MC# 20-32 - An Open-Label Hepatic Impairment Study of Tesetaxel in Patients with Advanced Solid Tumors

  • Agent(s): Tesetaxel
  • Disease Type(s): Solid tumors with Hepatic Impairment
  • Phase(s): I
  • Drug Classification(s): Cytotoxic Therapy
  • Molecular Target(s): EZH2

Mechanism of Action

Tesetaxel is a semi-synthetic orally-bioavailable taxane that binds to and stabilizes tubulin, promoting microtubule assembly and thereby preventing microtubule depolymerization.  This may lead to cell cycle arrest and an inhibition of cell proliferation.

Purpose

In this study, the sponsor and investigators want to learn:

  • The safety and tolerability of tesetaxel
  • How much of the orally administered tesetaxel is absorbed into the blood and how fast it is removed in research participants who have different degrees of liver function
Inclusion Criteria
  1. Female or male patients at least 18 years of age
  2. Any histologically or cytologically confirmed solid tumor for which no standard therapy exists (including surgery or radiotherapy).  Patients with raised alpha-fetoprotein level (≥ 500 ng/mL), positive serology for viral hepatitis, and liver mass consistent with a diagnosis of hepatocellular carcinoma may be considered to have a clinical diagnosis of hepatocellular cancer and will be eligible without the need for pathologic confirmation of the diagnosis.
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
  4. Patients must have expected time on Study (Screening through Follow-Up) of at least 3 months
  5. Known metastases to the CNS or primary non-lymphoma CNS cancers are permitted but not required.  The following criteria apply:
    • Patients must be neurologically stable and either off corticosteroids or currently treated with a maximum daily dose of 4 mg of dexamethasone (or equivalent), with no increase in corticosteroid dose within 7 days prior to Enrollment
    • Any radiographically evident CNS cancer must not be progressing radiographically on the most recent imaging scan
    • Patients with a history of CNS cancer but with no current evidence of CNS lesions following local therapy are eligible
    • Patients with current evidence of leptomeningeal disease are not eligible
    • Any prior whole brain radiation therapy must have been completed > 14 days prior to the date of Enrollment
    • Prior stereotactic brain radiosurgery is permitted
    • CNS surgical resection must have been completed > 28 days prior to the date of Enrollment; patient must have complete recovery from surgery
  6. Adequate haematologic, hepatic, and renal function, as evidenced by:
    • Absolute neutrophil count (ANC) ≥ 1,500/μL without colony-stimulating factor support
    • Platelet count ≥ 100,000/μL
    • Haemoglobin ≥ 8.5 g/dL without transfusion support at frequency of more than 2 units of packed red blood cells (PRBCs) every 6 weeks
    • ALT:
      • Cohort 1 only: Alanine aminotransferase (ALT) ≤ upper limit of normal (ULN)
      • Cohort 2 only: Any ALT
    • Alkaline phosphatase:
      • Cohort 1 only: Alkaline phosphatase < 2.5 × ULN
      • Cohort 2 only: Any ALP
    • Calculated creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula or local standard)
    • Serum albumin ≥ 2.0 g/dL
    • Prothrombin time (PT) ≤ 1.5 × ULN or international normalized ratio (INR) ≤ 1.3, and partial thromboplastin time (PTT)/activated PTT ≤ 1.5 × ULN, unless the patient is on a therapeutic anticoagulant
  7. No change in classification of hepatic function via NCI-ODWG on two samples taken 72 h apart, including one within 72 h of Cycle 1, Day 1, as follows:
    • Normal hepatic function (Cohort 1): total bilirubin (TBIL) ≤ ULN and AST ≤ ULN
    • Moderate hepatic impairment (Cohort 2): 1.5 × ULN < TBIL ≤ 3 × ULN and any AST

No distinction will be made between hepatic impairment due to metastases and hepatic impairment due to other causes.  If the specific cause of hepatic impairment is unknown, the patient should be worked up for other causes of hepatitis, including viral infection, alcoholic hepatitis, and concurrent medication, and his or her eligibility determined after consultation with the Sponsor medical team.  Patients with biliary obstruction for which a shunt has been placed are eligible, provided the shunt has been in place for at least 10 days prior to Cycle 1, Day 1, and the hepatic function has stabilized.  Two measurements at least 72 h apart that put the patient in the same hepatic impairment stratum will be accepted as evidence of stable hepatic function.

  1. Complete recovery to baseline or Grade 1 per NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 from adverse effects of prior surgery, radiotherapy, and any systemic therapy, as applicable, with the exception of: (1) Grade 2 alopecia from prior chemotherapy or radiotherapy; (2) Grade 2 lymphopenia; or (3) Grade 2 endocrine toxicity from prior treatment with immune checkpoint inhibitors
  2. Ability to swallow an oral solid-dosage form of medication
  3. A negative serum pregnancy test within 7 days prior to the first dose of Study treatment in women of childbearing potential (ie, all women except those who are postmenopausal for ≥ 1 year or who have a history of hysterectomy or surgical sterilization)
  4. Women of childbearing potential must use an effective form of contraception from Screening throughout the Treatment Phase and until 70 days after the last dose of Study treatment
    • Acceptable methods include: intrauterine device (must be non-hormonal intrauterine device for patients who have HR positive MBC) or double barrier methods, including male/female condoms with spermicide and use of contraceptive sponge, cervical cap, diaphragm, abstinence, bilateral tubal ligation or occlusion, or intercourse with a male partner who has had a vasectomy with medical confirmation of surgical success
    • In regions that mandate the use of highly effective methods of contraception, the following are options: copper intrauterine device, bilateral tubal ligation or occlusion, intercourse with a partner who has undergone vasectomy (with confirmation of surgical success), or abstinence
  5. Men must use an effective form of contraception from Screening throughout the Treatment Phase and until 130 days after the last dose of Study treatment
    • Acceptable methods include: male/female condoms with spermicide, abstinence, vasectomy with medical confirmation of surgical success, or intercourse with a female partner who is taking an oral hormone contraceptive, has an implanted hormone contraceptive, or has undergone placement of an intrauterine device, or bilateral tubal ligation or occlusion
    • In regions that mandate the use of highly effective methods of contraception, the following are options: intercourse with a female partner who has undergone placement of an intrauterine device or bilateral tubal ligation or occlusion, abstinence, or vasectomy with medical confirmation of surgical success
  6. Written informed consent and authorization to use and disclose health information
  7. Ability to comprehend and comply with the requirements of the Study
Exclusion Criteria
  1. Patients with active haemolysis or biliary sepsis
  2. Presence of Grade ≥ 2 encephalopathy
  3. Patients with hepatitis B virus (HBV) are not permitted unless HBV is chronic with an undetectable viral load on suppressive therapy, or HBV has resolved. Resolved HBV is defined as negative hepatitis B surface antigen (HBsAg), negative hepatitis B e-antigen (HBeAg), and HBV deoxyribonucleic acid (DNA) < 10 IU/mL
  4. Patients with a history of hepatitis C virus (HCV) infection are not permitted unless treated and cured (absence of detectable HCV ribonucleic acid [RNA] for at least 12 weeks after completion of therapy), or currently on treatment with an undetectable HCV viral load
  5. Patients with known human immunodeficiency virus (HIV) are not permitted unless on effective anti-retroviral therapy with undetectable viral load during the 6 months prior to Screening
  6. Patients with a severe acute or chronic medical condition (including gastric resection) or psychiatric condition or laboratory abnormality that may increase the risk associated with Study participation or investigational product administration or may interfere with the interpretation of Study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this Study
  7. Presence of neuropathy Grade > 1 per NCI CTCAE version 5.0
  8. Anticancer treatment, including hormonal therapy, radiotherapy, chemotherapy, biologic therapy, or therapy in an investigational clinical study, ≤ 14 days prior to Enrollment.  Stereotactic radiation may be allowed within less than 14 days with approval of Sponsor medical team.
  9. Major surgery ≤ 28 days prior to Enrollment; patient must have complete recovery from surgery
  10. Less than 2 weeks or 5 plasma half-lives (whichever is greater) since last use of a medication, beverage, or food that is a moderate or strong inhibitor or inducer of cytochrome P450 (CYP)3A prior to the first dose of Study treatment (patients should discontinue taking any regularly-taken medication that is a moderate or strong inhibitor or inducer of the CYP3A)
  11. History of hypersensitivity to taxanes; hypersensitivity to the solvent does not preclude patient participation in this Study
  12. Pregnant or breastfeeding
  13. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the Study

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

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Re: MC# 20-32