|LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma
|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
|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.
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
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
- Drug: LGX818
Combination of LGX818 and MEK162 (Part I)
- Drug: MEK162
Combination of LGX818 and MEK162 (Part I)
- Drug: LEE011
Combination of LGX818 + MEK162 + LEE011 (Part II)
- Drug: BGJ398
Combination of LGX818 + MEK162 + BGJ398 (Part II)
- Drug: BKM120
Combination of LGX818 + MEK162 + BKM120 (Part II)
- Drug: INC280
Combination of LGX818 + MEK162 + INC280 (Part II)
- Experimental: LGX818 + MEK162
- Experimental: LGX818 + MEK162 + LEE011
Intervention: Drug: LEE011
- Experimental: LGX818 + MEK162 + BGJ398
Intervention: Drug: BGJ398
- Experimental: LGX818 + MEK162 + BKM120
Intervention: Drug: BKM120
- Experimental: LGX818 + MEK162 + INC280
Intervention: Drug: INC280
|Active, not recruiting
|Same as current|
|December 2021 (Final data collection date for primary outcome measure)
- 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
- 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:
- 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
- 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
- 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.
|Sexes Eligible for Study:||All|
|18 Years and older (Adult, Older Adult)
|Contact information is only displayed when the study is recruiting subjects|
|Australia, Canada, Germany, Italy, Netherlands, Spain, Switzerland, United Kingdom, United States
C4221013 ( Other Identifier: Pfizer )
|Study Director:||Pfizer CT.gov Call Center||Pfizer|