A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination in Patients With HER2-Positive Advanced Solid Tumors

Last updated: August 29, 2024
Sponsor: Suzhou Zanrong Pharma Limited
Overall Status: Active - Recruiting

Phase

1

Condition

Neoplasms

Treatment

ZN-A-1041 200mg BID

ZN-A-1041 + T-DM1 3.6 mg/kg iv. for Phase1b

ZN-A-1041 400mg BID

Clinical Study ID

NCT05593094
ZN-A-1041-101-US
  • Ages > 18
  • All Genders

Study 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).

Eligibility Criteria

Inclusion

  • Inclusion Criteria:
  1. ECOG performance status of 0 to 1

  2. HER2 positive is defined as Immunohistochemistry (IHC) (++) and Fluorescence InSitu Hybridization (FISH) positive, or IHC (+++).

  3. Phase 1a study will enroll patients with unresectable or metastaticHER2-positive advanced solid tumor.For patients who have no brain metastases, the following criteria should bemet:

  4. Patients should be relapsed or refractory to existing therapy(ies) or havebeen intolerant of such therapies

  5. Patients with HER2-positive breast cancer should have previously receivedTrastuzumab, Pertuzumab, Trastuzumab emtansine(T-DM1) and a taxane.

  6. Patients with HER2-positive gastric cancer must have previously receivedtrastuzumab.

  7. Have measurable or non-measurable disease assessable by RECIST 1.1.For patients with brain metastasis, the following criteria should be met:

  8. Patients with HER2-positive breast cancer must have received priortreatment with Trastuzumab, Pertuzumab and T-DM1, and a taxane or patientdeclined the above treatment.

  9. Patients with HER2-positive gastric cancer must have previously receivedTrastuzumab

  10. Do not require immediate local treatment during the trial period, and meeteither of the following two criteria: i) For patients who have receivedprevious local treatment (surgery, whole brain radiotherapy (WBRT) andstereotactic radiosurgery (SRS)) for brain metastases, stable orprogression of intracranial lesions is required. Interval from prior localtherapy could be 3 weeks from WBRT and 2 weeks from SRS; ii) Symptomaticor not, patient has not received previous local treatment (surgery orradiotherapy) for brain metastases as long as no local therapy is neededduring the trial period.For patients who have received previous tyrosine kinase inhibitor (TKI)treatment, chemotherapy, antibody, or antibody-drug conjugate (ADC), theinterval between the last treatment and the first administration of the studydrug in this trial should be at least 2 weeks.

  11. Phase 1b and Phase 1c study will enroll patients with unresectable locallyadvanced or metastatic HER2+ breast cancer.For Phase 1b patients who have no brain metastases, the following criteriashould be met:

  12. For arm 1 and arm 2, patients should be relapsed or refractory to existingtherapy(ies), with a history of prior treatment with trastuzumab and ataxane. For arm3, patients have received 4-8 cycles (21-day cycles) ofprevious treatment with trastuzumab, pertuzumab, and taxane as first-linetherapy for advanced HER2+ breast cancer with no evidence of diseaseprogression.

  13. Have measurable or non-measurable disease assessable by RECIST 1.1For Phase 1c patients who have no brain metastases, the following criteriashould be met:

  14. For arm 1 and arm 2, patients should be refractory to existingtherapy(ies), with a history of prior treatment with trastuzumab. Forarm3, patients have received a pertuzumab plus trastuzumab or T-DXd foradvanced HER2+breast cancer with no evidence of disease progression.

  15. In arms 1 and 2, patients should have at least one measurable lesioneither extracranially or intracranially per RECIST v1.1.For patients with brain metastasis, the following criteria should be met:

  16. For arm 1 and arm 2 of phase 1b, patients should be relapsed or refractoryto existing therapy(ies), with a history of prior treatment withtrastuzumab and a taxane. For arm3, patients have received 4-8 cycles (21-day cycles) of previous treatment with trastuzumab, pertuzumab, andtaxane as first-line therapy for advanced HER2+ breast cancer with noevidence of disease progression. For arm 1 and arm 2 of phase 1c, patientsshould be refractory to existing therapy(ies), with a history of priortreatment with trastuzumab. For arm3, patients have received previoustreatment with a pertuzumab plus trastuzumab or T-DXd for advanced HER2+breast cancer with no evidence of disease progression (except brainmetastases).

  17. Do not require immediate local treatment during the trial period, and meeteither of the following two criteria: i) For patients who have receivedprevious local treatment (surgery, whole brain radiotherapy (WBRT) andstereotactic radiosurgery (SRS)) for brain metastases, stable orprogression of intracranial lesions is required. Interval from prior localtherapy could be 3 weeks from WBRT, 2 weeks from SRS and 4 weeks fromsurgery; ii) Symptomatic or not, patient has not received previous localtreatment (surgery or radiotherapy) for brain metastases as long as nolocal therapy is needed during the trial period.

