A Dose-Escalating Phase I/II Study in Patients with RAS-Mutated Metastatic Colorectal Cancer to Investigate Safety and Clinical Activity of the Triple Combination of: MEK-inhibitor binimetinib, Pan-EGFR inhibitor lapatinib and the Microtubule Targeting Agent (MTA) vinorelbine.
- Conditions
- RAS-mutated metastatic colorectal cancer10017991
- Registration Number
- NL-OMON54073
- Lead Sponsor
- niversitair Medisch Centrum Utrecht
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 50
1. Histological or cytological proof of CRC.
2. After failure of a minimum of 2 lines of standard of care regimens. Prior
lines of treatment must include: a minimum of 2 lines of prior systemic
treatment for metastatic disease, including at least fluoropyrimidine,
oxaliplatin and irinotecan based treatment (unless contra-indications for
either oxaliplatin and/or irinotecan). Adjuvant treatment completed < 6 months
before development of metastatic disease will be counted as 1st line for
metastatic disease.
3. Written documentation of a known pathogenic RAS mutation.
4. Age * 18 years.
5. Able and willing to give written informed consent.
6. Measurable disease according to RECIST 1.1
7. WHO performance status of 0 or 1.
8. Able to swallow and retain orally administered medications and does not have
clinically significant gastrointestinal abnormalities that may alter absorption
(e.g. malabsorption syndrome, ileostomy or major resection of the stomach or
bowel)
9. Able and willing to undergo blood sampling.
10. Able and willing to undergo a tumor biopsy prior to start and after two
weeks on therapy. Tumor biopsy should be histological. Cytological biopsies are
not accepted.
11. All toxicities related to prior treatment should have resolved to CTCAE
grade 1 or less (excluding alopecia)
12. Life expectancy * 3 months allowing adequate follow up of toxicity
evaluation and antitumor activity.
13. Women of childbearing potential must have a negative serum pregnancy test
within 14 days prior to registration and agree to use effective contraception,
throughout the treatment period, and for 4 months after the last dose of study
treatment.
14. Adequate organ functions:
Absolute neutrophil count >= 1.5 x 109/L
Hemoglobin >= 6.0 mmol/L
Platelets >= 100 x 109/L
PT/INR and aPTT within normal limits (unless anti-coagulant treatment)
Total bilirubin <= 1.5 x ULN
AST and ALT <= 2.5 x ULN or <= 5x ULN in case of liver metastases
Albumin >= 30.0 g/L
Lactate dehydrogenase <= 2x ULN
Serum creatinine <= 1.5 x ULN or Calculated creatinine clearance
by Cockcroft-Gault formula: >= 50 mL/min
Left Ventricular Ejection Fraction (LVEF) by ECHO or MUGA >= 50%
1. Any treatment with investigational drugs within 30 days or 5 half-lives
prior to receiving the first dose of investigational treatment.
2. History of another malignancy. Exceptions: Patients who have been
disease-free for at least 3 years after treatment with curative intent, or
patients with a history of completely resected non-melanoma skin cancer, in
situ carcinoma of the cervix and/or patients with indolent completely resected
second malignancies are eligible.
3. Symptomatic or untreated leptomeningeal disease.
4. Symptomatic brain metastases. Patients previously treated or untreated for
these conditions that are asymptomatic in the absence of corticosteroid and
anticonvulsant therapy (for at least 6 weeks) are allowed to enrol.
Radiotherapy for brain metastases must have been completed at least 6 weeks
prior to start of study treatment. Brain metastasis must be stable with
verification by imaging (e.g. brain MRI or CT completed at screening
demonstrating no current evidence of progressive brain metastases). Patients
are not permitted to receive anti-epileptic drugs or corticosteroids.
5. Patients previously treated with combination treatment of drugs known to
interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components,
including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK. Single agent
targeted therapies interfering with these pathways are allowed for inclusion in
phase I.
Exclusion criteria in phase II: patients previously treated with drugs known to
interfere with EGFR, HER-2, HER-3, HER-4, or MAPK- and PI3K-pathway components,
including inhibitors of PTEN, PI3K, AKT, mTOR, BRAF, MEK, and ERK, both as
single agent or in combination.
6. History of interstitial lung disease or pneumonitis
7. Women who are pregnant or breast feeding.
8. Unreliable contraceptive methods. Both men and women enrolled in this trial
must agree to use a reliable contraceptive method throughout the study
(adequate contraceptive methods are: condom, sterilization, other barrier
contraceptive measures preferably in combination with condoms).
9. Radio-, immuno- or chemotherapy within the last 4 weeks prior to receiving
the first dose of investigational treatment. Palliative radiation (1x 8Gy) is
allowed.
10. Patients who have undergone any major surgery within the last 3 weeks prior
to starting study drug or who would not have fully recovered from previous
surgery.
11. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1
or HIV-2 type patients.
12. Patients with known, active, hepatitis B (HBV) or C virus (HCV).
13. Patients with retinal degenerative disease (hereditary retinal degeneration
or age-related macular degeneration), or with a history of uveitis, retinal
vein occlusion, central serous retinopathy, or retinal detachment.
14. Patients with left ventricular ejection fraction (LVEF) < 50%.
15. History or evidence of cardiovascular risk including any of the following:
• A QT interval corrected for heart rate using the Bazett*s formula (QTcB;
Appendix X) *480 msec.
• History or evidence of current clinically significant uncontrolled
arrhythmias. Exception: Subjects with controlled atrial fibrillation for >30
days prior to randomization are eligible.
• History of acute coronary syndromes (including myocardial infar
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method