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

• Status: Active, not recruiting
• Trial end date: 2023-01-17
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Array BioPharma; Pfizer
• Treatments: Infigratinib

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.