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

Open to people ages 18 years and up

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.

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)