MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class

Inclusion criteria

• Written informed consent.
• Age at least 18 years (there is no upper age limit but patients must be judged to have a "biologic" age of 75 years or less).
• Life expectancy of at least 12 weeks (as per investigators clinical assessment).
• ECOG PFS 0 or 1.
• Patients must have measurable disease based on RECIST 1.1 criteria or evaluable metastatic disease unless otherwise specified in specific patient groups.
• Patients with any 1 of the following histologically confirmed tumors and who qualifies for new therapy and relapsing to/after standard therapy or the patient has refused or does not tolerate standard therapy Cohort 19

• Histologically or cytologically confirmed adenocarcinoma of prostate that is metastatic, hormone-refractory (confirmed by testing serum testosterone), and clinically progressive following at least one prior hormonal regimen. Prostate cancer patients must have measurable (patient with measurable bi-dimensional disease) or evaluable disease (defined as the presence of a non-measurable abnormality on CT or on physical examination coupled with an abnormal PSA value) or PSA relapse (Obtain sequence of rising values at a minimum of 1-week intervals, 1.0 ng/mL minimal value). Patients can only have received a taxane therapy in the pre-metastatic hormone refractory setting
• High Grade Serous Ovarian, Fallopian Tube or Primary Peritoneal Cancer that can be assessed radiological, clinically or biochemically.
• Cytologically or histologically confirmed endometrial cancer that is recurrent or metastatic and/or resistant to standard therapies, or for which no standard therapy is available. Patients must have measurable disease based on RECIST 1.1 criteria or evaluable metastatic disease.

Cohort 20

• Biopsy-proven carcinoma of the cervix that is either locally advanced or metastatic.
• Recurrent or metastatic head and neck adenocarcinoma who are not candidates for curative surgery or refusing surgical treatment
• Adequate bone marrow, hepatic and renal function defined as:

• Haemoglobin ≥ 95 g/L (blood transfusion not less than 21 days prior to screening).
• Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L.
• Total bilirubin < 1.5 x ULN (does not apply to patients with Gilberts Syndrome).
• AST and ALT ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of liver metastases).
• Serum creatinine not over ≤ ULN (if serum creatinine is between 1 and 1.5 x ULN, patients may be eligible provided that the calculated GFR is at least 50 ml/min using Cockcroft-Gault method).
• Albumin greater than or equal to 23 g/L.
• Subject must be able to take oral medication.
• Negative pregnancy test according to CTFG guidance 2014 for females of child-producing potential.
• Known HIV-infected patients with undetectable viral loads will be eligible for the study. HIV testing is mandatory

Exclusion criteria

• Age less than 18 years.
• Less than 4 weeks since stopping previous systemic cancer treatment or less than 5 half lifes of prior therapy, whichever is shorter.
• Less than 3 weeks since stopping palliative radiotherapy.
• Less than 3 weeks after minor surgery.
• Less than 6 months since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or TIA.
• Congestive heart failure NYHA class ≥ II.
• History of arrhythmias or arrhythmias discovered during the screening period (apart from atrial fibrillation without ventricular tachycardia and premature extra beats).
• Patients requiring anti-arrhythmic drugs.
• QTc interval >450 ms at baseline.
• Use of fentanyl (must be stopped at least 1 week prior to initiation of Karonudib).
• Use of anti-oxidants vitamins and acetylcysteine (must be stopped within 48 hours of starting treatment with Karonudib).
• Use of antidepressant medications which are substrate for CYP2D6 (must be stopped at least 3 weeks prior to starting treatment with Karonudib).
• Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of study results.
• Leptomeningeal metastases (patient with previously treated brain metastases are eligible provided that there is no evidence of disease progression for a minimum of 8 weeks prior to inclusion - in these cases a CNS MR is required within the screening period).
• Known acute or chronic infection with hepatitis B or C that is untreated.
• Pregnant or breast-feeding women.
• Patients with reproductive potential not implementing accepted and effective means of contraception.
• Participation in any other clinical trial within the previous 4 weeks.
• Unable to comply with study procedures.