Clinical trial NCT01436656: A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma
Official title: A Phase I, Multicenter, Open-label, Dose-escalation Study of Oral LGX818 in Adult Patients With Locally Advanced or Metastatic BRAF Mutant Melanoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Melanoma and Metastatic Colorectal Cancer
Keywords: BRAF mutant,
BRAF mutated,
melanoma,
metastatic,
advanced,
RAF kinase inhibitor
BRAF V600 mutation
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2011-09-20
Enrollment: 107
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase
timeFrame: Up to 28 days
measure: Number of Participants With DLT During Dose Expansion Phase
timeFrame: Up to 28 days
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase
timeFrame: From start of study treatment until 30 days after last dose of study treatment (maximum of 556.1 weeks of treatment exposure)
measure: Number of Participants With AEs and SAEs During Dose Expansion Phase
timeFrame: 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)
measure: Progression Free Survival (PFS): Dose Escalation Phase
timeFrame: 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)
measure: PFS: Dose Expansion Phase
timeFrame: 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)
measure: Duration of Response (DOR): Dose Escalation Phase
timeFrame: From first observation of response until first time of PD or death due to any cause (Maximum of 556.1 weeks of treatment exposure)
measure: Time to Response (TTR): Dose Escalation Phase
timeFrame: From date of start of treatment until CR or PR or censoring date (maximum of 556.1 weeks of treatment exposure)
measure: DOR: Dose Expansion Phase
timeFrame: 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)
measure: TTR: Dose Expansion Phase
timeFrame: 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)
measure: Overall Survival (OS): Dose Expansion Phase
timeFrame: 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)
measure: Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase
timeFrame: 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)
measure: Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation
timeFrame: 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)
measure: Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: Vz/F of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: Tmax of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: AUCinf of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: AUCtau of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: t1/2 of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: CL/F of LGX818: Dose Expansion Phase
timeFrame: 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)
measure: Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion
timeFrame: (Baseline) last non-missing value prior to the first dose (Baseline)
measure: Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion
timeFrame: 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)
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Westmead
country: Australia
facility: Western Sydney Local Health District
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital- Redbank Rd
state: New South Wales
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Toulouse
country: France
facility: EDOG - Institut Claudius Regaud - PPDS
state: Haute-garonne
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: ILE DE France - VAL DE Marne (94)
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: VAL DE Marne
city: Villejuif Cedex
country: France
facility: Institut Gustave Roussy
state: Val-de-marne
city: Villejuif
country: France
facility: Institut Gustave Roussy
state: Val-de-marne
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
state: Tokyo
city: Oslo
country: Norway
facility: Oslo Myeloma Center - PPDS
city: Badalona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital General Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro_CIOCC
city: Madrid
country: Spain
facility: START MADRID_Hospital Universitario HM Sanchinarro - CIOCC
city: Chur
country: Switzerland
facility: Kantonsspital Graubünden
state: Graubünden (DE)
city: Zürich
country: Switzerland
facility: Universität Zürich
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: