Study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in BRAF mutant metastatic colorectal cancer

• Register: EUCTR
• Last refreshed on: 19 February 2018
• Main ID: EUCTR2012-002138-35-IT
• Date of registration: 23/09/2013
• Prospective Registration: Yes
• Primary sponsor: ARRAY BIOPHARMA INC.
• Public title: Study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in BRAF mutant metastatic colorectal cancer
• Scientific title: A phase Ib/II multi-center, open-label, dose escalation study of LGX818 and cetuximab or LGX818, BYL719, and cetuximab in patients with BRAF mutant metastatic colorectal cancer
• Date of first enrolment: 17/12/2013
• Target sample size: 162
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002138-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Belgium, Canada, Germany, Italy, Netherlands, Spain, United States

Contacts

• Name: Margaret Vargo
• Affiliation: Array BioPharma Inc.

• Name: Margaret Vargo
• Affiliation: Array BioPharma Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Age = 18 years at the beginning of the administration of treatment (Phase Ib) or at the time of randomization (Phase II).
2. Histological or cytological proof of metastatic colorectal cancer (mCRC)
3. Progression after at least one prior standard of care regimen or be intolerant to irinotecan based regimens. Phase Ib only: Exception will be given to patients for whom, in the opinion of the investigator, no effective approved therapy is available
4. Written documentation of KRAS wild-type and BRAF V600E mutation, or any other BRAF V600 mutation. Patients with written documentation of other BRAF mutations may be considered for participation in phase Ib after consultation with the Sponsor’s clinical study team
5. Phase II only: fresh tumor biopsy at baseline
6. Evidence of measurable disease, as determined by RECIST v1.1.
Note: Lesions in areas of prior radiotherapy or other locoregional therapies (e.g., percutaneous ablation) should not be considered measurable, unless lesion progression has been documented since the therapy.
7. Life expectancy = 3 months
8. ECOG performance status = 1
9. Negative serum pregnancy test within 72 hours prior to the first dose of study treatment in all women of childbearing potential
10. Able to understand and voluntarily sign the informed consent form, and ability to comply with the study visit schedule and other protocol requirements. Written informed consent must be obtained prior to screen procedures.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 125
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 37

Exclusion criteria:
1. Phase II only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors
2. Phase II only: previous treatment with RAF-inhibitors, PI3K-inhibitors, and/or MEKinhibitors
3. Symptomatic or untreated leptomeningeal disease
4. Symptomatic brain metastasis.
5. Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting glucose = 140 mg/dL / 7.8 mmol/L, history of clinically significant gestational diabetes mellitus or documented steroid-induced diabetes mellitus. Phase Ib only: Exception will be given for patients assigned to dual combination treatment of LGX818 and cetuximab.
6. Known acute or chronic pancreatitis
7. Clinically significant cardiac disease including any of the following:
•Congestive heart failure requiring treatment (NYHA grade = 2), LVEF < 45% as determined by MUGA scan or ECHO, or uncontrolled hypertension
•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
8. 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
•Serum total bilirubin >1.5 x ULN, except for patients with Gilbert’s syndrome, who may be included if total bilirubin is = 3.0 x ULN and direct bilirubin is = 1.5 x ULN
•AST/SGOT and/or ALT/SGPT > 2.5 x ULN, or > 5 x ULN if liver metastases are present
9. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LGX818/BYL719
10. Previous or concurrent malignancy. Exceptions: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry; or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
11. Pregnant or nursing (lactating) women.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 3 months after study drug discontinuation. Post-menopausal women are allowed to participate in this study.
12. Sexually active males must use a condom during intercourse while taking the drug and for 3 months after stopping treatment and should not father a child in this period.
13. History of thromboembolic or cerebrovascular events within the last 6 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.
14. Patients who have received radiation therapy (that includes > 30% of the bone marrow reserve), chemotherapy, biological therapy (e.g., antibodies) within = 4 weeks (6 weeks for nitrosourea, mitomycin-C), or who have been treated with continuous or intermittent small molecule therapeutics or investigational agents within 5 half-lives of the agent (or = 4 weeks when half-life is unknown) prior to starting study drug or who have not recovered from the side effects of such therapy (except alopecia).
15

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

BRAF mutant metastatic colorectal cancer
MedDRA version: 20.0 Level: PT Classification code 10010035 Term: Colorectal cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10010034 Term: Colorectal cancer stage III System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0 Level: PT Classification code 10010030 Term: Colorectal cancer recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: BYL719
Product Code: BYL719
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BYL719
CAS Number: 1217486-61-7
Current Sponsor code: BYL719
Other descriptive name: BYL719
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Product Name: BYL719
Product Code: BYL719
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BYL719
CAS Number: 1217486-61-7
Current Sponsor code: BYL719
Other descriptive name: BYL719
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Product Name: BYL719
Product Code: BYL719
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BYL719
CAS Number: 1217486-61-7
Current Sponsor code: BYL719
Other descriptive name: BYL719
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: ERBITUX - 1 FLACONCINO DI SOLUZIONE PER INFUSIONE DA 50 ML
Product Name: Erbitux
Product Code: Erbitux
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CETUXIMAB
CAS Number: 205923-56-4
Current Sponsor code: CETUXIMAB
Other descriptive name: CETUXIMAB
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 2-

Product Name: LGX818
Product Code: LGX818
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LGX818
CAS Number: 1269440-17-6
Current Sponsor code: LGX818
Other descriptive name: LGX818
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Product Name: LGX818
Product Code: LGX818
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LGX818
Current Sponsor code: LGX818
Other descriptive name: LGX818
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Product Name: LGX818
Product Code: LGX818
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: LGX818
Current Sponsor code: LGX818
Other descriptive name: LGX818
Concentration unit: mg milligram(s)
Concentration type: equal
Con

Primary Outcome(s)

Secondary Objective: 1. To characterize the safety and tolerability of LGX818 in combination with cetuximab ± BYL719 as assessed by the incidence and severity of adverse events.
2. To determine the single dose and multiple dose pharmacokinetic profile of LGX818 in combination with cetuximab ± BYL719 as measured by plasma concentration.
3. To assess anti-tumor activity of LGX818 in combination with cetuximab ± BYL719 as measured by overall response rate, duration of response, time to response, progression free survival and overall survival.
4. Phase II: To assess gene alterations/expression relevant to the RAF/MEK/ERK and EGFR/PI3K/AKT pathways in tumor tissue as measured by baseline molecular status of potential predictive markers of tumor response or resistance

Main Objective: 1. Phase Ib: To estimate the maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of LGX818 in combination with cetuximab ± BYL719 as measured by
incidence of dose-limiting toxicities.
2. Phase II: To compare the efficacy of the dual (LGX818, cetuximab) and triple (LGX818, BYL719, cetuximab) combinations as measured by progression free survival

Primary end point(s): Phase Ib : incidence rate of dose-limiting toxicities
Phase II : Progression Free Survival

Timepoint(s) of evaluation of this end point: Phase Ib: 1.5 years
Phase II : 2.5 years

Secondary Outcome(s)

Secondary end point(s): 1- Incidence and severity of adverse events
2- Plasma concentration
3- Phase Ib/II:
a) Overall response rate
b) Duration of response
c) Time to response
d) Overall survival
Ph Ib : Progression free survival
Ph II : Overall survival
4- 2.5 years

Timepoint(s) of evaluation of this end point: 1- 2.5 years
2- 1.5 years
3- Phase Ib/II:
a) 2.5 years
b) 2.5 years
c) baseline, 2 years
d) 3 years
Phase Ib: 1.5 years
Phase II: 3 years
4- Baseline molecular status of potential predictive markers of tumor response or resistance

Secondary ID(s)

CLGX818X2103

2012-002138-35-ES

Source(s) of Monetary Support

Array Biopharma Inc.