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

• ClinicalTrials.gov Identifier: NCT04500587
• Recruitment Status: Recruiting
• First Posted: August 5, 2020
• Last Update Posted: December 15, 2021
• Sponsor: K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.

Study Description

Brief 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).

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia; Non Hodgkin Lymphoma	Drug: ZN-d5	Phase 1

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 85 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 13, 2020
• Estimated Primary Completion Date: October 2022
• Estimated Study Completion Date: May 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Znd5 Single Agent Dose Escalation - 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). 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.	Drug: ZN-d5; Oral agent; 25 mg or 100 mg formulation; Other Name: Study Drug
Experimental: Znd5 Single Agent Dose Escalation - AML; Subjects 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.	Drug: ZN-d5; Oral agent; 25 mg or 100 mg formulation; Other Name: Study Drug

Outcome Measures

Primary Outcome Measures :

1. 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 ]
   Observed Dose Limiting Toxicities (DLTs) in DLT evaluable subjects in order to evaluate safety and tolerability.
2. To determine the maximum tolerated dose (MTD) in NHL and AML [ Time Frame: Through study completion, an average of 2 years ]
   Incidence and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 5.0
3. To determine the recommended Phase 2 dose (RP2D) in NHL and AML [ Time Frame: Through study completion, an average of 2 years ]
   Incidence and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 5.0

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Anthony Fiorino, MD; 8582634333; info@zenopharma.com

Locations

Australia, New South Wales

Site 2708; Recruiting

Darlinghurst, New South Wales, Australia

Site 2704; Recruiting

Liverpool, New South Wales, Australia

Australia, Tasmania

Site 2709; Recruiting

Hobart, Tasmania, Australia

Bulgaria

Site 1202; Recruiting

Sofia, Bulgaria

Site 1203; Recruiting

Varna, Bulgaria

Croatia

Site 3201; Recruiting

Zagreb, Croatia

Korea, Republic of

Site 2901; Recruiting

Pusan, Korea, Republic of

Site 2903; Recruiting

Seoul, Korea, Republic of

Poland

Site 2403; Recruiting

Gdansk, Poland

Spain

Site 3001; Recruiting

Barcelona, Spain

Site 3001; Recruiting

Valencia, Spain

Ukraine

Site 2001; Recruiting

Kiev, Ukraine

Sponsors and Collaborators

K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.

Investigators

• Study Director: Anthony Fiorino, MD; K-Group Alpha

More Information

• Responsible Party: K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT04500587
• Other Study ID Numbers: ZN-d5-001
• First Posted: August 5, 2020
• Last Update Posted: December 15, 2021
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.:

Blood Cancers; Liquid Tumors

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases