Clinical Trials /

A Phase 1 First in Human Study of ZN-d5 as a Single Agent

NCT04500587

Description:

This is a Phase 1 dose escalation, open label, multicenter study, evaluating the safety, tolerability, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of ZN-d5 in subjects with Non-Hodgkin Lymphoma (NHL) and subjects with Acute Myeloid Leukemia (AML).

Related Conditions:
  • Acute Myeloid Leukemia
  • Anaplastic Large Cell Lymphoma
  • Diffuse Large B-Cell Lymphoma
  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
  • Peripheral T-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase 1 Study of ZN-d5 as a Single Agent
  • Official Title: Phase 1 First in Human Dose-Escalation Study of ZN-d5 as a Single Agent in Subjects With Non-Hodgkin Lymphoma or Acute Myeloid Leukemia

Clinical Trial IDs

  • ORG STUDY ID: ZN-d5-001
  • NCT ID: NCT04500587

Conditions

  • Acute Myeloid Leukemia
  • Non Hodgkin Lymphoma

Interventions

DrugSynonymsArms
ZN-d5Study DrugSingle Agent Dose Escalation - AML

Purpose

This is a Phase 1 dose escalation, open label, multicenter study, evaluating the safety, tolerability, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of ZNd5.

Detailed Description

      This is a Phase 1 dose escalation, open label, multicenter study, evaluating the safety,
      tolerability, clinical activity, pharmacokinetics (PK) and pharmacodynamics (PD) of ZN-d5 in
      subjects with Non-Hodgkin Lymphoma (NHL) and subjects with Acute Myeloid Leukemia (AML). NHL
      subjects will continue to dose escalate until either the MTD or the RP2D is identified.

      Subjects with AML will start enrolling into the trial once a safe dose is identified in
      subjects with NHL.
    

Trial Arms

NameTypeDescriptionInterventions
Single Agent Dose Escalation - NHLExperimentalDiffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), Mantle Cell Lymphoma (MCL), large cell lymphoma (LCL), and peripheral T-cell lymphoma (PTCL). Subjects must have relapsed or be refractory to at least 2 prior lines of therapy and have either failed or were not eligible for any available therapies expected to provide clinical benefit.
  • ZN-d5
Single Agent Dose Escalation - AMLExperimentalSubjects with relapsed and/or primary refractory AML as defined by WHO 2016 revised criteria, who have either relapsed or are refractory to previously available therapy.
  • ZN-d5

Eligibility Criteria

        • Inclusion Criteria Applicable for all Indications

        Provision of written informed consent approved by the Ethics Committee (EC)/ Institutional
        Review Board (IRB)

        White blood cell (WBC) count < 25 × 109/L. Cytoreduction prior to treatment is acceptable.

        Female subjects of childbearing potential must have a negative serum beta human chorionic
        gonadotropin (βHCG) test.

        Male subjects and female subjects of childbearing potential must agree to use an effective
        method of contraception per institutional standard prior to the first dose and for 90 days
        after the last dose of ZN-d5.

        Willingness to practice adequate sun protection (use of sunscreen or sun- protective
        clothing or limitation of sun exposure).

        Age ≥ 18 years or the minimum legal adult age (whichever is greater) at the time of
        Informed consent

        Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1

        Use of antifungal agents such as fluconazole is permitted except posaconazole and
        voriconazole, which are not permitted.

        - Inclusion Criteria for NHL

        Histologically or cytologically confirmed relapsed (recurrent after previous therapy) or
        refractory (no response to previous therapy) NHL: diffuse large B- cell lymphoma (DLBCL),
        follicular lymphoma (FL), marginal zone lymphoma (MZL), Mantle Cell Lymphoma (MCL), large
        cell lymphoma (LCL), and peripheral T-cell lymphoma (PTCL) based on the World Health
        Organization (WHO) criteria as determined by pathology review at the study site.

        Subject must have received at least 2 prior lines of therapy and have either failed or were
        not eligible for any available therapies expected to provide clinical benefit.

        For DLBCL, subjects should have failed CHOP or R-CHOP therapy and have failed salvage
        therapy including stem cell transplant, or not be candidates for these therapies.

        Subjects with B-cell NHL should have failed anti-CD20 therapy and anthracycline-based
        therapy, or not be candidates for these therapies.

        Subjects with indolent lymphomas should meet clinical criteria for treatment.

        . Adequate hematologic and organ function as defined by the following criteria: ANC ≥ 1.0 ×
        109/L after at least 7 days post the last dose of a growth factor

        Platelet count ≥ 75 × 109/L; excluding measurements obtained within 3 days after
        transfusion of platelets. A platelet count of ≥ 50 × 109/L is allowed if the percentage of
        lymphoma cells in the bone marrow is > 50%.

        Hemoglobin ≥ 8.0 g/dL after at least 7 days post the last transfusion or growth factor
        Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of
        normal (ULN). If liver function abnormalities are due to underlying liver involvement, AST
        and ALT ≤ 5 × ULN.

        Total serum bilirubin ≤ 1.5 × ULN or no limit in the case of Gilbert's disease Serum
        creatinine ≤ 1.5 × ULN or creatinine clearance (CrCl) ≥ 60 mL/min;

        - Inclusion Criteria for AML

        Relapsed and/or primary refractory AML as defined by WHO 2016 revised criteria

        Subjects must have AML, relapsed or refractory to previously available therapy.

        Adequate organ function as defined by the following criteria:

        Total serum bilirubin < 1.5 × ULN or no limit in the case of Gilbert's disease

        AST/ALT ≤ 3 × ULN. Levels of AST and/or ALT ≤ 5 × the ULN may be acceptable for subjects
        with known leukemic involvement of the liver after discussion with the study Medical
        Monitor.

