Study to evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Jazz Pharmaceuticals Ireland Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

9 Dec 2019 → 30 Jun 2025

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Jazz Pharmaceuticals Ireland Limited

External identifiers

EU CT number

2023-508135-30-00

EudraCT number

2019-002956-18

ClinicalTrials.gov

NCT04224272

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Dose response, Pharmacokinetic, Therapy, Safety

Part 1
To recommend a dose for ZW25 in combination with palbociclib plus fulvestrant for Part 2 by evaluating the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant in subjects with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-positive, hormone receptor (HR)-positive breast cancer
Part 2
To evaluate the anti-tumor activity of ZW25 in combination with palbociclib plus fulvestrant in subjects with locally advanced (unresectable) and/or metastatic HER2 positive , HR positive breast cancer

Secondary objectives 2

1. Part 1 - To evaluate the pharmacokinetics (PK) of ZW25 in combination with palbociclib plus fulvestrant - To evaluate the immunogenicity of ZW25 in combination with palbociclib plus fulvestrant Exploratory: To explore the utility of potential serum & tumor biomarkers
2. Part 2 - To evaluate additional measures of the anti-tumor activity of ZW25 in combination with palbociclib plus fulvestrant in subjects with locally advanced (unresectable) and/ or metastatic HER2-positive, HR-positive breast cancer - To evaluate the safety and tolerability of ZW25 in combination with palbociclib plus fulvestrant - To evaluate the PK of ZW25 in combination with palbociclib plus fulvestrant - To evaluate the immunogenicity of ZW25 in combination with palbociclib plus fulvestrant Exploratory: To explore the utility of potential serum and tumor biomarkers

Conditions and MedDRA coding

Breast cancer patients including those with locally advanced (unresectable) or metastatic HER2-positive, HR-positive breast cancer

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1.Pathologically-confirmed diagnosis of breast cancer with evidence of locally advanced (unresectable) and/or metastatic disease. All patients in both Parts 1 and 2 must have HER2 positive and HR positive disease as follows: •HER2 positive based on the HER2 Testing in Breast Cancer: American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice Guidelines (Wolff 2018). •HR positive defined as estrogen-receptor positive (ER positive) and/or progesterone-receptor positive (PgR positive) disease based on the ASCO/CAP Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer (Hammond 2010)."
2. 10.All toxicity related to prior cancer therapies must have resolved to ≤ XML File Identifier: 2LZ33yYQqmBiBGpwbnSiOMkiyFA= Page 32/51 Grade 1, with the exception of alopecia or ≤ Grade 2 neuropathy
3. 11.If female and of child-bearing potential, must have a negative pregnancy test ≤ 3 days prior to the first dose of ZW25
4. 12.For female subjects who are not surgically sterile or post-menopausal and for male subjects with a partner of child-bearing potential, willingness to use 2 methods of birth control with a failure rate of less than 1% per year during the study and for 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant). These include, but are not limited to, established use of oral, implanted, or injected hormonal contraceptives; placement of intra-uterine device or intrauterine system; or use of barrier methods, such as condom or diaphragm together with a spermicidal product.
5. 13.Female subjects must agree not to breastfeed or donate ova starting at screening and throughout the study period, and for at least 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant)
6. 14.Male subjects must not donate sperm starting at screening and throughout the study period, and for at least 12 months after the last dose of study drug (ZW25, palbociclib, and/or fulvestrant)
7. 15.Signed informed consent prior to any study procedures not considered standard of care
8. 2.Able to provide a new formalin-fixed, paraffin-embedded (FFPE) tumor sample (preferred) or archived tumor tissue (most recent sample available) for retrospective central review of HER2 status. Local assessments performed on a new tumor sample or archived tumor tissue in a Clinical Laboratory Improvements Amendments (CLIA)- certified lab using a combination of IHC and ISH/FISH methods may be used to determine HER2 and HR status for study eligibility. IHC must be used to determine HR status. Unless otherwise approved by the sponsor medical monitor, specimens should be provided for centralized retrospective review of HER2 status.
9. 3.Received prior treatment with trastuzumab, pertuzumab, AND adotrastuzumab emtansine (T-DM9); disease progression during or after the most recent prior therapy. Subjects in any part of the study who did not receive pertuzumab or T-DM1 because of lack of access (e.g., due to insurance coverage or because they were treated prior to regulatory agency approval of the agent in a relevant indication) or due to medical ineligibility for treatment with T-DM1 (e.g., history of severe infusion reactions to trastuzumab, ≥ Grade 2 peripheral neuropathy, or platelet count < 100 x 10E9/L) may be eligible for the study after discussion with and approval from the sponsor medical monitor. Prior treatment with endocrine therapy in the neoadjuvant, adjuvant, and/or metastatic setting is permitted.
10. 4.Sites of disease assessable per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (both measurable and non-measurable disease allowed)
11. 5.Male and female subjects aged 18 years or older
12. 6.An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
13. 7.Life expectancy of at least 3 months in the opinion of the investigator
14. 8.The following baseline laboratory data: a.Absolute neutrophil count (ANC) ≥ 1.5 x 10E9/L b.Platelet count ≥ 75 x 10E9/L c.Hemoglobin ≥ 9 g/dL d.Prothrombin time (PT) and/or International Normalized Ratio (INR) and partial thromboplastin time (PTT)/ a PTT /activated partial thromboplastin time)≤ 1.5 x upper limit of normal (ULN), unless on medication known to alter the INR or PTT e.Total bilirubin ≤ 1.5 x ULN per institutional values (subjects with known Gilbert's Syndrome may enroll with 2.5 x ULN provided the direct bilirubin is ≤ 1.5 mg/dL) f.Alanine transaminase (ALT) ≤ 3.0 x ULN per institutional values (if liver metastases are present, ≤ 5.0 x ULN) g.Aspartate transaminase (AST) ≤ 3.0 x ULN per institutional values (if liver metastases are present, ≤ 5.0 x ULN) h.Serum creatinine ≤ 1.5 X ULN or calculated glomerular filtration rate 50 mL/min
15. 9.Adequate cardiac left ventricular function, as defined by LVEF ≥ institutional standard of normal

