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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04487236
Recruitment Status : Recruiting
First Posted : July 27, 2020
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
Suzhou Zanrong Pharma Limited

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
Advanced Solid Tumors HER2-positive Breast Cancer Drug: ZN-A-1041 50mg BID Drug: ZN-A-1041 100mg BID Drug: ZN-A-1041 200mg BID Drug: ZN-A-1041 400mg BID Drug: ZN-A-1041 600mg BID Drug: ZN-A-1041 800mg BID Drug: ZN-A-1041 1000mg BID Drug: ZN-A-1041 Level 1 +Capecitabine Drug: ZN-A-1041 Level 2 +Capecitabine Drug: ZN-A-1041 Level 3 +Capecitabine 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 15, 2020
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine


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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules

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 Name: ZN-A-1041 Enteric Capsules




Primary Outcome Measures :
  1. The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a [ Time Frame: 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.

  2. The safety/tolerability of ZN-A-1041 in combination with Capecitabine on Phase 1b [ Time Frame: 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.

  3. The safety of ZN-A-1041 in combination with Capecitabine on Phase 1c [ Time Frame: 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 :
  1. Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c [ Time Frame: From baseline to Day 8 ]
    To assess the AUC of ZN-A-1041 and its major metabolites;

  2. 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 ]
    To assess the Cmax of ZN-A-1041 and its major metabolites;

  3. Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c [ Time Frame: From baseline to Day 8 ]
    To assess the Tmax of ZN-A-1041 and its major metabolites;

  4. 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 ]
    overall Response Rate (ORR);Progression free survival(PFS)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04487236


Contacts
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Contact: Fei Ma, MD +861087788060 drmafei@126.com
Contact: Qun Yi Li, MD +861087788120 liyiqun_chcams@foxmail.com

Locations
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China, Beijing
Cancer hospital Chinese academy of medical sciences Recruiting
Beijing, Beijing, China, 100000
Contact: Qun Yi LI, MD         
Sponsors and Collaborators
Suzhou Zanrong Pharma Limited
Investigators
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Principal Investigator: Fei Ma, MD Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College
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Responsible Party: Suzhou Zanrong Pharma Limited
ClinicalTrials.gov Identifier: NCT04487236    
Other Study ID Numbers: ZN-A-1041-101
First Posted: July 27, 2020    Key Record Dates
Last Update Posted: October 22, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Suzhou Zanrong Pharma Limited:
Phase 1
Advanced Solid Tumors
HER2-Positive Breast Cancer
Additional relevant MeSH terms:
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Neoplasms
Capecitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents