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

ENROLLING
Protocol # :
20-683
Conditions
Advanced Solid Tumors
HER2-positive Breast Cancer
Phase
I
Disease Sites
Healthy volunteer
Transplanted organ and tissue status, unspecified
Disease not specified
Neuroendocrine/Carcinoid
Gastroesophageal Junction
Gallbladder/Biliary
Other specified personal risk factors, not elsewhere classified
Lip, Oral Cavity and Pharynx
Esophagus
Stomach
Small Intestine
Colon
Rectum
Anus
Liver
Pancreas
Other Digestive Organ
Larynx
Lung
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Breast
Cervix
Corpus Uteri
Ovary
Other Female Genital
Prostate
Other Male Genital
Urinary Bladder
Kidney
Other Urinary
Eye and Orbit
Brain and Nervous System
Thyroid
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Donors
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Lin, Nancy, U
Site Research Nurses
Bowers, Jordan
Campbell, Margaret
Caradonna, Lisa
Casella, Allison
Cung, Connie
Ficociello, Samantha
Jeon, Maryangel, H.
Jeon, Maryangel, H.
Kasparian, Elizabeth
Kuhlman, Rachel
Loeser, Wendy
Macauley, Colleen
Orechia, Meghan
Patel, Nikita
Roche, Kathleen, A.
Rutter, Morgan

Trial Description

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 Requirements

- 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)

20-683