Exclusion criteria 23

1. 1.Prior treatment with trastuzumab, pertuzumab, lapatinib, T-DM1, or other anti-HER2-targeted therapy ≤ 3 weeks before the first dose of ZW25
2. 7.History of life-threatening hypersensitivity to monoclonal antibodies, XML File Identifier: 2LZ33yYQqmBiBGpwbnSiOMkiyFA= Page 34/51 recombinant proteins, or excipients in the drug formulation
3. 8.Prior treatment with palbociclib or any other CDK4/6 inhibitors, including experimental agents
4. 10.History of myocardial infarction or unstable angina within 6 months prior to enrollment, troponin levels consistent with myocardial infarction, or clinically significant cardiac disease, such as ventricular arrhythmia requiring therapy, uncontrolled hypertension, or any history of symptomatic congestive heart failure (CHF)
5. 9.Use of corticosteroids administered at doses equivalent to > 15 mg per day of prednisone within 2 weeks of first ZW25 dosing unless otherwise approved by the sponsor medical monitor. Topical, ocular, intra-articular, intranasal, and/or inhalational corticosteroids are permitted.
6. 11.QTc Fridericia (QTcF) >470 ms
7. 13.Active hepatitis B or hepatitis C infection
8. 14.Acute or chronic uncontrolled renal disease, pancreatitis, or severe liver disease (Child-Pugh Class C)
9. 2.Prior treatment with chemotherapy, other anti-cancer therapy not otherwise specified, or hormonal cancer therapy ≤ 3 weeks before the first dose of ZW25
10. 3.Prior treatment with experimental biologic and non-biologic therapies ≤ 4 weeks before the first dose of ZW25
11. 4.Prior treatment with radiation therapy other than for central nervous system (CNS) disease ≤ 3 weeks before the first dose of ZW25
12. 5.Treatment with anthracyclines within 90 days before first dose of ZW25 and/or total lifetime load exceeding 360 mg/m2 Adriamycin or equivalent
13. 6.Use of any medications or substances that are strong inhibitors or inducers of CYP3A isoenzymes within 7 days of first dose of any study drug
14. 14.Acute or chronic uncontrolled renal disease, pancreatitis, or severe liver disease (Child-Pugh Class C)
15. 15.Known infection with Human Immunodeficiency Virus (HIV)-1 or HIV-2 (Exception: patients with well- controlled HIV [e.g., cluster of differentiation 4 (CD4)-positive T cell count >350/mm3 and undetectable viral load] are eligible.)
16. 16.Major surgery ≤ 3 weeks prior to the first dose of ZW25
17. 17.Prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen
18. 18.Any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures
19. 19.Females who are breastfeeding or pregnant, and females and males planning a pregnancy
20. 20.Brain metastases: Untreated CNS metastases, symptomatic CNS metastases, or radiation treatment for CNS metastases within 4 weeks of start of study treatment. Stable, treated brain metastases are allowed (defined as subjects who are off steroids and anticonvulsants and are neurologically stable for at least 1 month at the time of screening).
21. 21.Poorly-controlled seizures
22. 22.History of or ongoing leptomeningeal disease (LMD). If LMD has been reported radiographically on baseline magnetic resonance imaging (MRI), but is not suspected clinically by the investigator, the patient must be free of neurological symptoms of LMD
23. 23.Grade 3 or greater peripheral neuropathy

