Phase 2
N=68
A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors
Solid Tumors Harboring a BRAF V600 Mutation
Bottom Line
View on ClinicalTrials.gov: NCT01543698 ↗Enrolled (actual)
68
Serious AEs
47.6%
Results posted
Mar 2024
Primary outcome: Primary: Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b — 0; 0; 0; 0 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- LGX818 (Drug); MEK162 (Drug); LEE011 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Pfizer
- Primary completion
- Mar 2023
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose Limiting Toxicities (DLTs): Phase 1b |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Disease Control Rate (DCR) at Week 16: Phase 2, Arm 1 (mCRC Participants) |
63.6 | — |
| PRIMARY Objective Response Rate (ORR): Phase 2, Arms 2, 3 and A |
42.3; 66.7; 59.5 | — |
| SECONDARY Number of Participants With Treatment Emergent Adverse Events (TEAEs): Overall Grades and AEs of Grade 3/4: Phase 1b |
6; 5; 4; 5; 13; 8 | — |
| SECONDARY Number of Participants With TEAEs: Overall Grades and AEs of Grade 3/4: Phase 2 |
11; 26; 42; 42; 5; 15 | — |
| SECONDARY Area Under the Concentration-time Curve From Time Zero to Infinity With Extrapolation of the Terminal Phase (AUCinf) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
3740; 11700; 22000; 42000; 36700; 57400 | — |
| SECONDARY Area Under the Concentration-Time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
3690; 11500; 22000; 40200; 36100; 57000 | — |
| SECONDARY AUClast at Steady State (AUClast,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
2620; 5510; 4620; 10200; 15900; 27300 | — |
| SECONDARY Area Under the Concentration-Time Curve From Time Zero to Tau After First Dose (AUCtau) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
3700; 11500; 22000; 40200; 36300; 57000 | — |
| SECONDARY AUCtau at Steady State (AUCtau,ss) of Encorafenib, Binimetinib and Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
2620; 5510; 4620; 10200; 15900; 27300 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b |
855; 1930; 3820; 6930; 7620; 10300 | — |
| SECONDARY Cmax at Steady State (Cmax,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
587; 1190; 1060; 3760; 4320; 11100 | — |
| SECONDARY Elimination Half-life (t1/2) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
3.68; 3.65; 2.88; 4.19; 3.47; 3.21 | — |
| SECONDARY t1/2 at Steady State (t1/2,ss) of Encorafenib, Binimetinib, Ribociclib, Metabolite of Binimetinib and Ribociclib: Phase 1b |
4.74; 4.47; 4.32; 4.21; 3.57; 3.40 | — |
| SECONDARY Accumulation Ratio (RA) of Encorafenib, Binimetinib, Ribociclib Metabolite of Binimetinib and Ribociclib: Phase 1b |
0.857; 0.601; 0.298; 0.348; 0.458; 0.473 | — |
| SECONDARY Objective Response Rate (ORR): Phase 1b |
66.7; 40.0; 25.0; 40.0; 53.8; 25.0 | — |
| SECONDARY Progression Free Survival (PFS): Phase 2 |
5.4; 3.8; 7.5; 9.0 | — |
| SECONDARY Time to Response (TTR): Phase 2 |
2.6; 1.8; 1.0; 1.9 | — |
| SECONDARY Duration of Response (DOR): Phase 2 |
7.1; 3.8; 10.9; 7.5 | — |
| SECONDARY Overall Survival (OS): Phase 2 |
9.5; 11.4; 23.1; 21.8 | — |
| SECONDARY Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 1b |
5; 4; 3; 4; 7; 7 | — |
| SECONDARY Number of Participants With Molecular Alterations of Tumor Tissues Using Potential Predictive Markers: Phase 2 |
4; 15; 20; 30; 0; 0 | — |
Summary
This is a multi-center, open-label, dose finding, Phase Ib dose escalation study to estimate the MTD(s) and/or RP2D(s) for the dual combination of LGX818 and MEK162 and the triple combination of LGX818 and MEK162 and LEE011, followed each independently by a Phase II part to assess the clinical efficacy and to further assess the safety of the combinations in selected patient populations. Oral LGX818 and MEK162 will be administered on a continuous schedule. Oral LEE011 will be administered once daily on a three weeks on, one week off schedule. Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. A cycle is defined as 28 days. The dose escalation parts of the trial will be conducted in adult patients with BRAF V600-dependent advanced solid tumors and is expected to enroll at least 18 patients for the dual combination and at least 12 patients for the triple combination. The dose escalation will be guided by a Bayesian logistic regression model (BLRM). Following MTD/RP2D declaration, patients will be enrolled in three Phase II arms for the dual combination and one Phase II arm for the triple combination. All patients will be followed for 30 days for safety assessments after study drugs discontinuation. All patients enrolled in the Phase II part of the study will be followed for survival.
Eligibility Criteria
Inclusion Criteria
Histologically confirmed diagnosis of locally advanced or metastatic melanoma (stage IIIB to IV per American Joint Committee on Cancer [AJCC]), or confirmed diagnosis of non-resectable advanced metastatic colorectal cancer (mCRC), or any other indication upon agreement with the Sponsor, whose disease has progressed despite previous antineoplastic therapy or for whom no further effective standard therapy is available
- Written documentation of BRAF V600E mutation, or any other BRAF V600 mutation
- Evidence of measurable disease as determined by RECIST v1.1
- World Health Organization (WHO) Performance Status ≤ 2
- Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential
Exclusion Criteria
Progressive disease following prior treatment with RAF-inhibitors in combination with MEK-inhibitors
- Symptomatic or untreated leptomeningeal disease
- Symptomatic brain metastases. Patients are not permitted to receive enzyme inducing anti-epileptic drugs
- Known acute or chronic pancreatitis
- History or current evidence of retinal disease, retinal vein occlusion or ophthalmopathy
- Clinically significant cardiac disease
- Patients with abnormal laboratory values at Screening/baseline
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/MEK162
- Previous or concurrent malignancy
- Pregnant or nursing (lactating) women
- For addition of LEE011 in the triple combination, congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ≥ 3, brain metastases at baseline, abnormal coagulation results PT/INR >1.5 x ULN or aPTT >1.5 x ULN.
Other protocol-defined inclusion/exclusion criteria may apply
Data sourced from ClinicalTrials.gov (NCT01543698). 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.