        Serum creatinine < 1.5 × ULN or CrCL ≥ 60 mL/min;

        Exclusion Criteria:

        • Exclusion Criteria Applicable to the Study and Indications

        Any of the following treatment interventions within the specified time frame prior to Cycle
        1 Day 1/Ramp-up Cycle Day 1:

        Major surgery within 28 days (the surgical incision should be fully healed prior to study
        drug administration).

        Radiation therapy within 14 days;

        Presence of a clinically significant nonhematologic toxicity of prior chemotherapy that has
        not resolved to ≤ Grade 1 or Baseline, whichever is greater, as determined by CTCAE v 5.0
        (Section 14.2), with the exception of alopecia, neuropathy or skin pigmentation.

        Autologous or allogeneic stem cell transplant within 2 months.

        Receiving immunosuppression or having active fungal disease or active graft- versus-host
        disease after allogeneic stem cell transplantation on Cycle 1 Day 1/ Ramp-up Cycle Day 1.

        Current use of an investigational agent that is not expected to be cleared by the first
        dosing of study drug or that has demonstrated to have prolonged side effects.

        A serious illness or medical condition(s) including, but not limited to, the following:

        Unstable brain lymphoma with clinical symptoms.

        Known active Central Nervous System (CNS) leukemia. Controlled CNS leukemia is defined by
        the absence of active clinical signs of CNS disease and no evidence of CNS leukemia on the
        most recent 2 simultaneous cerebral spinal fluid (CSF) evaluations.

        Subjects with myocardial impairment of any cause (e.g., cardiomyopathy, ischemic heart
        disease, significant valvular dysfunction, hypertensive heart disease, and congestive heart
        failure) resulting in heart failure by New York Heart Association (NYHA) Classification
        (Class III or IV).

        Acquired immunodeficiency syndrome (AIDS) related illness or hepatitis B or C with
        cirrhosis of the liver.

        Other severe acute or chronic medical or psychiatric condition or laboratory abnormality
        that may increase the risk associated with study participation or study drug
        administration, or may interfere with the interpretation of study results, and in the
        judgment of the

        Investigator would make the subject inappropriate for entry into this study.

        Significant gastrointestinal abnormalities, including an inability to take oral medication,
        requirement for IV alimentation, active peptic ulcer, chronic diarrhea or vomiting
        considered to be clinically significant in the judgment of the Investigator, or prior
        surgical procedures affecting absorption.

        Inability to take the medication orally.

        Active or uncontrolled infection. Subjects with an infection receiving treatment
        (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be
        afebrile and hemodynamically stable for ≥ 72 hours.

        Current evidence of invasive fungal infection (blood or tissue culture); subjects with
        recent fungal infection must have a subsequent negative culture to be eligible.

        Prior therapy with venetoclax.

        Pregnant or lactating females (including the cessation of lactation) or females of
        childbearing potential who have a positive pregnancy test (urine or serum) within 14 days
        prior to Cycle 1 Day 1/Ramp-up Cycle Day 1. Males and females who do not agree to adequate
        birth control if conception is possible during the clinical study and for 90 days after the
        last dose are excluded.

        Subjects with active (uncontrolled, metastatic) second malignancies.

        Subjects who are judged by the Investigator to be unsuitable as study subjects. 12 lead
        electrocardiogram (ECG) demonstrating a QTcF of > 480 msec, except for subjects with
        atrioventricular pacemakers or other conditions (e.g., right bundle branch block) that
        render the QT measurement invalid.

        History or current evidence of congenital long QT syndrome. Taking medications that lead to
        significant QT prolongation.

        Administration of strong CYP3A4 inhibitors or strong or moderate CYP3A4 inducers

          -  Exclusion Criteria for NHL No additional criteria

          -  Exclusion Criteria for AML Any of the following treatment interventions within the
             specified time frame prior to Ramp-up Cycle Day#1:

        Any prior systemic neoplastic agents within 14 days or at least 5 half-lives (whichever is
        shorter) for cytotoxic/noncytotoxic agents. The half-life for the therapy in question will
        be based on published PK literature (abstracts, manuscripts, investigator brochures, or
        drug administration manuals).

        Hydroxyurea, hematopoietic growth factors, or tretinoin (all trans retinoic acid) are
        allowed for subjects with rapidly proliferative disease, up to 24 hours before Ramp-up
        Cycle Day 1 and for the first 7 days of Cycle 1 for peripheral blast control. One dose of
        cytarabine (up to 2 g/m2) is allowed for subjects with rapidly proliferative disease, up to
        48 hours before Ramp-up Cycle Day#1.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To investigate the incidence of treatment-emergent Adverse Events f ZN-d5 in subjects with NHL and AML
Time Frame:AEs through Phase 1 completion, an average of 1 year and DLTs through Cycle 1 (each cycle is 21 days) In Phase 1, an average of 1 year
Safety Issue:
Description:Observed Dose Limiting Toxicities (DLTs) in DLT evaluable subjects in order to evaluate safety and tolerability.

Secondary Outcome Measures

Measure:To investigate the clinical activity of ZN-d5 in subjects with NHL and AM
Time Frame:Through study completion, an average of 2 years
Safety Issue:
Description:For NHL, as defined by the Lugano response criteria for NHL;For AML - clinical activity will be assessed based on ELN Response Criteria

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:K-Group Alpha, Inc.

Trial Keywords

  • Blood Cancers
  • Liquid Tumors

Last Updated

August 3, 2020