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OpenTrials
Completed

NCT Number: NCT02159066

LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma

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.

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Key information

Conditions

Melanoma Neoplasms Neoplasms by Histologic Type Neoplasms by Site Neoplasms, Germ Cell and Embryonal Neoplasms, Nerve Tissue Neuroectodermal Tumors Neuroendocrine Tumors Nevi and Melanomas Skin Diseases Skin Neoplasms Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

East St Kilda Eye Clinic, Melbourne, Victoria, Australia

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About this study

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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

LGX818

Drug

Combination of LGX818 and MEK162 (Part I)

MEK162

Drug

Combination of LGX818 and MEK162 (Part I)

LEE011

Drug

Combination of LGX818 + MEK162 + LEE011 (Part II)

BGJ398

Drug

Combination of LGX818 + MEK162 + BGJ398 (Part II)

BKM120

Drug

Combination of LGX818 + MEK162 + BKM120 (Part II)

INC280

Drug

Combination of LGX818 + MEK162 + INC280 (Part II)

Primary outcomes

  1. Overall Response Rate (ORR): Part II

    Time frame: 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)

    ORR: percentage of participants with confirmed complete response (CR) and partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions that had a reduction in short axis to less than (<) 10 millimeter (mm). Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30 percent (%) decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Any radiological assessments taken more than 30 days after the last dose of study therapy or after antineoplastic agents other than study treatments taken by the participants was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from the previous radiological assessment.

Secondary outcomes

  1. Number of Participants With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

    Time frame: 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)

    DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (first 21 days for infigratinib and capmatinib; 28 days for ribociclib and buparlisib) of treatment initiation and met the defined criteria for study.

  2. Number of Participants With Adverse Events (AEs) and Serious AEs (SAEs): Part I

    Time frame: Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks)

    An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after participants' signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. AEs included both SAEs and all Non-SAEs.

  3. Number of Participants With AEs and SAEs: Part II

    Time frame: Day 1 up to 30 days after last dose (maximum treatment exposure for Part II was 97.0 weeks)

    An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after participants' signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. AEs included both SAEs and all Non-SAEs.

  4. Number of Participants With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) v4.03 Grade: Part I

    Time frame: Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

    Parameters evaluated were: Activated partial thromboplastin time (APTT) (seconds [sec]) - CTCAE graded high, fibrinogen (gram per liter [g/L]) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, prothrombin international normalized ratio (PINR) - CTCAE graded high, lymphocytes (10^9 cells/L) - CTCAE graded low, lymphocytes (10^9 cells/L) - CTCAE graded high, neutrophils (10^9 cells/L) - CTCAE graded low, platelets (10^9 cells/L) - CTCAE graded low, leukocytes (10^9 cells/L) - CTCAE graded low, leukocytes (10^9 cells/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Baseline = last non-missing value prior to the first dose of study treatment.

  5. Number of Participants With Worst Post-baseline Hematology Results Based on CTCAE v4.03 Grade: Part II

    Time frame: Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

    Parameters evaluated were: APTT (sec) - CTCAE graded high, fibrinogen (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, PINR - CTCAE graded high, lymphocytes (10^9 cells/L) - CTCAE graded low, lymphocytes (10^9 cells/L) - CTCAE graded high, neutrophils (10^9 cells/L) - CTCAE graded low, platelets (10^9 cells/L) - CTCAE graded low, leukocytes (10^9 cells/L) - CTCAE graded low, leukocytes (10^9 cells/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Baseline = last non-missing value prior to the first dose of study treatment in Part II.

  6. Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part I

    Time frame: Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

    Parameters evaluated were: albumin (g/L)- CTCAE graded low, alkaline phosphatase (units per liter [U/L])- CTCAE graded high, alanine aminotransferase (U/L)- CTCAE graded high, amylase (U/L - CTCAE graded high, aspartate aminotransferase(U/L)- CTCAE graded high, bilirubin (micromole per liter [umol/L])- CTCAE graded high, creatinine (umol/L) - CTCAE graded high, creatine kinase (U/L)- CTCAE graded high, gamma glutamyl transferase (U/L)- CTCAE graded high, glucose (millimole per liter [mmol/L])- CTCAE graded low, high, potassium (mmol/L)- CTCAE graded low, potassium (mmol/L)- CTCAE graded high, magnesium (mmol/L)- CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded high, urate (umol/L)- CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher.

  7. Number of Participants With Worst Post-baseline Serum Chemistry Results Based on CTCAE v4.03 Grade: Part II

    Time frame: Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

    Parameters evaluated were: albumin (g/L)- CTCAE graded low, alkaline phosphatase (U/L)- CTCAE graded high, alanine aminotransferase (U/L)- CTCAE graded high, amylase (U/L) - CTCAE graded high, aspartate aminotransferase(U/L)- CTCAE graded high, bilirubin (umol/L)- CTCAE graded high, creatinine (umol/L) - CTCAE graded high, creatine kinase (U/L)- CTCAE graded high, gamma glutamyl transferase (U/L)- CTCAE graded high, glucose (mmol/L)- CTCAE graded low, high, potassium (mmol/L)- CTCAE graded low, potassium (mmol/L)- CTCAE graded high, magnesium (mmol/L)- CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded high, urate (umol/L)- CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher.

  8. Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part I

    Time frame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

    Vital signs evaluated were: Low/high systolic blood pressure (BP) (millimeter of Mercury [mmHg]): less than or equal to (<=) 90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (beats per minute [bpm]): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kilogram [kg]): >=20% decrease/increase from baseline; and low/high body temperature (degree Celsius [C]): <=36 C / >= 37.5 C.

  9. Number of Participants With Newly Occurring Notably Abnormal Vital Signs: Part II

    Time frame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

    Vital signs evaluated were: Low/high systolic BP (mmHg): <=90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (bpm): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kg): >=20% decrease/increase from baseline; and low/high body temperature (C): <=36 C / >= 37.5 C.

  10. Number of Participants With Notable Electrocardiograms (ECG) Values: Part I

    Time frame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

    Number of participants with notable ECG values were reported in this outcome measure. Abnormality categories were: Heart rate (HR): increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 millisecond (ms); QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and Corrected QT interval by Fridericia (QTcF): increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value.

  11. Number of Participants With Notable ECG Values: Part II

    Time frame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

    Number of participants with notable ECG values were reported in this outcome measure. Abnormality categories were: HR: increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 ms; QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and QTcF: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value.

  12. Number of Participants With At Least One Dose Interruption: Part I

    Time frame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

    In this outcome measure number of participants with at least 1 dose interruption for encorafenib and binimetinib were reported.

  13. Number of Participants With At Least One Dose Interruption: Part II

    Time frame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

    In this outcome measure number of participants with at least 1 dose interruption for encorafenib, binimetinib, and each third combination agent were reported.

  14. Number of Participants With At Least One Dose Reduction: Part I

    Time frame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

    In this outcome measure number of participants with at least 1 dose reduction for encorafenib and binimetinib were reported.

  15. Number of Participants With At Least One Dose Reduction: Part II

    Time frame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

    In this outcome measure number of participants with at least 1 dose reduction for encorafenib, binimetinib, and each third combination agent were reported.

  16. Actual Dose Intensity: Part I

    Time frame: During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

    Dose intensity across all cycles = cumulative dose/duration of exposure. Treatment cycle for encorafenib and binimetinib =21 days.

  17. Actual Dose Intensity: Part II

    Time frame: During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

    Dose intensity = cumulative dose/ duration of exposure. Treatment cycle = 21days for the combination treatment with buparlisib and capmatinib and 28 days for the combination treatment with ribociclib and infigratinib.

  18. Progression-Free Survival (PFS): Part I

    Time frame: 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)

    PFS was defined as the time from the start date of study drug in Part I until documented PD or death due to any cause. All participants who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. Per RECIST 1.1, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Kaplan Meier method used for estimation.

  19. PFS: Part II

    Time frame: 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)

    PFS was defined as the time from the start date of study drug in Part II until documented PD or death due to any cause. All participants who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. Per RECIST 1.1, PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Kaplan Meier method used for estimation.

  20. Duration of Response (DOR): Part I

    Time frame: 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)

    DOR: time between date of first documented response (CR or PR) and date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the participant was censored at the date of last tumor assessment other than unknown. RECIST v1.1: CR = disappearance of all non-nodal target lesions. Any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. All lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR = at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters; c) PD= At least a 20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, sum must also demonstrate an absolute increase of at least 5 mm.