  18. Suspected or confirmed leptomeningeal metastasis are allowed.

  19. In Phase 1b arm1 and arm2, patients who have received previous tyrosine kinaseinhibitor (TKI) treatment, chemotherapy, antibody, or antibody-drug conjugate (ADC), the interval between the last treatment and the first administration ofthe study drug in this trial should be at least 2 weeks. For arm3, patientsshould not have prior treatment for unresectable locally-advanced or metastaticHER2+ breast cancer with and without brain metastasis, except for ongoingHerceptin, Perjeta or PHESGO and taxane.

  20. In Phase 1c arm1 and arm2, Patients should not have received prior treatmentwith tucatinib, afatinib, or any other investigational anti-HER2, anti-EGFR, orHER2 TKI agent. Prior treatment with lapatinib or neratinib within 12 months ofstarting study treatment (except in cases where they were given for ≤ 21 daysand was discontinued for reasons other than disease progression or severetoxicity). Prior treatment with pyrotinib for recurrent of mBC (except in caseswhere pyrotinib was given for ≤ 21 days and was discontinued for reasons otherthan disease progression or severe toxicity). For arm3, patients should nothave prior treatment for unresectable locally-advanced or metastatic HER2+breast cancer with and without brain metastasis, except for ongoing Herceptin,Perjeta or PHESGO or T-Dxd based induction.

Exclusion

  • Exclusion Criteria:
  1. Subjects who have participated in any clinical study or received any clinicalstudy drug within 4 weeks prior to the first administration except for on-goingHerceptin, Perjeta or PHESGO in arm3

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

  3. Progressive neurologic impairment or increased intracranial pressure (including nausea, vomiting, blurred vision, headache, epilepsy, etc.)

  4. Any intracranial lesion thought to require immediate local therapy

  5. Require antiepileptic treatment (except for these patients with stableseizures require continuous Levetiracetam therapy).

  6. Ongoing use of systemic corticosteroids for control of symptoms of brainmetastases at a total daily dose of > 2 mg of dexamethasone (orequivalent)

Study Design

Total Participants: 210
Treatment Group(s): 13
Primary Treatment: ZN-A-1041 200mg BID
Phase: 1
Study Start date:
October 15, 2020
Estimated Completion Date:
October 30, 2026

Study 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 assessed for an appropriate arm by the sponsor and the investigator 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 or T-DXd based induction regimen. Patients will be assessed for an appropriate arm by the sponsor and the investigator 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.

Connect with a study center

  • Andrew Love Cancer Center

    Geelong, Victoria 3220
    Australia

    Site Not Available

  • Sunshine Hospital - Australia

    St Albans, Victoria 3021
    Australia

    Site Not Available

  • Centre Oscar Lambret - PPDS

    Lille, Nord 59000
    France

    Site Not Available

  • Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes

    Lyon, 69373
    France

    Site Not Available

  • Institut Claudius Regaud - PPDS

    Toulouse, 31059
    France

    Site Not Available

  • Auckland City Hospital

    Auckland, 1023
    New Zealand

    Site Not Available

  • Hospital Clinic de Barcelona

    Barcelona, 8036
    Spain

    Site Not Available

  • Instituto Oncologico Dr. Rosell-Hospital Universitari Dexeus-Grupo Quironsalud

    Barcelona, 8028
    Spain

    Site Not Available

  • Instituto de Investigacion Oncologica Vall dHebron (VHIO) - EPON

    Barcelona, 8035
    Spain

    Site Not Available

  • Hospital Universitario de Jaen

    Jaén, 23007
    Spain

    Site Not Available

  • Hospital Clinico San Carlos

    Madrid, 28040
    Spain

    Site Not Available

  • Hospital Universitario Ramon y Cajal

    Madrid, 28034
    Spain

    Active - Recruiting

  • Hospital Clinico Universitario de Santiago

    Santiago de Compostela, 15706
    Spain

    Site Not Available

  • Hospital Universitario Virgen Macarena

    Sevilla, 41009
    Spain

    Site Not Available

  • Fundacion Instituto Valenciano de Oncologia

    Valencia, 46026
    Spain

    Active - Recruiting

  • The Christie - PPDS

    Manchester, Lancashire M20 4BX
    United Kingdom

    Site Not Available

  • ACRC/Arizona Clinical Research Center, Inc

    Tucson, Arizona 85715
    United States

    Active - Recruiting

  • TOI Clinical Research

    Cerritos, California 90703-2684
    United States

    Active - Recruiting

  • Innovative Clinical Research Institute

    Whittier, California 90603
    United States

    Active - Recruiting

  • Dana-Farber Cancer Insitute

    Boston, Massachusetts 02215
    United States

    Active - Recruiting

  • University of Michigan

    Ann Arbor, Michigan 48109
    United States

    Site Not Available

  • Barbara Ann Karmanos Cancer center

    Detroit, Michigan 48201
    United States

    Active - Recruiting

  • Duke Cancer Institute

    Durham, North Carolina 27710
    United States

    Active - Recruiting

  • Md Anderson Cancer center

    Houston, Texas 77030
    United States

    Active - Recruiting

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