >=G2 blood bilirubin; >=G3 persistent hypertension with more than one drug or more intensive therapy or cardiac disorders or AE excluding on-target side-effect that is manageable; G3 fatigue/asthenia for >7 consecutive days; >= G3 vomiting or nausea or diarrhea lasting more than 48 hours despite treatment; >=G3 pancreatitis, rash/photosensitivity (G3 for > 7 consecutive days despite skin toxicity treatment or G4); G3 or G4 eye disorders.	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase	An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated.	From start of study treatment until 30 days after last dose of study treatment (maximum of 556.1 weeks of treatment exposure)
Number of Participants With AEs and SAEs During Dose Expansion Phase	An AE was defined as the appearance of (or worsening of any pre-existing) undesirable signs, symptoms, or medical conditions. An SAE was defined as one of the following: fatal or life-threatening; resulted in significant disability/incapacity; congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization unless for routine treatment, elective or pre-planned treatment for a pre-existing condition, treatment on an emergency outpatient basis, social reasons and respite care in the absence of any deterioration in the participants general condition, any SAEs that were expected due to the condition being treated.	From start of study treatment until 30 days after last dose of study treatment (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Progression Free Survival (PFS): Dose Escalation Phase	PFS was defined as time from date of first study treatment intake to date of first documented disease progression (PD) or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of greater than or equal to (>=) 5 mm, or appearance of >=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method.	From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure)
PFS: Dose Expansion Phase	PFS was defined as time from date of first study treatment intake to date of first documented PD or death due to any cause. If a participant did not have an event, data censoring was done at the date of last adequate tumor assessment. PD was defined for target disease as at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study (this included baseline sum if that was smallest on study), sum also demonstrated absolute increase of >= 5 mm, or appearance of >=1 new lesions. For non-target disease: PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion was also considered PD. Analysis was performed using Kaplan-Meier method.	From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Duration of Response (DOR): Dose Escalation Phase	DOR was defined as the time from first observation of response CR or partial response [PR]) to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions, and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of >= 5 mm, or appearance of >=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.	From first observation of response until first time of PD or death due to any cause (Maximum of 556.1 weeks of treatment exposure)
Time to Response (TTR): Dose Escalation Phase	TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure.	From date of start of treatment until CR or PR or censoring date (maximum of 556.1 weeks of treatment exposure)
DOR: Dose Expansion Phase	DOR was defined as the time from first observation of response (CR or PR] to the first time of progression or death. CR was defined as complete disappearance of all target and non-target lesions and sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to (<10 mm. PR defined as at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of >= 5 mm, or appearance of >=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.	From first observation of response until first time of PD or death due to any cause (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
TTR: Dose Expansion Phase	TTR was defined as the time from date of treatment until first documented response (CR or PR). CR was defined as complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR was defined as at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Participants who did not achieve a confirmed PR or CR, were censored at last adequate tumor assessment date when they did not progress (including deaths not due to underlying disease) or at maximum follow-up (from study start to study end date) when participant had an event for progression-free survival. Individual participant data have been reported for this outcome measure.	From date of start of treatment until CR or PR or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Overall Survival (OS): Dose Expansion Phase	Overall survival was defined as the time from the date of first study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.	From start of study treatment until date of death or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)
Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase		Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase		Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase	AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.	Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase		Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase	t1/2 was the time measured for the plasma concentration to decrease by one half. Terminal phase half-life expressed in hours (hr).	Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase		Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase		Pre-dose (0 hour), 0.5, 3, 4, 6, 8, 10 (only for BID arms), 24 hours post dose on Day 1 and 15 of Cycle 1 (each cycle=28 days)
Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation	Tumor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of >= 5 mm, or appearance of >=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.	From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 556.1 weeks of treatment exposure)
Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase		Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Vz/F of LGX818: Dose Expansion Phase		Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Tmax of LGX818: Dose Expansion Phase	Tmax was the time required to reach the maximum plasma concentration (Cmax). First observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in hours (hr).	Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
AUCinf of LGX818: Dose Expansion Phase	AUC (inf) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time.	Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
AUCtau of LGX818: Dose Expansion Phase		Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
t1/2 of LGX818: Dose Expansion Phase		Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
CL/F of LGX818: Dose Expansion Phase		Predose (0 hour), 0.5, 2, 4, 6, 8, 24 hours post dose on Day 1,8 and 15 of Cycle 1 (cycle=28 days)
Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion	Number of participants according to BRAF V600 mutation status as V600E (i.e., mutation of the BRAF gene in which valine [V] was substituted by glutamic acid [E] at amino acid 600) or other is reported in this outcome measure.	(Baseline) last non-missing value prior to the first dose (Baseline)
Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion	umor response included: CR, PR, stable disease and disease progression (PD). CR=complete disappearance of all target and non-target lesions sustained for at least 4 weeks apart before progression. Any pathological lymph nodes (whether target or non-target) reduced in short axis to <10 mm. PR=at least 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease=neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. For target disease, PD=at least a 20% increase in sum of longest diameters of all measured target lesions, taking as reference smallest sum on study, sum also demonstrated absolute increase of >= 5 mm, or appearance of >=1 new lesions. For non-target disease: PD=unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy; appearance of any new unequivocal malignant lesion.	From start of study treatment until first documentation of PD or death due to any cause or censoring date (maximum of 257.3 weeks and 114.6 weeks of treatment exposure for melanoma participants and mCRC participants respectively)

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2011
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): November 7, 2022

Study Registration Dates

• First Submitted: April 14, 2011
• First Submitted That Met QC Criteria: September 19, 2011
• First Posted (Estimated): September 20, 2011

Study Record Updates

• Last Update Posted (Actual): October 28, 2024
• Last Update Submitted That Met QC Criteria: August 13, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: BRAF V600 mutation; metastatic,; BRAF mutant,; BRAF mutated,; melanoma,; advanced,; RAF kinase inhibitor
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Melanoma
• Other Study ID Numbers: CLGX818X2101; C4221010 (Other Identifier: Alias Study Number); 2011-000556-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: No