4SC-201 (Resminostat) in Advanced Colorectal Carcinoma (SHORE)

Inclusion Criteria Phase I:

• Histologically or cytologically confirmed advanced stage colorectal carcinoma
• Documented progression after precedent treatment according to RECIST criteria
• ECOG performance status 0 - 2
• Live expectancy of 12 weeks or more
• Patients must have previously received treatment with 5-FU alone or in combination with other anti-tumor medications
• Patients foreseen for chemotherapy with FOLFIRI in second or further line treatment

Exclusion Criteria Phase I:

• Patients who have received previous treatment with an HDAC inhibitor
• Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study
• Therapy with agents known to prolong the QT interval, such as certain antibiotics (e.g. erythromycin, clarithromycin), antidepressants (e.g. doxepin, amitryptiline) or neuroleptics (e.g. haloperidol, clozapine)
• Patients who are homozygous for the UGT1A1 and characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter ((TA)7TAA)). For patients having shown good tolerability of irinotecan in a precedent treatment line according to the investigator's judgement, availability of UGT1A1 result is not mandatory for study inclusion
• Therapy with strong CYP3A4 inhibitors (e.g. ketoconazole) or inductors (e.g. carbamazepine, phenytoin, St. John's Wort)
• Severe internal disease: insufficiently treated or uncontrolled arterial hypertension, hemoptoe, New York Heart Association (NYHA) grade II or greater congestive heart failure, symptomatic coronary heart disease, myocardial infarction (≤ 12 months prior to inclusion), serious cardiac arrhythmia requiring medication, peripheral arterial occlusive disease stage II or greater, uncontrolled severe disease
• Patients with a confirmed QTcF > 480 ms, or a history of additional risk factors for Torsades de Pointes
• Major surgery within the last 4 weeks

Inclusion Criteria Phase II :

• Histologically or cytologically confirmed advanced stage colorectal carcinoma
• Documented progression after precedent treatment according to RECIST criteria
• K-ras mutation (which contraindicates EGFR inhibitor therapy, results from local pathology will be accepted for inclusion
• ECOG performance status 0 - 2
• Live expectancy of 12 weeks or more
• Patients must have previously received treatment with 5-FU alone or in combination with other anti-tumor medications
• Patients foreseen for chemotherapy with FOLFIRI in second line treatment

Exclusion Criteria Phase II arm:

• Patients who have received previous treatment with an HDAC inhibitor
• Anticipation of need for a major surgical procedure or radiation therapy (RT) during the study
• Therapy with agents known to prolong the QT interval, such as certain antibiotics (e.g. erythromycin, clarithromycin), antidepressants (e.g. doxepin, amitryptiline) or neuroleptics (e.g. haloperidol, clozapine)
• Patients who are homozygous for the UGT1A1 and characterized by the presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter ((TA)7TAA)).
• Therapy with strong CYP3A4 inhibitors (e.g. ketoconazole) or inductors (e.g. carbamazepine, phenytoin, St. John's Wort)
• Severe internal disease: insufficiently treated or uncontrolled arterial hypertension, hemoptoe, New York Heart Association (NYHA) grade II or greater congestive heart failure, symptomatic coronary heart disease, myocardial infarction (≤ 12 months prior to inclusion), serious cardiac arrhythmia requiring medication, peripheral arterial occlusive disease stage II or greater, uncontrolled severe disease
• Patients with a confirmed QTcF > 480 ms, or a history of additional risk factors for Torsades de Pointes
• Major surgery within the last 4 weeks