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

• Status: Recruiting
• Trial end date: 2023-05-01
• Target enrollment: 0
• Participant gender: All

Summary

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).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: K-Group Alpha, Inc.

Criteria

• Inclusion Criteria Applicable for all Indications

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.

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 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 (the surgical incision should be fully healed prior to study drug administration).

Radiation therapy

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

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

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.

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)

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 AML

Any prior systemic neoplastic agents within 14 days or at least 5 half-lives (whichever is shorter) for cytotoxic/noncytotoxic agents.

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.