Description:
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).
Title
- Brief Title: Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors
- Official Title: A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of ZN-A-1041 Enteric Capsules as a Single Agent or in Combination With Capecitabine Tablets in Patients With HER2-Positive Advanced Solid Tumors
Clinical Trial IDs
- ORG STUDY ID:
ZN-A-1041-101
- NCT ID:
NCT04487236
Conditions
- Advanced Solid Tumors
- HER2-positive Breast Cancer
Interventions
Drug | Synonyms | Arms |
---|
ZN-A-1041 50mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 50mg |
ZN-A-1041 100mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 100mg |
ZN-A-1041 200mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 200mg |
ZN-A-1041 400mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 400mg |
ZN-A-1041 600mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 600mg |
ZN-A-1041 800mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 800mg |
ZN-A-1041 1000mg BID | ZN-A-1041 Enteric Capsules | ZN-A-1041 1000mg |
ZN-A-1041 Level 1 +Capecitabine | ZN-A-1041 Enteric Capsules | ZN-A-1041 level 1+Capecitabine 1000 mg/m2 |
ZN-A-1041 Level 2 +Capecitabine | ZN-A-1041 Enteric Capsules | ZN-A-1041 level 2+Capecitabine 1000 mg/m2 |
ZN-A-1041 Level 3 +Capecitabine | ZN-A-1041 Enteric Capsules | ZN-A-1041 level 3 +Capecitabine |
Purpose
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).
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.
Trial Arms
Name | Type | Description | Interventions |
---|
ZN-A-1041 50mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle | |
ZN-A-1041 100mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle | |
ZN-A-1041 200mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle | |
ZN-A-1041 400mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle | |
ZN-A-1041 600mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle | |
ZN-A-1041 800mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle | |
ZN-A-1041 1000mg | Experimental | Phase 1a:
Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle | |
ZN-A-1041 level 1+Capecitabine 1000 mg/m2 | Experimental | 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. | - ZN-A-1041 Level 1 +Capecitabine
|
ZN-A-1041 level 2+Capecitabine 1000 mg/m2 | Experimental | 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. | - ZN-A-1041 Level 2 +Capecitabine
|
ZN-A-1041 level 3 +Capecitabine | Experimental | 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. | - ZN-A-1041 Level 3 +Capecitabine
|
Eligibility 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.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a |
Time Frame: | 23days |
Safety Issue: | |
Description: | Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity. |
Secondary Outcome Measures
Measure: | Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c |
Time Frame: | From baseline to Day 8 |
Safety Issue: | |
Description: | To assess the AUC of ZN-A-1041 and its major metabolites; |
Measure: | Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c |
Time Frame: | From baseline to Day 8 |
Safety Issue: | |
Description: | To assess the Cmax of ZN-A-1041 and its major metabolites; |
Measure: | Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c |
Time Frame: | From baseline to Day 8 |
Safety Issue: | |
Description: | To assess the Tmax of ZN-A-1041 and its major metabolites; |
Measure: | The preliminary efficacy of ZN-A-1041 as a monotherapy or combination with with Capecitabine on Phase 1a,phase 1b and 1c |
Time Frame: | through study completion, an average of 3 year |
Safety Issue: | |
Description: | overall Response Rate (ORR);Progression free survival(PFS) |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Suzhou Zanrong Pharma Limited |
Trial Keywords
- Phase 1
- Advanced Solid Tumors
- HER2-Positive Breast Cancer
Last Updated
October 22, 2020