MC# 21-32 - An Open-label, Multicenter Trial of the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of M1774 in Participants with Metastatic or Locally Advanced Unresectable Solid Tumors

  • Agent(s): M1774
  • Disease Type(s): Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Small Molecule, Targeted Therapy
  • Molecular Target(s): ATR

Mechanism of Action

M1774 selectively inhibits ATR activity and blocks the downstream phosphorylation of the serine/threonine protein kinase checkpoint kinase 1 (CHK1). This prevents ATR-mediated signaling, which results in the inhibition of DNA damage checkpoint activation, the disruption of DNA damage repair, and the induction of tumor cell apoptosis.

Purpose

In this part of the study, the sponsor and investigators want to learn on patients with advanced solid tumors harboring above noted molecular aberrations in biomarker-defined cohorts:

  • About the safety and tolerability of M1774
  • How M1774 is acting on your body
  • The effects of M1774 (good and bad)
  • How much of M1774 is absorbed into the blood and how fast it is removed
  • If research tests can be used in the future to predict who will benefit from M1774
Inclusion Criteria
  1. Are ≥ 18 years of age at the time of signing the informed consent.
  2. Locally advanced or metastatic disease that is refractory to standard therapy or for which no standard therapy is judged appropriate by the Investigator (i.e., participants who have exhausted all standard of care options according to International Guidelines), which may convey clinical benefit.

Part A3 only: Participants whose tumor has at least 1 of the following molecular defects:

  • Cohort 1: loss of function mutations in the gene for ARID1A
  • Cohort 2: loss of function mutations in the genes for ATRX and/or DAXX
  • Cohort 3: loss of function mutation in the gene for ATM.

These can be determined according to local data, generated by an assay with appropriate regulatory status, in either tumor or liquid biopsy; if local data are not available they can be determined by a clinical trial assay at a central laboratory with appropriate regulatory status, in an archival (or fresh) tumor biopsy (i.e., no liquid biopsy clinical trial assay at a central laboratory will be used for enrollment).

  1. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
  2. Participants with clinically controlled brain metastases, which is defined as individuals with central nervous system metastases that have been treated for, are asymptomatic, and have discontinued steroids (for the treatment of brain metastases) for > 28 days may be enrolled. Participants with meningeal carcinomatosis are excluded.
  3. Part A3 only: measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.
  4. Have adequate hematologic function as indicated by:
    • Platelet count ≥ 100,000/mm3.
    • Hemoglobin ≥ 9.0 g/dL.
    • Absolute neutrophil count ≥ 1,500/μL with no growth factor treatment within the last 14 days.
  5. Adequate hepatic function defined: by a total bilirubin level ≤ 1.5 × upper limit of normal (ULN) (if Gilbert’s Syndrome may have total bilirubin > 1.5 × ULN), an aspartate aminotransferase (AST) level ≤ 3 × ULN, and an alanine aminotransferase (ALT) level ≤ 3 × ULN or ≤ 5 × ULN in presence of liver metastases.
  6. Adequate renal function defined as: serum creatinine ≤ 1.5 × ULN. If serum creatinine is > 1.5 × ULN, creatinine clearance needs to be ≥ 50 mL/min by calculation using the Cockcroft-Gault formula or by measured 24-hour urine collection. The Cockcroft-Gault formula is (glomerular filtration rate [mL/min] = {(l40–age) × weight / (72 × serum creatinine [mg/dL])} × 0.85 [if female]).
  7. Are male or female.
  8. Contraceptive use by males or females will be consistent with local regulations on contraception methods for those participating in clinical studies.

Male participants: Agree to the following during the study intervention period and for at least 3 months after the last dose of study intervention:

  • Refrain from donating sperm. PLUS, either:
  • Abstain from any activity that allows for exposure to ejaculate. OR
  • Use a male condom: When having sexual intercourse with a woman of childbearing potential (WOCBP), and advise her to use a highly effective contraceptive method with a failure rate of < 1% per year, since a condom may break or leak.
  • Male participants must use a condom with pregnant female partners during the study.