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Part 1 Frequency of dose-limiting toxicities (DLTs) Frequency and severity of adverse events (AEs) Frequency of serious adverse events (SAEs) and deaths Frequency and severity of clinical laboratory abnormalities Frequency of electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) abnormalities
2. Frequency and severity of adverse events of special interest (AESIs), including absolute decreases in LVEF maior or equal 10 percentage points from baseline, symptomatic heart failure, infusion-related reactions, and all maior and equal Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis
3. Frequency of dose reductions of ZW25 Frequency of dose reductions of components of combination therapy Frequency of treatment discontinuations due to adeverse event (AEs).
4. Part 2 Progression-free survival 6 (PFS6, defined as the % of modified intent to treat (mITT)subjects with PFS 24 weeks)

Secondary endpoints 5

1. Part 1 Serum concentrations of ZW25 as a function of time post-dosing PK parameters for single (first) dose and multiple doses of ZW25 Frequency, duration, and time of onset of anti-drug antibodies (ADA) and neutralizing antibodies, if applicable
2. Part 2 Objetive response rate (ORR) Duration of response (DOR) Disease control rate (DCR) Progression-free survival (PFS) Overall Survival (OS) Frequency and severity of AEs Frequency of SAEs and deaths Frequency and severity of clinical laboratory abnormalities Frequency of ECG and LVEF abnormalities
3. Frequency and severity of AESIs, including decreases in LVEF mayor or equal 10% points from baseline),symptomatic heart failure all mayor or equal Grade 3 infusion-related reactions, and all Grade 2 events of pneumonitis and/or interstitial lung disease, including pulmonary fibrosis Frequency of dose reductions of ZW25 Frequency of dose reductions of components of combination therapy Frequency of treatment discontinuations due to AEs
4. Frequency of dose reductions of ZW25 Frequency of dose reductions of components of combination therapy
5. Frequency of treatment discontinuations due to AEs Serum concentrations of ZW25 as a function of time post-dosing PK parameters for single (first) dose and multiple doses of ZW25 Frequency, duration, and time of onset of ADA and neutralizing antibodies, if applicable

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Jazz Pharmaceuticals Ireland Limited

Sponsor organisation

Jazz Pharmaceuticals Ireland Limited

Address

5th Floor, Waterloo Exchange, Waterloo Road Waterloo Exchange Waterloo Road

City

Dublin 4

Postcode

D04 E5W7

Country

Ireland

Scientific contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Kavita Shah

Public contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Kavita Shah

Third parties 6

Locations

1 EU/EEA country · 4 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications