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A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination 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: NCT05593094
Recruitment Status : Recruiting
First Posted : October 25, 2022
Last Update Posted : July 28, 2023
Sponsor:
Information provided by (Responsible Party):
Suzhou Zanrong Pharma Limited

Study Description
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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 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 combination therapy) and Phase 1c (dose expansion with ZN-A-1041 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 + T-DM1 3.6 mg/kg iv. for Phase1b Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1b Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1b Drug: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1c Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1c Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1c 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. The dose levels will be based on the results of the Phase 1a study and the results of a food effect study. In Phase 1b, patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis will be enrolled in three arms: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd. Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta and 4-8-cycle treatment of taxane Patients will be assigned to an appropriate arm by the sponsor and the investigator based on his/her eligibility at the time of consent. Patients with unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis are planned to be enrolled in Phase 1c of the study: Arm1 will receive multiple doses of ZN-A-1041 in combination with T-DM1; Arm2 will receive multiple doses of ZN-A-1041 in combination with T-DXd; Arm 3 will receive multiple doses of ZN-A-1041 in combination with PHESGO or Herceptin plus Perjeta after Herceptin plus Perjeta and 4-8-cycle treatment of taxane. Patients will be assigned to an appropriate arm by the sponsor and the investigator based on his/her eligibility at the time of consent. Arm1 of Phase 1c can start independently after the DLT observation period of the last patient in Phase 1b Arm1. Arm 2 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 2. Arm 3 of Phase 1c can start independently after the DLT observation of the last patient in Phase 1b Arm 3. The dose levels used in Phase 1c will be based on the recommended doses obtained from the Phase 1b study.

Each phase of the study includes a screening period (from 28 days prior to the first administration of the study drug), a treatment period (until there are no clinical benefits as deemed by the Investigator, disease progression, death, intolerable toxicity, withdrawal of informed consent, loss of follow-up, or the start of new anti-tumor treatment), and a follow-up period (until 28 days after the last administration of the study drug). During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as monotherapy and in combination in the subjects will be collected and analyzed, thereby providing RP2D for subsequent future clinical trials.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 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 in Patients With HER2-Positive Advanced Solid Tumors
Actual Study Start Date : October 15, 2020
Estimated Primary Completion Date : October 30, 2023
Estimated Study Completion Date : October 30, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
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
twice a day (BID) via oral administration
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1b: ZN-A-1041 + T-DM1 3.6 mg/kg iv.

Phase 1b Arm1:

  1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2)
  2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
 Drug: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1b
ZN-A-1041: twice a day (BID) via oral administration T-DM1: 3.6 mg/kg given as an intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1b: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.

Phase 1b Arm2:

  1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2)
  2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
 Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1b
ZN-A-1041: twice a day (BID) via oral administration T-DXd: 5.4 mg/kg given as an intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1b: ZN-A-1041 + PHESGO / Herceptin plus Perjeta

Phase 1b Arm3:

  1. If the MTD of ZN-A-1041 is identified in Phase 1a study: The 2 tentative dose levels of ZN-A-1041 are MTD-1 (Level 1) and MTD (Level 2)
  2. If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
 Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1b
ZN-A-1041: twice a day (BID) via oral administration PHESGO dose is 600 mg pertuzumab/600 mg trastuzumab/2000 unites hyaluronidase every 3 weeks for subcutaneous administrations (21-day cycle) Perjeta is 420 mg administered as an intravenous infusion Herceptin is 6 mg/kg administered as an intravenous infusion
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1c: ZN-A-1041 + T-DM1 3.6 mg/kg iv.

Phase 1c Arm1:

The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

 Drug: ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1c
ZN-A-1041: twice a day (BID) via oral administration T-DM1: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1c: ZN-A-1041 + T-Dxd 5.4 mg/kg iv.

Phase 1c Arm2:

The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

 Drug: ZN-A-1041 + T-Dxd 5.4 mg/kg iv. for Phase1c
ZN-A-1041: twice a day (BID) via oral administration T-DXd: intravenous infusion on the first day of each treatment cycle, once every 3 weeks (21-day cycle)
Other Name: ZN-A-1041 Enteric Capsules
Experimental: 1c: ZN-A-1041 + Herceptin plus Perjeta/PHESGO

Phase 1c Arm3:

The dose levels of ZN-A-1041 in the Phase 1c study will be the recommended doses determined in the Phase 1b study.

 Drug: ZN-A-1041 + PHESGO / Herceptin plus Perjeta injection for Phase1c
ZN-A-1041: twice a day (BID) via oral administration PHESGO: every 3 weeks for subcutaneous administrations (21-day cycle) Perjeta: intravenous infusion Herceptin: intravenous infusion
Other Name: ZN-A-1041 Enteric Capsules


Outcome Measures
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Primary Outcome Measures :
  1. The Incidence of Treatment-Emergent Adverse Events of ZN-A-1041 as a monotherapy in Phase 1a [ Time Frame: 23 days ]
    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 Incidence of Treatment-Emergent Adverse Events of ZN-A-1041 in combination with T-DM1 or with T-DXd, or in combination with PHESGO or Herceptin plus Perjeta [ Time Frame: 21 days ]
    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. RP2D Dose [ Time Frame: through study completion, an average of 1 year ]
    To evaluate the safety of ZN-A-1041 in combination with T-DM1 or with T-DXd, or in combination with PHESGO or Herceptin plus Perjeta in patients on the RP2D Dose


Secondary Outcome Measures :
  1. AUC. 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 AUC of ZN-A-1041 and its major metabolites

  2. Cmax. 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 Cmax of ZN-A-1041 and its major metabolites

  3. Tmax. 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. overall Response Rate (ORR) [ Time Frame: through study completion, an average of 1 year ]
    The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c

  5. Progression free survival(PFS) [ Time Frame: through study completion, an average of 1 year ]
    The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c


Eligibility Criteria
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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

  • Inclusion Criteria:

    1. ECOG performance status of 0 to 1
    2. HER2 positive is defined as Immunohistochemistry (IHC) (++) and Fluorescence In Situ Hybridization (FISH) positive, or IHC (+++).

    3. Phase 1a study will enroll patients with unresectable or metastatic HER2-positive advanced solid tumor.

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

      1. Patients should be relapsed or refractory to existing therapy(ies) or have been intolerant of such therapies
      2. Patients with HER2-positive breast cancer should have previously received Trastuzumab, Pertuzumab, Trastuzumab emtansine(T-DM1) and a taxane.
      3. Patients with HER2-positive gastric cancer must have previously received trastuzumab.
      4. Have measurable or non-measurable disease assessable by RECIST 1.1.

      For patients with brain metastasis, the following criteria should be met:

      1. Patients with HER2-positive breast cancer must have received prior treatment with Trastuzumab, Pertuzumab and T-DM1, and a taxane or patient declined the above treatment.
      2. Patients with HER2-positive gastric cancer must have previously received Trastuzumab
      3. Do not require immediate local treatment during the trial period, and meet either of the following two criteria: i) For patients who have received previous local treatment (surgery, whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS)) for brain metastases, stable or progression of intracranial lesions is required. Interval from prior local therapy could be 3 weeks from WBRT and 2 weeks from SRS; ii) Symptomatic or not, patient has not received previous local treatment (surgery or radiotherapy) for brain metastases as long as no local therapy is needed during the trial period.

      For patients who have received previous tyrosine kinase inhibitor (TKI) treatment, chemotherapy, 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 2 weeks.

    4. Phase 1b and Phase 1c study will enroll patients with unresectable locally advanced or metastatic HER2+ breast cancer.

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

      1. For arm 1 and arm 2, patients should be relapsed or refractory to existing therapy(ies), with a history of prior treatment with trastuzumab and a taxane. For arm3, patients have received 4-8 cycles (21-day cycles) of previous treatment with trastuzumab, pertuzumab, and taxane as first-line therapy for advanced HER2+ breast cancer with no evidence of disease progression.
      2. Have measurable or non-measurable disease assessable by RECIST 1.1

      For patients with brain metastasis, the following criteria should be met:

      1. For arm 1 and arm 2, patients should be relapsed or refractory to existing therapy(ies), with a history of prior treatment with trastuzumab and a taxane. For arm3, patients have received 4-8 cycles (21-day cycles) of previous treatment with trastuzumab, pertuzumab, and taxane as first-line therapy for advanced HER2+ breast cancer with no evidence of disease progression.
      2. Do not require immediate local treatment during the trial period, and meet either of the following two criteria: i) For patients who have received previous local treatment (surgery, whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS)) for brain metastases, stable or progression of intracranial lesions is required. Interval from prior local therapy could be 3 weeks from WBRT, 2 weeks from SRS and 4 weeks from surgery; ii) Symptomatic or not, patient has not received previous local treatment (surgery or radiotherapy) for brain metastases as long as no local therapy is needed during the trial period.
    5. Suspected or confirmed leptomeningeal metastasis are allowed in Phase 1b, but not allowed in Phase 1c.
    6. In Phase 1b arm1 and arm2, patients who have received previous tyrosine kinase inhibitor (TKI) treatment, chemotherapy, 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 2 weeks. For arm3, patients should not have prior treatment for unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis, except for ongoing Herceptin, Perjeta or PHESGO and taxane.
    7. In Phase 1c arm1 and arm2, Patients should not have received prior treatment with tucatinib, afatinib, or any other investigational anti-HER2, anti-EGFR, or HER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months of starting study treatment (except in cases where they were given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity). Prior treatment with pyrotinib for recurrent of mBC (except in cases where pyrotinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity). For arm3, patients should not have prior treatment for unresectable locally-advanced or metastatic HER2+ breast cancer with and without brain metastasis, except for ongoing Herceptin, Perjeta or PHESGO and taxane.

  • 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 except for on-going Herceptin, Perjeta or PHESGO in arm3

    2. CNS Exclusion - Based on screening brain MRI and clinical assessment

      1. Progressive neurologic impairment or increased intracranial pressure (including nausea, vomiting, blurred vision, headache, epilepsy, etc.)
      2. Any intracranial lesion thought to require immediate local therapy
      3. Require antiepileptic treatment (except for these patients with stable seizures require continuous Levetiracetam therapy).
      4. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT05593094


Contacts
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Contact: Ding Zhou, Ph.D (86)-13916360900 ding.zhou@zionpharma.com

Locations
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United States, Arizona
ACRC/Arizona Clinical Research Center, Inc Recruiting
Tucson, Arizona, United States, 85715
Contact: Plezia PharmD    520-290-2510    pplezia@acrcresearch.com   
Principal Investigator: Manuel R Modiano, MD         
United States, California
Innovative Clinical Research Institute Recruiting
Whittier, California, United States, 90603
Contact: Leslie Posadas    562-693-4477    leslieposadas@theoncologyinstitute.com   
Principal Investigator: Arati Chand, MD         
United States, Massachusetts
Dana-Farber Cancer Insitute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Olivia Postel    877-338-7425    OliviaG_Postel@DFCI.HARVARD.EDU   
Principal Investigator: Nancy Lin, MD         
United States, Michigan
University of Michigan Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Caner AnswerLine    800-865-1125    CancerAnswerLine@med.umich.edu   
Principal Investigator: Aki Morikawa, MD         
Barbara Ann Karmanos Cancer center Recruiting
Detroit, Michigan, United States, 48201
Contact: Hadeel Assad, MD    313-576-8716    Assadh@karmanos.org   
Principal Investigator: Hadeel Assad, MD         
United States, North Carolina
Duke Cancer Institute Recruiting
Durham, North Carolina, United States, 27710
Contact: JoAnna Gontarz    919-684-6342    joanna.gontarz@duke.edu   
Principal Investigator: Carey Anders, MD         
United States, Texas
Md Anderson Cancer center Recruiting
Houston, Texas, United States, 77030
Contact: Rashmi Murthy, MD    713-792-2817    RMurthy1@mdanderson.org   
Principal Investigator: Rashmi Murthy, MD         
Sponsors and Collaborators
Suzhou Zanrong Pharma Limited
Investigators
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Principal Investigator: Anders Carey K, MD Duke Cancer Institute
More Information
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Responsible Party: Suzhou Zanrong Pharma Limited
ClinicalTrials.gov Identifier: NCT05593094    
Other Study ID Numbers: ZN-A-1041-101-US
First Posted: October 25, 2022    Key Record Dates
Last Update Posted: July 28, 2023
Last Verified: July 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Suzhou Zanrong Pharma Limited:
Phase 1
Advanced Solid Tumors
HER2 postive
Brain metastases
Herceptin
 Perjeta
PHESGO
First Line
1st Line
Additional relevant MeSH terms:
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Neoplasms
Trastuzumab
Pertuzumab
Ado-Trastuzumab Emtansine
Maytansine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunotoxins
 Immunoconjugates
Immunologic Factors
Physiological Effects of Drugs
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic