Clinical trial NCT02159066: LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma
Official title: The LOGIC 2 Trial A Phase II, Multi-center, Open-label Study of Sequential LGX818/MEK162 Combination Followed by a Rational Combination With Targeted Agents After Progression, to Overcome Resistance in Adult Patients With Locally Advanced or Metastatic BRAF V600 Melanoma.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Melanoma
Keywords: Melanoma
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2014-06-09
Enrollment: 158
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to assess the anti-tumor activity of LGX818/MEK162 in combination with targeted agents after progression on LGX818/MEK162 combination therapy, as well as the safety and tolerability of the novel triple combinations.

Detailed description: This study consists of two parts: in Part I/Run-In, patients naïve to selective BRAF and MEK inhibitors will be treated with the LGX818/MEK162 combination until disease progression (as defined per RECIST v1.1). Based on the genetic analysis of a tumor biopsy obtained at that time, patients will enter Part II of the study for tailored combination treatment in one of four arms of LGX818/MEK162 + either BKM120, BGJ398, INC280 or LEE011 Patients with BRAF mutant melanoma treated by LGX818/MEK162 combination in other studies can be enrolled directly in Part II of CLGX818X2109 after relapse.

Dose-escalations in the combination arms for which no MTD has been established will be based on the recommendations of a Bayesian logistic regression model guided by an escalation with overdose control criterion

Eligibility criteria: INCLUSION CRITERIA:

* Age ≥ 18 years
* Histologically confirmed diagnosis of unresectable stage III or metastatic melanoma (stage IIIC to IV per American Joint Committee on Cancer \[AJCC\])
* Documented evidence of BRAF V600 mutation.
* Newly obtained tumor biopsy at baseline, and patient agrees to a mandatory biopsy at the time of progression, if not medically contraindicated.
* Evidence of measurable disease, as determined by RECIST v1.1.

INCLUSION CRITERIA for triple combinations:

Progressive disease following prior treatment with LGX818/MEK162 combination. PRINCIPAL EXCLUSION CRITERIA Symptomatic or untreated leptomeningeal disease.

* Symptomatic brain metastases. Patients previously treated or untreated for brain metastases that are asymptomatic in the absence of corticosteroid therapy or on a stable dose of steroids for four weeks are allowed to enroll. Brain metastases must be stable at least 4 weeks with verification by imaging (e.g. brain MRI completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs.
* Patients who have developed brain metastases during Part I of the study may continue to Part II upon discussion with Novartis Medical Monitor. The brain metastasis must be either asymptomatic or treated and stable for at least 4 weeks and on a stable or tapering dose of steroids for at least 2 weeks. Patients with brain metastasis are not eligible for the combination with LEE011.
* Known acute or chronic pancreatitis.
* History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);
* Clinically significant cardiac disease including any of the following:
* CHF requiring treatment (NYH grade ≥ 2),
* LVEF \< 50% as determined by MUGA scan or ECHO
* History or presence of clinically significant ventricular arrhythmias or atrial fibrillation
* Clinically significant resting bradycardia
* Unstable angina pectoris ≤ 3 months prior to starting study drug
* Acute Myocardial Infarction (AMI) ≤ 3 months prior to starting study drug,
* QTcF \> 480 msec. Patients with any of the following laboratory values at

Screening/baseline:

* Absolute neutrophil count (ANC) \<1,500/mm3 \[1.5 x 109/L\]
* Platelets \< 100,000/mm3 \[100 x 109/L\]
* Hemoglobin \< 9.0 g/dL
* Serum creatinine \>1.5 x ULN or calculated or directly measured CrCl \< 50% LLN (lower limit of normal)
* Serum total bilirubin \>1.5 x ULN
* AST/SGOT or ALT/SGPT \> 2.5 x ULN, or \> 5 x ULN if liver metastases are present

Additional exclusion criteria for the triple combinations:

LGX818/MEK162/BKM120:

* Patients with fasting glucose \> 120 mg/dL or 6.7 mmol/L, and HbA1c \> 8 %.
* Patient has any of the following mood disorders as judged by the

Investigator or a Psychiatrist:

* Patient has a score ≥ 12 on the PHQ-9 questionnaire
* Patient has ≥ CTCAE grade 3 anxiety

LGX818/MEK162/BGJ398:

* History and/or current evidence of significant ectopic mineralization/ calcification with the exception of calcified lymph nodes and asymptomatic vascular calcification.
* Current evidence of corneal disorder/ keratopathy incl. but not limited to bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits etc., confirmed by ophthalmologic examination

LGX818/MEK162/LEE011:

* Patients with uncontrolled hypertension (please refer to WHO-ISHguidelines) are excluded from study.
* QTcF \>450 ms for males and \>470 ms for females Congenital long QT syndrome or family history of unexpected sudden cardiac death and/or hypokalemia CTCAE Grade ≥ 3 and magnesium levels below the clinically relevant lower limits at study entry
* Current evidence of brain metastasis or brain metastasis detected by mandatory CT/MRI at screening
* PT/INR or aPTT \> 1.5xULN

Other protocol-defined inclusion/exclusion criteria may apply.

Primary outcomes:
measure: Overall Response Rate (ORR): Part II
timeFrame: From the start of the treatment until disease/clinical progression or death or early study discontinuation, whichever happened earlier (maximum treatment exposure for Part II was 97.0 weeks)
Secondary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II
timeFrame: Cycle 1 (21 days following the first dose of the combination treatment with buparlisib and capmatinib; 28 days for the combination with ribociclib and infigratinib)
measure: Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs): Part I
timeFrame: Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With AEs and SAEs: Part II
timeFrame: Day 1 up to 30 days after last dose (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade: Part I
timeFrame: Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With Worst Post-baseline Hematology Results Based on CTCAE v4.03 Grade: Part II
timeFrame: Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part I
timeFrame: Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part II
timeFrame: Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part I
timeFrame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part II
timeFrame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With Notable Electrocardiograms (ECG) Values: Part I
timeFrame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With Notable ECG Values: Part II
timeFrame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With At Least One Dose Interruption: Part I
timeFrame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With At Least One Dose Interruption: Part II
timeFrame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)
measure: Number of Participants With At Least One Dose Reduction: Part I
timeFrame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)
measure: Number of Participants With At Least One Dose Reduction: Part II
timeFrame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)
measure: Actual Dose Intensity: Part I
timeFrame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)
measure: Actual Dose Intensity: Part II
timeFrame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)
measure: Progression-Free Survival (PFS): Part I
timeFrame: From start of study drug until documented PD or death due to any cause or censoring date (maximum treatment exposure for Part I was 403.7 weeks)
measure: PFS: Part II
timeFrame: From start of study drug until documented PD or death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks)
measure: Duration of Response (DOR): Part I
timeFrame: From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part I was 403.7 weeks)
measure: DOR: Part II
timeFrame: From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part II was 97.0 weeks)
measure: Time to Response (TTR): Part I
timeFrame: From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part I was 403.7 weeks)
measure: TTR: Part II
timeFrame: From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part II was 97.0 weeks)
measure: Disease Control Rate (DCR): Part I
timeFrame: From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part I was 403.7 weeks)
measure: DCR: Part II
timeFrame: From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part II was 97.0 weeks)
measure: Overall Survival (OS): Part II
timeFrame: From date of start of treatment to date of death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks)
measure: Summary of Genomic Biomarkers From Tumor Samples: Part I
timeFrame: Baseline up to end of treatment (EOT) (maximum treatment exposure for Part I was 403.7 weeks)
measure: Plasma Concentration for Encorafenib (LGX): Part I
timeFrame: C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT
measure: Plasma Concentration for Encorafenib (LGX): Part II
timeFrame: C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT
measure: Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part I
timeFrame: C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT
measure: Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part II
timeFrame: C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT
measure: Plasma Concentration for Ribociclib (LEE) and Its Metabolite: Part II
timeFrame: C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT
measure: Plasma Concentration for Infigratinib (BGJ) and Its Metabolites: Part II
timeFrame: C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; EOT
measure: Plasma Concentration for Capmatinib (INC): Part II
timeFrame: C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT
measure: Plasma Concentration for Buparlisib (BKM): Part II
timeFrame: C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT
measure: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 (minutes) min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Area Under the Concentration-time Curve From Time Zero to Time Tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Last Measurable Plasma Concentration at Steady State (Clast, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour
measure: Measured Concentration at the End of a Dosing Interval at Steady State (Ctrough, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II
timeFrame: C1 D15: at the end of a dosing interval at steady-state (24 hour ± 2 hour), taken directly before next administration
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles
state: California
city: Los Angeles
country: United States
facility: Cancer Care Center
state: California
city: Los Angeles
country: United States
facility: Doris Stein Research Center Building
state: California
city: Los Angeles
country: United States
facility: Ronald Reagan UCLA Medical Center Drug Information Center Department of Pharmaceutical Services
state: California
city: Los Angeles
country: United States
facility: UCLA Dermatology Clinic
state: California
city: Los Angeles
country: United States
facility: UCLA Oncology Center
state: California
city: Los Angeles
country: United States
facility: UCLA Radiology
state: California
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Attn: Geny O'neill
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Inpatient Hospital & Main Campus
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center- Outpatient Clinic
state: New York
city: Portland
country: United States
facility: OHSU Knight Cancer Institute
state: Oregon
city: Portland
country: United States
facility: OHSU Center for Health and Healing 2
state: Oregon
city: Portland
country: United States
facility: OHSU Center for Health and Healing
state: Oregon
city: Portland
country: United States
facility: OHSU Research Pharmacy Services
state: Oregon
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: East St Kilda Eye Clinic
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Cancer Center
state: Ontario
city: Monteral
country: Canada
facility: Sir Mortimer B. Davis-Jewish General Hospital
state: Quebec
city: Heidelberg
country: Germany
facility: University Clinic Heidelberg PPDS
state: Baden-württemberg
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
state: Bayern
city: Köln
country: Germany
facility: Uniklinik Köln
city: Muenchen
country: Germany
facility: Städtisches Klinikum München
city: Wuerzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Napoli
country: Italy
facility: Azienda Ospedaliera Monaldi
state: Campania
city: Napoli
country: Italy
facility: U.O.C. Oncologia Medica e Terapie Innovative Dipartimento di Melanoma IRCCS Fondazione G. Pascale
city: Amsterdam
country: Netherlands
facility: Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis
city: Barcelona Cataluna
country: Spain
facility: Hospital Universitario Vall d'Hebrón - PPDS
state: Barcelona
city: Zurich Flughafen
country: Switzerland
facility: Universitätsspital Zürich
city: Oxford
country: United Kingdom
facility: Churchill Hospital
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Nassar KW, Hintzsche JD, Bagby SM, Espinoza V, Langouet-Astrie C, Amato CM, Chimed TS, Fujita M, Robinson W, Tan AC, Schweppe RE. Targeting CDK4/6 Represents a Therapeutic Vulnerability in Acquired BRAF/MEK Inhibitor-Resistant Melanoma. Mol Cancer Ther. 2021 Oct;20(10):2049-2060. doi: 10.1158/1535-7163.MCT-20-1126. Epub 2021 Aug 10.