Clinical trial NCT05593094: A Phase 1 Trial of ZN-A-1041 Enteric Capsules or Combination 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 in Patients With HER2-Positive Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumors
HER2-positive Breast Cancer
Keywords: Phase 1
Advanced Solid Tumors
HER2 postive
Brain metastases
Herceptin
Perjeta
PHESGO
First Line
1st Line
Lead sponsor: Suzhou Zanrong Pharma Limited
Sponsor class: INDUSTRY
First posted: 2022-10-25
Enrollment: 210
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).

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 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.

Eligibility 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 Phase 1b 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 Phase 1c patients who have no brain metastases, the following criteria should be met:
     1. For arm 1 and arm 2, patients should be refractory to existing therapy(ies), with a history of prior treatment with trastuzumab. For arm3, patients have received a pertuzumab plus trastuzumab or T-DXd for advanced HER2+breast cancer with no evidence of disease progression.
     2. In arms 1 and 2, patients should have at least one measurable lesion either extracranially or intracranially per RECIST v1.1.

     For patients with brain metastasis, the following criteria should be met:
     1. For arm 1 and arm 2 of phase 1b, 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. For arm 1 and arm 2 of phase 1c, patients should be refractory to existing therapy(ies), with a history of prior treatment with trastuzumab. For arm3, patients have received previous treatment with a pertuzumab plus trastuzumab or T-DXd for advanced HER2+ breast cancer with no evidence of disease progression (except brain metastases).
     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.
  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 or T-Dxd based induction.
* 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)

Primary outcomes:
measure: The Incidence of Treatment-Emergent Adverse Events of ZN-A-1041 as a monotherapy in Phase 1a
timeFrame: 23 days
measure: 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
timeFrame: 21 days
measure: RP2D Dose
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Plasma, urine and potentially CSF level of ZN-A-1041 and its main metabolites
timeFrame: From baseline to Cycle 9 (each cycel is 21 days)
measure: Serum level of combination drugs in phase 1c
timeFrame: through study completion, an average of 2 year
measure: Anti-drug antibodies (ADAs) evaluation in Phase 1c
timeFrame: through study completion, an average of 2 year
measure: overall Response Rate (ORR)
timeFrame: through study completion, an average of 2 year
measure: Progression free survival(PFS)
timeFrame: through study completion, an average of 2 year
Other outcomes:
Locations:
city: Tucson
country: United States
facility: ACRC/Arizona Clinical Research Center, Inc
state: Arizona
city: Cerritos
country: United States
facility: TOI Clinical Research
state: California
city: Whittier
country: United States
facility: Innovative Clinical Research Institute
state: California
city: Boston
country: United States
facility: Dana-Farber Cancer Insitute
state: Massachusetts
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer center
state: Michigan
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Houston
country: United States
facility: Md Anderson Cancer center
state: Texas
city: Geelong
country: Australia
facility: Andrew Love Cancer Center
state: Victoria
city: St Albans
country: Australia
facility: Sunshine Hospital - Australia
state: Victoria
city: Lille
country: France
facility: Centre Oscar Lambret - PPDS
state: Nord
city: Lyon
country: France
facility: Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes
city: Toulouse
country: France
facility: Institut Claudius Regaud - PPDS
city: Auckland
country: New Zealand
facility: Auckland City Hospital
city: Barcelona
country: Spain
facility: Instituto Oncologico Dr. Rosell-Hospital Universitari Dexeus-Grupo Quironsalud
city: Barcelona
country: Spain
facility: Instituto de Investigacion Oncologica Vall dHebron (VHIO) - EPON
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Jaén
country: Spain
facility: Hospital Universitario de Jaen
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Manchester
country: United Kingdom
facility: The Christie - PPDS
state: Lancashire
Study officials:
affiliation: Duke Cancer Institute
name: Anders Carey K, MD
role: PRINCIPAL_INVESTIGATOR
References: