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

NCT02159066

Last updated date
Study Location
University of California Los Angeles
Los Angeles, California, 90024, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Melanoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years

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NCT01909453
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Advanced Information
Descriptive Information
Brief Title  ICMJE LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma
Official Title  ICMJE 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
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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • 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)
Study Arms  ICMJE
  • Experimental: LGX818 + MEK162
    Interventions:
    • Drug: LGX818
    • Drug: 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
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: September 1, 2020)
158
Original Estimated Enrollment  ICMJE
 (submitted: June 5, 2014)
140
Estimated Study Completion Date  ICMJE January 31, 2022
Estimated Primary Completion Date January 17, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Canada,   Germany,   Italy,   Netherlands,   Spain,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02159066
Other Study ID Numbers  ICMJE CLGX818X2109
C4221013 ( Other Identifier: Alias Study Number )
2013-004552-38 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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/d….
URL:https://www.pfizer.com/science/clinical_trials/trial_data_and_results/d…
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director:Pfizer CT.gov Call CenterPfizer
PRS Account Pfizer
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP