Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors
Study Details
Study Description
Brief 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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7 planned dose levels. Patients with HER2-positive advanced solid tumor (including those with brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041 followed by multiple-dose administration of ZN-A-1041.Phase 1b of the study will adopt the "traditional 3+3" dose escalation design with a total of 2 planned dose levels. The dose levels will be determined based on the MTD identified in the phase 1a study.
In phase 1b, patients with HER2-positive advanced breast cancer (including those with brain metastases) will be enrolled to receive multiple doses of ZN-A-1041 in combination with Capecitabine. Patients with HER2-positive breast cancer with brain metastases were planned to be enrolled in the Phase 1c of the study to receive ZN-A-1041 in combination with Capecitabine. The dose levels will be determined based on the recommended doses obtained from the Phase 1b study.
Each phase of the study includes a screening period, a treatment period and a follow-up period. During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as monotherapy and in combination with Capecitabine in the subjects will be collected and analyzed, thereby providing RP2D for the subsequent clinical trials.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ZN-A-1041 50mg Phase 1a: Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 50mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 100mg Phase 1a: Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 100mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 200mg Phase 1a: Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 200mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 400mg Phase 1a: Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 400mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 600mg Phase 1a: Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 600mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 800mg Phase 1a: Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 800mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 1000mg Phase 1a: Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle |
Drug: ZN-A-1041 1000mg BID
Orally 21days for one cycle
Other Names:
|
| Experimental: ZN-A-1041 level 1+Capecitabine 1000 mg/m2 Phase 1b: ZN-A-1041 level 1+Capecitabine 1000 mg/m2; ZN-A-1041 Level 1 (The previous dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study. Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle. |
Drug: ZN-A-1041 Level 1 +Capecitabine
ZN-A-1041 level 1 BID; Capecitabine 1000 mg/m2 BID
Other Names:
|
| Experimental: ZN-A-1041 level 2+Capecitabine 1000 mg/m2 Phase 1b: ZN-A-1041 level 2+Capecitabine 1000 mg/m2; ZN-A-1041 Level 2 ( dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study. Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle. |
Drug: ZN-A-1041 Level 2 +Capecitabine
ZN-A-1041 level 2 BID; Capecitabine 1000 mg/m2 BID
Other Names:
|
| Experimental: ZN-A-1041 level 3 +Capecitabine Phase 1c: The actual dose levels of ZN-A-1041 to be used in the combination Capecitabine will be determined based on the MTD identified in the Phase 1b study. |
Drug: ZN-A-1041 Level 3 +Capecitabine
ZN-A-1041 (RP2D level) BID; Capecitabine (RP2D level) BID
Other Names:
|
Outcome Measures
Primary Outcome Measures
- The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a [23days]
Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
- The safety/tolerability of ZN-A-1041 in combination with Capecitabine on Phase 1b [21days]
Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
- The safety of ZN-A-1041 in combination with Capecitabine on Phase 1c [through study completion, an average of 3 year]
To evaluate the safety of ZN-A-1041 in combination with Capecitabine in patients on the RP2D Dose
Secondary Outcome Measures
- Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c [From baseline to Day 8]
To assess the AUC of ZN-A-1041 and its major metabolites;
- Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c [From baseline to Day 8]
To assess the Cmax of ZN-A-1041 and its major metabolites;
- Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c [From baseline to Day 8]
To assess the Tmax of ZN-A-1041 and its major metabolites;
- The preliminary efficacy of ZN-A-1041 as a monotherapy or combination with with Capecitabine on Phase 1a,phase 1b and 1c [through study completion, an average of 3 year]
overall Response Rate (ORR);Progression free survival(PFS)
Eligibility Criteria
Criteria
Key inclusion criteria:
-
Ages Eligible for Study: 18 Years and older
-
Sexes Eligible for Study: All
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ECOG performance status of 0 to 1
-
Patients are defined as follows:
- 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.
- 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.
- Phase 1c study will enroll patients with HER2-positive breast cancer with brain metastases:
- HER2 positive is defined as IHC () and FISH positive, or IHC (+);
-
Patients do not require immediate local treatment during the trial period according to the protocol requirements.
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Patients should have at least one measurable intracranial lesion accurately measured at baseline by magnetic resonance imaging (MRI).
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Life expectancy ≥6 months;
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Have adequate organ and bone marrow function within 7 days before the first administration according to the protocol
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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.
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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:
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Subjects who have participated in any clinical study or received any clinical study drug within 4 weeks prior to the first administration;
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Based on screening brain MRI, any of the following criteria for patients with brain metastasis:
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progressive neurologic impairment or increased intracranial pressure
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any intracranial lesion thought to require immediate local therapy
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require antiepileptic treatment
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Subjects who have opportunistic infection or progressive (severe) infection
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Subjects who have undergone large surgeries within 4 weeks prior to the initiation of treatment or need large surgeries during the trials (excluding biopsy);
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Subjects who have intracranial hemorrhage or stroke within 6 months prior to the first administration;
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Subjects who have active gastrointestinal disorders or other diseases, which may significantly affect the absorption, distribution, metabolism or excretion of ZN-A-1041;
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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;
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Subjects who meet one of the following cardiac criteria:
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Congestive heart failure (New York Heart Association functional classification) of ≥ 2
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Peripheral arterial disease (PAD), like Coronary artery disease, hypertrophic cardiomyopathy (HCM)or Dilated cardiomyopathy
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Abnormalities in the ECG Measurements: such as First-degree heart block, Second-degree heart block, Third-degree heart block, Prolonged PR: > 0.20s
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Any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention
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Angina requiring treatment
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Myocardial infarction within the past 12 months
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Percutaneous transluminal coronary angioplasty/stenting (PTCA), coronary artery bypass graft (CABG) within 6 months of the first dose of the study treatment
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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)
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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;
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Pregnant or lactating women
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Subjects who are known to be allergic to ZN-A-1041 and its metabolites or its pharmaceutical excipients (active or not)
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Subjects who have serious accompanying diseases or an abnormal laboratory finding.
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Subjects who have serious psychological or mental abnormalities.
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Subjects who have complications of the central nervous system which require urgent neurosurgical interventions.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cancer hospital Chinese academy of medical sciences | Beijing | Beijing | China | 100000 |
Sponsors and Collaborators
- Suzhou Zanrong Pharma Limited
Investigators
- Principal Investigator: Fei Ma, MD, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ZN-A-1041-101