Female participants: Are not pregnant or breastfeeding, and at least 1 of the following conditions applies:

  • Not a WOCBP OR
  • If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% per year), preferably with low user dependency, for the following time periods:
    • Before the first dose of the study intervention(s), if using hormonal contraception:
      • Has completed at least one 4-week cycle of an oral contraception pill and either had or has begun her menses OR
      • Has used a depot contraceptive or extended-cycle oral contraceptive for least 28 days and has a documented negative pregnancy test using a highly sensitive assay.
    • During the intervention period
    • After the study intervention period (i.e., after the last dose of study intervention is administered) for at least 6 months after the last dose of study intervention and agree not to donate eggs (ova, oocytes) for reproduction during this period
  • The Investigator evaluates the effectiveness of the contraceptive method in relationship to the first dose of study intervention
    • Have a negative serum pregnancy test, as required by local regulations, within 24 hours before the first dose of study intervention
    • Women should not breastfeed during the study and for at least 1 month after the study period, (i.e., after the last dose of study intervention is administered).
  • The Investigator reviews the medical history, menstrual history, and  recent sexual activity to decrease the risk for inclusion of a female with an early undetected pregnancy.
  1. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.

 

Exclusion Criteria
  1. Presence of toxicities due to prior anticancer therapies (e.g., radiotherapy, chemotherapy, immunotherapies, etc.) that do not recover to ≤ Grade 1 with the exception of toxicities that do not pose a safety risk to the participant in the judgment of the Investigator (e.g., ongoing Grade 2 alopecia).
  2. Unstable angina, myocardial infarction, congestive heart failure ≥ II or a coronary revascularization procedure within 180 days of study entry. Calculated QTc average (using the Fridericia correction calculation) of > 450 msec for males and > 470 msec for females, that does not resolve with correction of electrolyte abnormalities.
  3. Active fungal, bacterial, and/or viral infection. Individuals with known human immunodeficiency virus and/or viral hepatitis (B and/or C) are excluded. However, individuals with hepatitis C treated with curative therapy are not considered actively infected.
  4. Treatment with live or live attenuated vaccine within 30 days of dosing (non-replicating vector vaccines are permitted).
  5. Any other clinical condition or uncontrolled concurrent illness which in the Investigator’s opinion would not make the participant a good candidate for the clinical study.
  6. Major surgery (as deemed by the Investigator) for any reason, except diagnostic biopsy, within 4 weeks of the study intervention and/or if the participant has not fully recovered from the surgery within 4 weeks of the study intervention.
  7. Concurrent treatment with a nonpermitted drug/intervention:
    • Prohibited concomitant medication, as listed in this protocol.
    • Anticancer treatment within 28 days or 5 half-lives, whichever is shorter, prior to Day 1 of study intervention (6 weeks for nitrosoureas or mitomycin C).
      • Continuation of background luteinizing hormone-releasing hormone (LHRH) agonist or antagonist treatment in participants with prostate cancer or premenopausal women with breast cancer is permitted.
    • Palliative radiation that irradiates a target lesion.
    • Another investigational drug within 28 days or 5 half-lives, whichever is shorter, prior to start of administration of study intervention.
    • Received hematopoietic growth factor (e.g., granulocyte colony-stimulating factor, erythropoietin) within 14 days prior to the first dose of study intervention.
    • Strong inhibitors or inducers of CYP3A4 or CYP1A2 enzymes.
    • Participants receiving treatment with proton-pump inhibitors that cannot be discontinued at least 1 week before first dose of study intervention and for the duration of the study.
  8. Prior use of ATR inhibitor and/or CHK1 inhibitor.
  9. Participants who cannot comply with restrictions for medications or food.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04170153

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Re: MC# 21-32