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

Phase 1

Conditions: BRAF mutant metastatic colorectal cancer
MedDRA version: 20.0Level: PTClassification code 10010035Term: Colorectal cancer stage IVSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10010034Term: Colorectal cancer stage IIISystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 20.0Level: PTClassification code 10010030Term: Colorectal cancer recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2012-002138-35-IT

Lead Sponsor: ARRAY BIOPHARMA INC.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 162

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

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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