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

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ClinicalTrials.gov Identifier: NCT03036228
Recruitment Status : Recruiting
First Posted : January 30, 2017
Last Update Posted : February 4, 2021
Sponsor:
Information provided by (Responsible Party):
Thomas Helleday Foundation

Tracking Information
First Submitted Date  ICMJE January 13, 2017
First Posted Date  ICMJE January 30, 2017
Last Update Posted Date February 4, 2021
Actual Study Start Date  ICMJE January 14, 2017
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 26, 2017)
Safety and tolerability of Karonudib (TH1579) will be evaluated. [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 11, 2020)
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Peak Plasma Concentration, Cmax
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 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. [ Time Frame: 28 days, first treatment cycle for the patient ]
    biological half-life (plasma T1/2)
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Area under the Curve (AUC)
  • To determine preliminary signs of clinical efficacy of Karonudib. [ Time Frame: 54 days, two treatment cycles for the patient ]
    RECIST 1.1
Original Secondary Outcome Measures  ICMJE
 (submitted: January 26, 2017)
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Peak Plasma Concentration, Cmax
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 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. [ Time Frame: 28 days, first treatment cycle for the patient ]
    biological half-life (plasma T1/2)
  • To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Area under the Curve (AUC)
  • To determine preliminary signs of clinical efficacy of Karonudib. [ Time Frame: 54 days, two treatment cycles for the patient ]
    RECIST 1.1
  • To determine overall survival. [ Time Frame: Up to 12 months. ]
    SAE
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class
Official Title  ICMJE MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class
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

  • 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:
13 different dose cohorts with escalating doses are planned.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Cancer
Intervention  ICMJE Drug: Karonudib
Dose escalation of administration with Karonudib.
Study Arms  ICMJE 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.
Intervention: Drug: Karonudib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 11, 2020)
35
Original Estimated Enrollment  ICMJE
 (submitted: January 26, 2017)
20
Estimated Study Completion Date  ICMJE June 30, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent.
  2. 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).
  3. Histological or cytological confirmation of cancer (imaging/AFP are sufficient for patients with HCC according to international standards).
  4. The patient has received standard of care treatments and has progressive disease with only experimental therapies as further treatment options.
  5. Life expectancy of at least 12 weeks (as per investigators clinical assessment).
  6. ECOG PFS 0 or 1.
  7. Patients must have measurable disease based on RECIST 1.1 criteria or evaluable metastatic disease.
  8. Adequate bone marrow, hepatic and renal function defined as:

    1. Haemoglobin ≥ 95 g/L (blood transfusion not less than 21 days prior to screening).
    2. Absolute neutrophil count ≥ 1.5 x 109/L, platelets ≥100 x 109/L.
    3. Total bilirubin < 1.5 x ULN (does not apply to patients with Gilberts Syndrome).
    4. AST and ALT ≤ 1.5 x ULN (or ≤ 3 x ULN in the presence of liver metastases).
    5. 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).
    6. Albumin greater than or equal to 23 g/L.
  9. Subject must be able to take oral medication.
  10. Negative pregnancy test according to CTFG guidance 2014 for females of child-producing potential.

Exclusion Criteria:

  1. Age less than 18 years.
  2. Less than 4 weeks since stopping previous systemic cancer treatment.
  3. Less than 3 weeks since stopping palliative radiotherapy.
  4. Less than 3 weeks after minor surgery.
  5. Less than 6 months since a clinically significant cardiovascular event such as myocardial infarction, unstable angina, angioplasty, bypass surgery, stroke or TIA.
  6. Congestive heart failure NYHA class ≥ II.
  7. History of arrhythmias or arrhythmias discovered during the screening period (apart from atrial fibrillation without ventricular tachycardia and premature extra beats).
  8. Patients requiring anti-arrhythmic drugs.
  9. QTc interval >450 ms at baseline.
  10. Use of fentanyl (must be stopped at least 1 week prior to initiation of Karonudib).
  11. Use of anti-oxidants vitamins and acetylcysteine (must be stopped within 48 hours of starting treatment with Karonudib).
  12. Use of antidepressant medications which are substrate for CYP2D6 (must be stopped at least 3 weeks prior to starting treatment with Karonudib).
  13. Any severe acute or chronic medical condition that places the patient at increased risk or interferes with the interpretation of study results.
  14. 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).
  15. Known acute or chronic infection with hepatitis B or C.
  16. Known HIV infection.
  17. Pregnant or breast-feeding women.
  18. Patients with reproductive potential not implementing accepted and effective means of contraception.
  19. Participation in any other clinical trial within the previous 4 weeks.
  20. Unable to comply with study procedures.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Teresa Sandvall, MSc teresa.sandvall@oxcia.se
Listed Location Countries  ICMJE Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03036228
Other Study ID Numbers  ICMJE MASTIFF
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Thomas Helleday Foundation
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Thomas Helleday Foundation
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Teresa Sandvall, MSc Oxcia
PRS Account Thomas Helleday Foundation
Verification Date February 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP