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

Study Overview
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Brief Summary
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Primary Objective • To determine the safety and tolerability of Karonudib (TH1579) in escalating doses for the treatment of patients with advanced solid malignant tumours. Secondary Objective To define DLT and MTD. To determine a recommended phase 2 dose (RP2D) and schedule. To determine the pharmacokinetics of Karonudib. To determine preliminary signs of clinical efficacy of Karonudib. To determine overall survival.

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

Conditions
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Cancer

Intervention / Treatment
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* Drug: Karonudib


Participation Criteria
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Eligibility Criteria
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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). Histological or cytological confirmation of cancer (imaging/AFP are sufficient for patients with HCC according to international standards). The patient has received standard of care treatments and has progressive disease with only experimental therapies as further treatment options. 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. 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. Exclusion Criteria: Age less than 18 years. Less than 4 weeks since stopping previous systemic cancer treatment. 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. Known HIV infection. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: 13 different dose cohorts with escalating doses are planned.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose escalation<br>Karonudib is an oral inhibitor of MTH1 and will be supplied as an oral solution or tablets to be taken BID. Each cycle is defined as 28 days. | Drug: Karonudib<br>* Dose escalation of administration with Karonudib.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of Karonudib (TH1579) will be evaluated. | Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD). DLTs will be assessed during first cycle of therapy, week 1-4 based on Haematological toxicity and Non-haematological toxicity. MTD: The highest dose of Karonudib that does not cause unacceptable side effects is defined as the MTD. | 28 days, first treatment cycle for the patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the pharmacokinetics of Karonudib. | Peak Plasma Concentration, Cmax | 28 days, first treatment cycle for the patient | 
| To determine the pharmacokinetics of Karonudib. | Tmax, time is the time to reach Cmax (Peak Plasma Concentration) | 28 days, first treatment cycle for the patient | 
| To determine the pharmacokinetics of Karonudib. | biological half-life (plasma T1/2) | 28 days, first treatment cycle for the patient | 
| To determine the pharmacokinetics of Karonudib. | Area under the Curve (AUC) | 28 days, first treatment cycle for the patient | 
| To determine preliminary signs of clinical efficacy of Karonudib. | RECIST 1.1 | 54 days, two treatment cycles for the patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumours