Phase 1 First in Human Study of ZN-d5 as a Single Agent
Study Details
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 |
|---|---|---|
| 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
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 Names:
|
| 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 Names:
|
Outcome Measures
Primary Outcome Measures
- To investigate the incidence of treatment-emergent Adverse Events f ZN-d5 in subjects with NHL and AML [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.
- To determine the maximum tolerated dose (MTD) in NHL and AML [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
- To determine the recommended Phase 2 dose (RP2D) in NHL and AML [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
- To investigate the clinical activity of ZN-d5 in subjects with NHL and AM [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
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
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Site 2708 | Darlinghurst | New South Wales | Australia | |
| 2 | Site 2704 | Liverpool | New South Wales | Australia | |
| 3 | Site 2709 | Hobart | Tasmania | Australia | |
| 4 | Site 1202 | Sofia | Bulgaria | ||
| 5 | Site 1203 | Varna | Bulgaria | ||
| 6 | Site 3201 | Zagreb | Croatia | ||
| 7 | Site 2901 | Pusan | Korea, Republic of | ||
| 8 | Site 2903 | Seoul | Korea, Republic of | ||
| 9 | Site 2403 | Gdansk | Poland | ||
| 10 | Site 3001 | Barcelona | Spain | ||
| 11 | Site 3001 | Valencia | Spain | ||
| 12 | Site 2001 | Kiev | Ukraine |
Sponsors and Collaborators
- K-Group Alpha, Inc.
Investigators
- Study Director: Anthony Fiorino, MD, K-Group Alpha
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ZN-d5-001