  21. DOR: Part II

    Time frame: 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)

    DOR: time between date of first documented response (CR or PR) and date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the participant was censored at the date of last tumor assessment other than unknown. RECIST v1.1: CR = disappearance of all non-nodal target lesions. Any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. All lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR = at least a 30% decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters; c) PD= At least a 20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, sum must also demonstrate an absolute increase of at least 5 mm.

  22. Time to Response (TTR): Part I

    Time frame: From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part I was 403.7 weeks)

    TTR was defined as the time between the start date of study drug in Part I and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Kaplan Meier method used for estimation.

  23. TTR: Part II

    Time frame: From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part II was 97.0 weeks)

    TTR was defined as the time between the start date of study drug in Part II and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. Kaplan Meier method used for estimation.

  24. Disease Control Rate (DCR): Part I

    Time frame: 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)

    DCR was defined as percentage of participants with a best overall response of CR or PR or SD. RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters and c) SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

  25. DCR: Part II

    Time frame: 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)

    DCR was defined as percentage of participants with a best overall response of CR or PR or SD. RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters and c) SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. PD= At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

  26. Overall Survival (OS): Part II

    Time frame: 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)

    OS was defined as the time from the start date of study treatment (3rd agent combined with encorafenib and binimetinib) to date of death due to any cause. If a participant was not known to have died, survival was censored at the date of last known date participant alive. Kaplan Meier method used for estimation.

  27. Summary of Genomic Biomarkers From Tumor Samples: Part I

    Time frame: Baseline up to end of treatment (EOT) (maximum treatment exposure for Part I was 403.7 weeks)

    Number of participants with multiple alterations in genomic biomarkers like biomarker BRAF, CCND1, CDK4, EGFR, FGFR1, FGFR4, KRAS, MET, NRAS, PIK3CA, and PTEN were reported and alterations included copy number variant/copy number ratio (CNV/CNR), rearrangement, short variant. It was not necessary that all biomarkers had all alterations. Baseline = last non-missing value prior to the first dose of study treatment.

  28. Plasma Concentration for Encorafenib (LGX): Part I

    Time frame: 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

    In results reported below, following abbreviation have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5) and end of treatment (EOT). Maximum treatment exposure for Part I was of 403.7 weeks.

  29. Plasma Concentration for Encorafenib (LGX): Part II

    Time frame: 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

    In results reported below, following abbreviation have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 16 (D16), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5). Maximum treatment exposure for Part II was of 97.0 weeks.

  30. Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part I

    Time frame: 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

    AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part I was of 403.7 weeks.

  31. Plasma Concentration for Binimetinib (MEK) and Its Metabolite: Part II

    Time frame: 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

    AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part II was of 97.0 weeks.

  32. Plasma Concentration for Ribociclib (LEE) and Its Metabolite: Part II

    Time frame: 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

    LEQ803 is metabolite of ribociclib. Maximum treatment exposure for Part II was of 97.0 weeks.

  33. Plasma Concentration for Infigratinib (BGJ) and Its Metabolites: Part II

    Time frame: 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

    BHS697 and CQM157 are metabolites of infigratinib. Maximum treatment exposure for Part II was of 97.0 weeks.

  34. Plasma Concentration for Capmatinib (INC): Part II

    Time frame: 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

    Maximum treatment exposure for Part II was of 97.0 weeks.

  35. Plasma Concentration for Buparlisib (BKM): Part II

    Time frame: 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

    Maximum treatment exposure for Part II was of 97.0 weeks.

  36. 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

    Time frame: 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

  37. 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

    Time frame: 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

  38. 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

    Time frame: 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

  39. Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

    Time frame: 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

    Elimination half-life means the time required for the plasma concentration to decline by 50% during the elimination phase.

  40. Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

    Time frame: 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

    Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.

  41. Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

    Time frame: 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

    Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution is the apparent volume of distribution at steady-state.

  42. 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

    Time frame: 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

  43. 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

    Time frame: C1 D15: at the end of a dosing interval at steady-state (24 hour ± 2 hour), taken directly before next administration

Sponsors and collaborators

Lead sponsor

Pfizer

Industry

Registry information

Official study 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.

Acronym: LOGIC-2

Important dates

Study start
2014
Primary completion
2023
Study completion
2023
First posted
Jun 9, 2014
Registry last updated
Mar 5, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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