Phase 1
N=54
A Phase I Study of Oral LGX818 in Adult Patients With Advanced or Metastatic BRAF Mutant Melanoma
Melanoma and Metastatic Colorectal Cancer
Bottom Line
View on ClinicalTrials.gov: NCT01436656 ↗Enrolled (actual)
54
Serious AEs
57.0%
Results posted
Oct 2024
Primary outcome: Primary: Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase — 0; 1; 0; 0 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 1
- Interventions
- LGX818 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Pfizer
- Primary completion
- Oct 2012
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose-Limiting Toxicity (DLT) During Dose Escalation Phase |
0; 1; 0; 0; 0; 1 | — |
| PRIMARY Number of Participants With DLT During Dose Expansion Phase |
2; 2; 0; 4; 1; 0 | — |
| SECONDARY Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs) During Dose Escalation Phase |
4; 10; 6; 3; 4; 5 | — |
| SECONDARY Number of Participants With AEs and SAEs During Dose Expansion Phase |
9; 6; 2; 16; 2; 6 | — |
| SECONDARY Progression Free Survival (PFS): Dose Escalation Phase |
75.0; 10.0; 50.0; 33.3; 50.0; 40.0 | — |
| SECONDARY PFS: Dose Expansion Phase |
16.5; 19.3; 0.6; 2.0; 20.1; 4.5 | — |
| SECONDARY Duration of Response (DOR): Dose Escalation Phase |
NA; NA; NA; NA; NA; NA | — |
| SECONDARY Time to Response (TTR): Dose Escalation Phase |
57; 952; 22; 55; 897; 21 | — |
| SECONDARY DOR: Dose Expansion Phase |
NA; NA; NA; NA; NA | — |
| SECONDARY TTR: Dose Expansion Phase |
211; 22; 23; 22; 56; 23 | — |
| SECONDARY Overall Survival (OS): Dose Expansion Phase |
NA; 12.5; NA; 9.5; NA; 7.2 | — |
| SECONDARY Maximum Observed Plasma Concentration of LGX818: Dose Escalation Phase |
970; 846; 1630; 1020; 1570; 733 | — |
| SECONDARY Time Point of Maximum Concentration (Tmax) of LGX818: Dose Escalation Phase |
2; 0.5; 2; 2; 2; 2.02 | — |
| SECONDARY Area Under the Concentration-Time Curve From Time Zero to Infinity (AUCinf) of LGX818: Dose Escalation Phase |
5470; 2340; 7660; 5050; 9520; 2220 | — |
| SECONDARY Area Under the Concentration-Time Curve From Time Zero to Tau (AUCtau) of LGX818: Dose Escalation Phase |
5360; 2330; 7610; 5010; 9400; 3210 | — |
| SECONDARY Elimination Half-life (t1/2) of LGX818: Dose Escalation Phase |
4.38; 3.77; 3.47; 3.7; 3.66; 2.82 | — |
| SECONDARY Apparent Total Plasma Clearance of Drug (CL/F) of LGX818: Dose Escalation Phase |
9.14; 21.3; 13; 19.8; 15.8; 33.8 | — |
| SECONDARY Apparent Volume of Distribution (Vz/F) of LGX818: Dose Escalation Phase |
57.8; 120; 67; 104; 84.5; 116 | — |
| SECONDARY Number of Participants According to Tumor Response Per RECIST Criteria- Dose Escalation |
1; 0; 0; 0; 1; 0 | — |
| SECONDARY Maximum Observed Plasma Concentration of LGX818: Dose Expansion Phase |
4310; 5650; 7790; 6580; NA; 1340 | — |
| SECONDARY Vz/F of LGX818: Dose Expansion Phase |
79.1; 25.3; 59.7; NA; 44.6; 219 | — |
| SECONDARY Tmax of LGX818: Dose Expansion Phase |
1.97; 2.08; 3.97; 2; NA; 2 | — |
| SECONDARY AUCinf of LGX818: Dose Expansion Phase |
18200; 70900; 33300; NA; 54400; 4290 | — |
| SECONDARY AUCtau of LGX818: Dose Expansion Phase |
18100; 35300; 69300; 33200; NA; 54400 | — |
| SECONDARY t1/2 of LGX818: Dose Expansion Phase |
3.36; 4.04; 4.14; 3.07; NA; 3.63 | — |
| SECONDARY CL/F of LGX818: Dose Expansion Phase |
16.5; 4.23; 13.5; NA; 8.27; 70.1 | — |
| SECONDARY Number of Participants According to BRAF V600 Mutation Status at Baseline: Dose Expansion |
8; 5; 1; 16; 1; 6 | — |
| SECONDARY Number of Participants According to Tumor Response Per RECIST Criteria: Dose Expansion |
1; 0; 0; 0; 0; 0 | — |
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:
- 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.
- Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation.
- Evidence of measurable disease
Exclusion Criteria
- Previous therapy with a MEK inhibitor.
- Symptomatic or untreated leptomeningeal disease.
- 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.
- Known acute or chronic pancreatitis.
- Clinically significant cardiac disease
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818
- 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.
- 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).
- History of thromboembolic or cerebrovascular events within the last 6 months
Other protocol-defined inclusion/exclusion criteria may apply
Data sourced from ClinicalTrials.gov (NCT01436656). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.