Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors

• Status: Recruiting
• Trial end date: 2024-06-30
• Target enrollment: 0
• Participant gender: All

Summary

This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability, PK and efficacy of ZN-A-1041 as a monotherapy or in combination with Capecitabine in patients with HER2-positive advanced solid tumors with or without brain metastases.

The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041 monotherapy), phase 1b (dose escalation with ZN-A-1041 and Capecitabine combination therapy) and phase 1c (dose expansion with ZN-A-1041 and Capecitabine combination therapy).

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Suzhou Zanrong Pharma Limited
• Treatments: Capecitabine

Criteria

Key inclusion criteria:

1. Ages Eligible for Study: 18 Years and older

2. Sexes Eligible for Study: All

3. ECOG performance status of 0 to 1

4. Patients are defined as follows:

a) Phase 1a study will enroll patients with HER2-positive advanced solid tumor ; Phase 1b study will enroll patients with HER2-positive advanced breast cancer.

i.HER2-positive is defined as Immunohistochemistry (IHC) (++) and Fluorescence In Situ Hybridization (FISH) positive, or IHC (+++).

ii.For patients who have no brain metastases, the following criteria should be met:

(1) Patients should be relapsed or refractory to existing therapy(ies) known to provide clinical benefit for the underlying cancer or have been intolerant of such therapies (2) Have at least one extracranial measurable lesion per RECIST v1. 1 iii. For patients with brain metastasis, the following criteria should be met: (1) Have received prior treatment or declined the above treatment according to the protocol requirements; (2) Patients with HER2-positive gastric cancer must have previously received Trastuzumab (3) Do not require immediate local treatment during the trial period according to the protocol requirements.

iv. For patients who have received previous tyrosine kinase inhibitor (TKI) treatment or chemotherapy, the interval between the last treatment and the first administration of the study drug in this trial should be at least 3 weeks. For patients who receive antibody or antibody-drug conjugate (ADC), the interval between the last treatment and the first administration of the study drug in this trial should be at least 4 weeks.

b) Phase 1c study will enroll patients with HER2-positive breast cancer with brain metastases:

i. HER2 positive is defined as IHC (++) and FISH positive, or IHC (+++);

ii. Patients do not require immediate local treatment during the trial period according to the protocol requirements.

iii. Patients should have at least one measurable intracranial lesion accurately measured at baseline by magnetic resonance imaging (MRI).

5. Life expectancy ≥6 months;

6. Have adequate organ and bone marrow function within 7 days before the first administration according to the protocol

7. Man of reproductive potential or women of child-bearing potential shall be use of highly effective methods of birth control (such as oral contraceptives, intrauterine contraceptive device, abstinence or barrier contraception in combination with spermicide) during the trial, and continue to practice contraception for 3 months after the last administration.

8. Subject or legally authorized representative of a subject must provide signed informed consent document, have good compliance, and are cooperative with the follow-ups.

Key exclusion criteria:

1. Subjects who have participated in any clinical study or received any clinical study drug within 4 weeks prior to the first administration;

2. Based on screening brain MRI, any of the following criteria for patients with brain metastasis:

1. progressive neurologic impairment or increased intracranial pressure

2. any intracranial lesion thought to require immediate local therapy

3. require antiepileptic treatment

3. Subjects who have opportunistic infection or progressive (severe) infection

4. Subjects who have undergone large surgeries within 4 weeks prior to the initiation of treatment or need large surgeries during the trials (excluding biopsy);

5. Subjects who have intracranial hemorrhage or stroke within 6 months prior to the first administration;

6. Subjects who have active gastrointestinal disorders or other diseases, which may significantly affect the absorption, distribution, metabolism or excretion of ZN-A-1041;

7. Subjects who are currently using (or will not discontinue at least 1 week prior to the first administration of the trial) any drug or herbal medicine known to inhibit or induce CYP3A4 and CYP2C8 activity;

8. Subjects who meet one of the following cardiac criteria:

1. Congestive heart failure (New York Heart Association functional classification) of ≥ 2

2. Peripheral arterial disease (PAD), like Coronary artery disease, hypertrophic cardiomyopathy (HCM)or Dilated cardiomyopathy

3. Abnormalities in the ECG Measurements: such as First-degree heart block, Second-degree heart block, Third-degree heart block, Prolonged PR: > 0.20s

4. Any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention

5. Angina requiring treatment

6. Myocardial infarction within the past 12 months

7. Percutaneous transluminal coronary angioplasty/stenting (PTCA), coronary artery bypass graft (CABG) within 6 months of the first dose of the study treatment

8. QTcF prolongation (> 470 ms for women and > 450 ms for man (Fridericia-corrected)), a known history of QTcF prolongation or Torsade de Pointes; or is on drugs that are required for existing medical conditions and that may result in QT prolongation (e.g., anti-arrhythmic drugs)

9. Subjects who have not fully recovered from previous treatment and still has CTCAE grade 1 or higher AEs, excluding alopecia. prior to the first administration;

10. Pregnant or lactating women

11. Subjects who are known to be allergic to ZN-A-1041 and its metabolites or its pharmaceutical excipients (active or not)

12. Subjects who have serious accompanying diseases or an abnormal laboratory finding.

13. Subjects who have serious psychological or mental abnormalities.

14. Subjects who have complications of the central nervous system which require urgent neurosurgical interventions.