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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT04500587




Registration number
NCT04500587
Ethics application status
Date submitted
30/07/2020
Date registered
5/08/2020
Date last updated
3/03/2021

Titles & IDs
Public title
A Phase 1 First in Human Study of ZN-d5 as a Single Agent
Scientific 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
Secondary ID [1] 0 0
ZN-d5-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Non Hodgkin Lymphoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
Cancer 0 0 0 0
Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - ZN-d5

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.

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.


Treatment: Drugs: ZN-d5
Oral agent; 25 mg or 100 mg formulation

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
To investigate the incidence of treatment-emergent Adverse Events f ZN-d5 in subjects with NHL and AML - Observed Dose Limiting Toxicities (DLTs) in DLT evaluable subjects in order to evaluate safety and tolerability.
Timepoint [1] 0 0
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
Primary outcome [2] 0 0
To determine the maximum tolerated dose (MTD) in NHL and AML - Incidence and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 5.0
Timepoint [2] 0 0
Through study completion, an average of 2 years
Primary outcome [3] 0 0
To determine the recommended Phase 2 dose (RP2D) in NHL and AML - Incidence and severity of AEs, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v 5.0
Timepoint [3] 0 0
Through study completion, an average of 2 years
Secondary outcome [1] 0 0
To investigate the clinical activity of ZN-d5 in subjects with NHL and AM - For NHL, as defined by the Lugano response criteria for NHL;For AML - clinical activity will be assessed based on ELN Response Criteria
Timepoint [1] 0 0
Through study completion, an average of 2 years

Eligibility
Key inclusion 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 (ßHCG) 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;
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,TAS
Recruitment hospital [1] 0 0
Site 2708 - Darlinghurst
Recruitment hospital [2] 0 0
Site 2704 - Liverpool
Recruitment hospital [3] 0 0
Site 2709 - Hobart
Recruitment postcode(s) [1] 0 0
- Darlinghurst
Recruitment postcode(s) [2] 0 0
- Liverpool
Recruitment postcode(s) [3] 0 0
- Hobart
Recruitment outside Australia
Country [1] 0 0
Bulgaria
State/province [1] 0 0
Sofia
Country [2] 0 0
Bulgaria
State/province [2] 0 0
Varna
Country [3] 0 0
Croatia
State/province [3] 0 0
Zagreb
Country [4] 0 0
Korea, Republic of
State/province [4] 0 0
Pusan
Country [5] 0 0
Korea, Republic of
State/province [5] 0 0
Seoul
Country [6] 0 0
Poland
State/province [6] 0 0
Gdansk
Country [7] 0 0
Spain
State/province [7] 0 0
Barcelona
Country [8] 0 0
Spain
State/province [8] 0 0
Valencia
Country [9] 0 0
Ukraine
State/province [9] 0 0
Kiev

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
K-Group Alpha, Inc.
Address
Country

Ethics approval
Ethics application status

Summary
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).
Trial website
https://clinicaltrials.gov/show/NCT04500587
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Anthony Fiorino, MD
Address 0 0
K-Group Alpha
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Anthony Fiorino, MD
Address 0 0
Country 0 0
Phone 0 0
8582634333
Fax 0 0
Email 0 0
info@zenopharma.com
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT04500587