A phase Ib/II, open-label, multi-center, dose escalation study of MEK162 in combination with panitumumab in adult patients with mutant RAS or wild-type RAS metastatic colorectal cancer
- Conditions
- metastatic colorectal cancer10017991
- Registration Number
- NL-OMON41524
- Lead Sponsor
- Array Biopharma
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 7
1. Histological or cytological confirmation of mCRC
2. Progression on or following standard therapy or for whom no standard therapy exists.
3. Written documentation of WT RAS or somatic mutation in exon 2 (codons 12/13), 3 (codons 59/61) or 4 (codons 117/146) in either KRAS or NRAS in medical history.
4. Phase Ib only: Availability of a representative tumor sample at Screening/baseline (newly obtained or if not feasible, archival with a corresponding pathology report)
5. Phase II only: A newly obtained tumor sample must be collected to document the WT RAS or somatic mutation status (as described above) during the molecular pre-screening period at a local or a Novartis designated central laboratory. The tumor sample must be collected after the last anti-neoplastic treatment, and within 3 months prior to start of treatment on this study.
6. Evidence of measurable disease, as determined by RECIST v1.1.
7. ECOG performance status <= 2.
1. Phase II arms 1 and 4 only: previous treatment with cetuximab, panitumumab, and/or other EGFR inhibitors
2. Previous treatment with MEK-inhibitors
3. History of severe infusion reactions to monoclonal antibodies.
4. Known hypersensitivity and/or contraindication to any of the study medications or their excipients
5. Symptomatic or untreated leptomeningeal disease.
6. Symptomatic brain metastasis.
7. History or current evidence of retinal disease or ophthalmopathy as assessed by ophthalmologic examination at baseline that would be considered a risk factor for CSR/RVO
8. History of keratitis or ulcerative keratitis.
9. Known acute or chronic pancreatitis.
10. Clinically significant cardiac disease including any of the following:
• Congestive heart failure (NYHA grade >= 2),
• Left ventricular ejection fraction (LVEF) < 45%
• Uncontrolled arterial hypertension (as defined > 140 (systolic) /100 (diastolic) mmHg
• 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
11. 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 (upper limit of normal) 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
• Magnesium < the lower limit of normal
12. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral MEK162.
13. 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.
14. History of thromboembolic or cerebrovascular events within the last 6 months.
15. 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 to grade <= 1 from the side effects of such therapy (except alopecia).
16. Any major surgery within the last 2 weeks prior to starting study drug or who would not have fully recovered from previous surgery.
17. Known human immunodeficiency virus (HIV) infection.
18. Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Phase Ib: Incidence of Dose Limiting Toxicities in Cycle 1<br /><br>Phase II: Outcome: Overall response rate (ORR) as per RECIST v1.1</p><br>
- Secondary Outcome Measures
Name Time Method <p>Phase Ib and Phase II: Frequency and severity of AEs, SAEs, changes in<br /><br>laboratory values, vital signs, and electrocardiograms<br /><br><br /><br>Phase Ib only: Objective Response Rate (ORR), Progression-free survival, (PFS),<br /><br>duration of response<br /><br>(DOR), disease control rate (DCR) as per RECIST v1.1<br /><br>Phase II only: Progression-free survival, (PFS), duration of response (DOR),<br /><br>disease control rate (DCR) as per RECIST v1.1</p><br>