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A Phase Ib/II Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF Dependent Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT01543698
Recruitment Status : Active, not recruiting
First Posted : March 5, 2012
Last Update Posted : January 5, 2023
Sponsor:
Information provided by (Responsible Party):
Pfizer

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
Solid Tumors Harboring a BRAF V600 Mutation Drug: LGX818 Drug: MEK162 Drug: LEE011 Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 189 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: A Phase Ib/II, Multicenter, Open-label, Dose Escalation Study of LGX818 in Combination With MEK162 in Adult Patients With BRAF V600 - Dependent Advanced Solid Tumors
Actual Study Start Date : May 30, 2012
Estimated Primary Completion Date : March 2, 2023
Estimated Study Completion Date : March 2, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: dual combination
LGX818 QD and MEK162 BID
 Drug: LGX818
Drug: MEK162
Experimental: triple combination
LGX818 QD and MEK162 BID and LEE011 QD 3 weeks on, 1 week off.
 Drug: LGX818
Drug: MEK162
Drug: LEE011


Outcome Measures
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Primary Outcome Measures :
  1. Phase Ib: Estimation of Maximum Tolerated Dose (MTD) by measuring incidence of dose limiting toxicities (DLT) [ Time Frame: up to 8 months ]
    To estimate the MTD(s) and/or recommended phase 2 dose(s) (RP2D(s)) of oral LGX818 in combination with oral MEK162, and of oral LGX818 in combination with oral MEK162 and oral LEE011 in patients with BRAF V600-dependent advanced solid tumors by measuring the incidence of DLTs as defined by the protocol.

  2. Phase II: Clinical efficacy [ Time Frame: up to 14 months ]
    Assess clinical efficacy of the LGX818 and MEK162 dual combination and LGX818 and MEK162 and LEE011 triple combination in the Phase II populations by evaluating the disease control rate (DCR) and objective response rate (ORR) as per RECIST 1.1


Secondary Outcome Measures :
  1. Safety and tolerability of LGX818 and MEK162 dual combination, and LGX818 and MEK162 and LEE011 triple combination by evaluating the incidence and severity of adverse events (AE). [ Time Frame: up to 17 months ]
    To characterize the safety and tolerability of LGX818 and MEK162 in combination, and LGX818 and MEK162 and LEE011 in combination by evaluating the incidence and severity (as per CTCAE grading) of AEs in all patients enrolled in the study.

  2. Determination of single and multiple dose of Pharmacokinetics (PK) profile by measuring plasma concentrations versus time after study drug combination dosing (Phase Ib) [ Time Frame: up to 8 months ]
    To determine the single and multiple dose PK profile of the LGX818 and MEK162 combination and LGX818 and MEK162 and LEE011 combination, by measuring plasma concentrations of MEK162 and LGX818 and LEE011 resp. at different timepoints prior and post study drug combination dosing on several days within cycle 1 and subsequent cycles.

  3. Preliminary clinical anti-tumor activity by evaluating the objective response rate (Phase Ib) [ Time Frame: up to 8 months ]
    To assess preliminary anti-tumor activity of the LGX818 and MEK162 combination, and the LGX818 and MEK162 and LEE011 combination by evaluating the ORR as per RECIST 1.1. Safety Issue?: (FDAAA) No

  4. Further clinical efficacy (phase II) [ Time Frame: up to 14 months ]
    To further assess clinical efficacy of the LGX818 and MEK162 combination and the LGX818 and MEK162 and LEE011 combination in the Phase II populations by measuring progression free survival (PFS) as per RECIST 1.1


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01543698


Locations
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Sponsors and Collaborators
Pfizer
Investigators
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Study Director: Pfizer Pfizer CT.gov Call Center Pfizer
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT01543698    
Other Study ID Numbers: CMEK162X2110
C4221005 ( Other Identifier: Alias Study Number )
2011-005875-17 ( EudraCT Number )
First Posted: March 5, 2012    Key Record Dates
Last Update Posted: January 5, 2023
Last Verified: January 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Keywords provided by Pfizer:
Advanced solid tumor,
BRAF V600 mutation
Additional relevant MeSH terms:
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Neoplasms