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

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ClinicalTrials.gov Identifier: NCT04500587
Recruitment Status : Recruiting
First Posted : August 5, 2020
Last Update Posted : January 22, 2021
Sponsor:
Information provided by (Responsible Party):
K-Group Alpha, Inc.

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.

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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


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




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



Information from the National Library of Medicine

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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

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04500587


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

Locations
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Australia, New South Wales
Site 2708 Recruiting
Darlinghurst, New South Wales, Australia
Site 2704 Recruiting
Liverpool, New South Wales, Australia
Australia, Tasmania
Site 2709 Not yet recruiting
Hobart, Tasmania, Australia
Bulgaria
Site 1202 Recruiting
Sofia, Bulgaria
Site 1203 Not yet recruiting
Varna, Bulgaria
Croatia
Site 3201 Not yet recruiting
Zagreb, Croatia
Korea, Republic of
Site 2901 Not yet recruiting
Busan, Korea, Republic of
Site 2903 Not yet recruiting
Seoul, Korea, Republic of
Poland
Site 2403 Recruiting
Gdansk, Poland
Spain
Site 3001 Not yet recruiting
Barcelona, Spain
Site 3001 Recruiting
Valencia, Spain
Ukraine
Site 2001 Recruiting
Kiev, Ukraine
Sponsors and Collaborators
K-Group Alpha, Inc.
Investigators
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Study Director: Anthony Fiorino, MD K-Group Alpha
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Responsible Party: K-Group Alpha, Inc.
ClinicalTrials.gov Identifier: NCT04500587    
Other Study ID Numbers: ZN-d5-001
First Posted: August 5, 2020    Key Record Dates
Last Update Posted: January 22, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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.:
Blood Cancers
Liquid Tumors
Additional relevant MeSH terms:
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Lymphoma
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases