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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 22, 2018
Sponsor:
Information provided by (Responsible Party):
Thomas Helleday Foundation

Brief Summary:

The primary objective of this study is to determine safety and tolerability of Karonudib for the treatment of cancer.

Secondary objectives are to determine a recommended RP2D and schedule for further development of Karonudib, to determine the pharmacokinetics of Karonudib, to look for evidence of treatment efficacy. Overall survival will also be recorded.


Condition or disease Intervention/treatment Phase
Cancer Drug: Karonudib Phase 1

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MTH1, A Phase I, Study on Tumors Inhibition, First in Human, First in Class
Actual Study Start Date : January 2017
Estimated Primary Completion Date : August 2018
Estimated Study Completion Date : September 2018

Arm Intervention/treatment
Experimental: Dose escalation
Karonudib is an oral inhibitor of MTH1 and will be supplied as an oral solution to be taken every other day. There are eight planned dose cohorts. Patients will be given every second day dosing from week 1 (after evaluation of PK data and safety).
Drug: Karonudib
Dose escalation of administration with oral solution of Karonudib.




Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Peak Plasma Concentration, Cmax

  2. 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)

  3. To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    biological half-life (plasma T1/2)

  4. To determine the pharmacokinetics of Karonudib. [ Time Frame: 28 days, first treatment cycle for the patient ]
    Area under the Curve (AUC)

  5. To determine preliminary signs of clinical efficacy of Karonudib. [ Time Frame: 54 days, two treatment cycles for the patient ]
    RECIST 1.1

  6. To determine overall survival. [ Time Frame: Up to 12 months. ]
    SAE



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
  8. Adequate bone marrow, hepatic and renal function defined as:

    1. Haemoglobin ≥ 100 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 24 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03036228


Contacts
Contact: Teresa Sandvall, MSc teresa.sandvall@oxcia.se

Locations
Sweden
Karolinska University Hospital Recruiting
Stockholm, Sweden
Contact: Jeffrey Yachnin, MD, PhD         
Principal Investigator: Jeffrey Yachnin, MD, PhD         
Sponsors and Collaborators
Thomas Helleday Foundation
Investigators
Study Director: Teresa Sandvall, MSc Oxcia

Responsible Party: Thomas Helleday Foundation
ClinicalTrials.gov Identifier: NCT03036228     History of Changes
Other Study ID Numbers: MASTIFF
First Posted: January 30, 2017    Key Record Dates
Last Update Posted: February 22, 2018
Last Verified: February 2018

Keywords provided by Thomas Helleday Foundation:
Solid tumours