MASTIFF: MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class
Study Details
Study Description
Brief Summary
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
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To define DLT and MTD.
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To determine a recommended phase 2 dose (RP2D) and schedule.
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To determine the pharmacokinetics of Karonudib.
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To determine preliminary signs of clinical efficacy of Karonudib.
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To determine overall survival.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose escalation 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
Dose escalation of administration with Karonudib.
|
Outcome Measures
Primary Outcome Measures
- Safety and tolerability of Karonudib (TH1579) will be evaluated. [28 days, first treatment cycle for the patient.]
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.
Secondary Outcome Measures
- To determine the pharmacokinetics of Karonudib. [28 days, first treatment cycle for the patient]
Peak Plasma Concentration, Cmax
- To determine the pharmacokinetics of Karonudib. [28 days, first treatment cycle for the patient]
Tmax, time is the time to reach Cmax (Peak Plasma Concentration)
- To determine the pharmacokinetics of Karonudib. [28 days, first treatment cycle for the patient]
biological half-life (plasma T1/2)
- To determine the pharmacokinetics of Karonudib. [28 days, first treatment cycle for the patient]
Area under the Curve (AUC)
- To determine preliminary signs of clinical efficacy of Karonudib. [54 days, two treatment cycles for the patient]
RECIST 1.1
Eligibility Criteria
Criteria
Inclusion Criteria:
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Written informed consent.
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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).
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Histological or cytological confirmation of cancer (imaging/AFP are sufficient for patients with HCC according to international standards).
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The patient has received standard of care treatments and has progressive disease with only experimental therapies as further treatment options.
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Life expectancy of at least 12 weeks (as per investigators clinical assessment).
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ECOG PFS 0 or 1.
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Patients must have measurable disease based on RECIST 1.1 criteria or evaluable metastatic disease.
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Adequate bone marrow, hepatic and renal function defined as:
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Haemoglobin ≥ 95 g/L (blood transfusion not less than 21 days prior to screening).
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Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L.
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Total bilirubin < 1.5 x ULN (does not apply to patients with Gilberts Syndrome).
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AST and ALT ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of liver metastases).
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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).
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Albumin greater than or equal to 23 g/L.
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Subject must be able to take oral medication.
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Negative pregnancy test according to CTFG guidance 2014 for females of child-producing potential.
Exclusion Criteria:
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Age less than 18 years.
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Less than 4 weeks since stopping previous systemic cancer treatment.
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Less than 3 weeks since stopping palliative radiotherapy.
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Less than 3 weeks after minor surgery.
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Less than 6 months since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or TIA.
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Congestive heart failure NYHA class ≥ II.
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History of arrhythmias or arrhythmias discovered during the screening period (apart from atrial fibrillation without ventricular tachycardia and premature extra beats).
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Patients requiring anti-arrhythmic drugs.
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QTc interval >450 ms at baseline.
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Use of fentanyl (must be stopped at least 1 week prior to initiation of Karonudib).
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Use of anti-oxidants vitamins and acetylcysteine (must be stopped within 48 hours of starting treatment with Karonudib).
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Use of antidepressant medications which are substrate for CYP2D6 (must be stopped at least 3 weeks prior to starting treatment with Karonudib).
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Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of study results.
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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).
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Known acute or chronic infection with hepatitis B or C.
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Known HIV infection.
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Pregnant or breast-feeding women.
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Patients with reproductive potential not implementing accepted and effective means of contraception.
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Participation in any other clinical trial within the previous 4 weeks.
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Unable to comply with study procedures.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Karolinska University Hospital | Stockholm | Sweden |
Sponsors and Collaborators
- Thomas Helleday Foundation
Investigators
- Study Director: Teresa Sandvall, MSc, Oxcia
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- MASTIFF