Efficacy and Safety of the Prophylactic Use of Doxycycline +/- Vitamin K Cream

A Double Blind Placebo Controlled Randomized Phase II Study Evaluating the Efficacy and Safety of the Prophylactic Use of Doxycycline +/- Vitamin K Cream in First Line mCRC Patients Treated With Erbitux and FOLFIRI.

The aim of this Phase 2, two-arm, randomized, double blind placebo controlled study is to evaluate the efficacy of combination therapy of doxycycline and Vitamin K1 compared to doxycycline plus placebo for the prevention of acne-like skin rash in mCRC patients receiving first line cetuximab treatment.

The aim of this Phase 2, two-arm, randomized, double blind placebo controlled study is to evaluate the efficacy of combination therapy of doxycycline and Vitamin K1 compared to doxycycline plus placebo for the prevention of acne-like skin rash in mCRC patients receiving first line cetuximab treatment.

Inclusion Criteria:

• Written informed consent must be given
• Patient ≥ 18 years
• Histologically proven and measurable metastatic adenocarcinoma of the colon or rectum (according to modified RECIST criteria v.1.1)
• Patients eligible for Erbitux and FOLFIRI treatment K-Ras wild type tumour
• Metastatic disease
• Life expectancy of at least 12 weeks
• WHO performance status of 0 or 1
• Effective contraception for both male and female patients if the risk of conception exists
• Adequate organ function
• Adequate bone marrow, hepatic and renal function (Hemoglobin > 10.0 g/dL, platelet count > 100 x 109/L, absolute neutrophil count > 1.5 x 109/L; ALAT, ASAT < 2.5 x ULN (upper limit of normal range) or < 5x ULN in case of liver metastasis; Alkaline phosphatase < 2.5 x ULN; Total bilirubin < 1.5 x ULN; Creatinine clearance > 50 mL/min (calculated according to Cockcroft and Gault formula)).

Exclusion Criteria:

• Prior treatment for metastatic disease (adjuvant therapy with 5-FU/oxaliplatin based regimens) allowed if stopped 6 months prior to registration on study
• Prior treatment with EGFR inhibitor
• Surgery (excluding diagnostic biopsy) or irradiation within 4 weeks prior to study entry
• Administration of any investigational drug or agent/procedure, i.e. participation in another trial within 4 weeks before beginning treatment with study drugs
• Concurrent chronic systemic immune therapy, chemotherapy, radiation therapy or hormone therapy not indicated in the study protocol
• Any active dermatological condition > grade 1 at baseline possibly interfering with or influencing the results or conduct of the present study
• Brain metastasis (known or suspected)
• Significant impairment of intestinal resorption (e.g. chronic diarrhea, inflammatory bowel disease)
• Any other uncontrolled concomitant illness, including serious uncontrolled intercurrent infection
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction within the last twelve months, significant arrhythmias)
• Known allergy or any other adverse reaction to any of the study drugs or to any related compound.
• Any organ allograft requiring immunosuppressive therapy.
• Pregnancy (absence to be confirmed by serum/urine beta human chorion gonadotrophin (HCG)) or breast-feeding.
• Other previous malignancy within 5 years, with exception of a history of a previous basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix surgically cured or adequately treated.
• Known drug abuse / alcohol abuse
• Legal incapacity or limited legal capacity
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and followup schedule; those conditions should be discussed with the patient before registration in the trial.
• Medical or psychological condition which, in the opinion of the investigator, would not permit the patient to complete the study or meaningfully sign informed consent.
• Known M. Meulengracht (Gilbert´s disease) or DPD-insufficiency
• Known coagulation disorders
• Ongoing or planned treatment with coumarin derivates