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LOGIC-2: LGX818 and MEK162 in Combination With a Third Agent (BKM120, LEE011, BGJ398 or INC280) in Advanced BRAF Melanoma

Sponsor
Pfizer (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02159066
Collaborator
(none)
160
Enrollment
32
Locations
5
Arms
101.8
Anticipated Duration (Months)
5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Actual Enrollment :
160 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Jul 23, 2014
Anticipated Primary Completion Date :
Jan 17, 2023
Anticipated Study Completion Date :
Jan 17, 2023

Arms and Interventions

Arm Intervention/Treatment
Experimental: LGX818 + MEK162

Drug: LGX818
Combination of LGX818 and MEK162 (Part I)

Drug: MEK162
Combination of LGX818 and MEK162 (Part I)
Experimental: LGX818 + MEK162 + LEE011

Drug: LEE011
Combination of LGX818 + MEK162 + LEE011 (Part II)
Experimental: LGX818 + MEK162 + BGJ398

Drug: BGJ398
Combination of LGX818 + MEK162 + BGJ398 (Part II)
Experimental: LGX818 + MEK162 + BKM120

Drug: BKM120
Combination of LGX818 + MEK162 + BKM120 (Part II)
Experimental: LGX818 + MEK162 + INC280

Drug: INC280
Combination of LGX818 + MEK162 + INC280 (Part II)

Outcome Measures

Primary Outcome Measures

  1. Overall Response Rate (ORR) (Part II) [2 years]

Secondary Outcome Measures

  1. Incidence of adverse events [2 years]

  2. Incidence rate of Dose Limiting Toxicities (DLTs) [2 years]

    in Cycle 1 of Combination Part (Part II); cycle 1 = 21 days or 28 days

  3. Plasma Pharmacokinetics (PK) parameters of LGX818 + MEK162 and triple combination partners [2 years]

    AUCtau, ss; Cmax; Cmax, ss; Tmax; Tmax, ss; Ctrough; Clast, ss; T1/2, ss; CL,ss/F; Vz,ss/F

  4. Overall Response Rate (ORR) (Part II) [2 years]

  5. Progression Free Survival (PFS)(Part I and II) [2 years]

  6. Duration Of Response (DOR) (Part I and II) [2 years]

  7. Overall Survival (OS) (Part II) [2 years]

  8. Molecular status [baseline, at progression with LGX818 + MEK162 combination treatment up to 2 years]

    Molecular Status includes mutation, amplification, expression of markers relevant to the RAF/MEK/ERK and PI3K/AKT pathways

  9. Time to Response (TTR) (Part I and II) [2 years]

  10. Disease Control Rate (DCR) (Part I and II) [2 years]

  11. Severity of adverse events [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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.

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of California Los Angeles Los Angeles California United States 90024
2 Cancer Care Center Los Angeles California United States 90095
3 Doris Stein Research Center Building Los Angeles California United States 90095
4 Ronald Reagan UCLA Medical Center Drug Information Center Department of Pharmaceutical Services Los Angeles California United States 90095
5 UCLA Dermatology Clinic Los Angeles California United States 90095
6 UCLA Oncology Center Los Angeles California United States 90095
7 UCLA Radiology Los Angeles California United States 90095
8 Memorial Sloan Kettering Cancer Center Attn: Geny O'neill New York New York United States 10065
9 Memorial Sloan Kettering Cancer Center Inpatient Hospital & Main Campus New York New York United States 10065
10 Memorial Sloan Kettering Cancer Center- Outpatient Clinic New York New York United States 10065
11 OHSU Knight Cancer Institute Portland Oregon United States 97201
12 OHSU Center for Health and Healing 2 Portland Oregon United States 97239
13 OHSU Center for Health and Healing Portland Oregon United States 97239
14 OHSU Research Pharmacy Services Portland Oregon United States 97239
15 Oregon Health and Science University Portland Oregon United States 97239
16 Sarah Cannon Research Institute Nashville Tennessee United States 37203
17 Tennessee Oncology, PLLC Nashville Tennessee United States 37203
18 Peter MacCallum Cancer Centre Melbourne Victoria Australia 3000
19 East St Kilda Eye Clinic Melbourne Victoria Australia 3183
20 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
21 Sir Mortimer B. Davis-Jewish General Hospital Monteral Quebec Canada H3T 1E2
22 University Clinic Heidelberg PPDS Heidelberg Baden-württemberg Germany 69120
23 Universitätsklinikum Würzburg Würzburg Bayern Germany 97080
24 Uniklinik Köln Köln Germany 50937
25 Städtisches Klinikum München Muenchen Germany 80337
26 Universitätsklinikum Würzburg Wuerzburg Germany 97080
27 Azienda Ospedaliera Monaldi Napoli Campania Italy 80131
28 U.O.C. Oncologia Medica e Terapie Innovative Dipartimento di Melanoma IRCCS Fondazione G. Pascale Napoli Italy 80131
29 Het Nederlands Kanker Instituut Antoni Van Leeuwenhoek Ziekenhuis Amsterdam Netherlands 1066 CX
30 Hospital Universitario Vall d'Hebrón - PPDS Barcelona Cataluna Barcelona Spain 08035
31 Universitätsspital Zürich Zuerich Switzerland 8091
32 Churchill Hospital Oxford United Kingdom OX2 7JL

Sponsors and Collaborators

  • Pfizer

Investigators

  • Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Pfizer
ClinicalTrials.gov Identifier:
NCT02159066
Other Study ID Numbers:
  • CLGX818X2109
  • C4221013
  • 2013-004552-38
First Posted:
Jun 9, 2014
Last Update Posted:
Jun 15, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Pfizer
Melanoma
Additional relevant MeSH terms:
Melanoma
Infigratinib

Study Results

No Results Posted as of Jun 15, 2021