A Dose-escalation, Expansion Study of ARX788, in Advanced Solid Tumors Subjects With HER2 Expression (ACE-Pan Tumor 01)

This 2-part, Phase 1, open-label study will determine the recommended Phase 2 dose (RP2D) of ARX788 in subjects with advanced HER2 positive cancers and will assess the safety and anticancer activity in breast, gastric and other advanced HER2 positive solid tumors.

Phase 1a will determine the recommended Phase 2 dose (RP2D) in subjects with advanced cancer whose HER2 test results are in situ hybridization (ISH) positive or immunohistochemistry (IHC) 3+, based on safety, tolerability, PK findings and antitumor activity. Phase 1b will assess the safety, tolerability, and PK and anticancer activity in five expansion cohorts, including breast cancer, gastric cancer / gastroesophageal adenocarcinoma, and other advanced HER2-positive solid tumors.

Eligibility Criteria:
Inclusion Criteria:

* Age \>18 years
* Life expectancy \>3 months.
* Female or male subjects whose advanced HER2 expressing cancer has failed standard of care treatments, or for whom such therapy is not acceptable to the subject. Subjects with advanced breast, gastric cancer, or other solid tumor who test positive for HER2 by ASCO/CAP criteria (either IHC or FISH) must have received prior treatment with a trastuzumab containing therapy. Subjects who have been previously treated with pertuzumab, TDM-1, lapatinib, or other available and accessible HER2-directed therapies or investigational therapies are eligible.
* Disease measurability:

  * Phase 1a: measurable or non-measurable disease per RECIST v 1.1.
  * Phase 1b: measurable disease per RECIST v 1.1 (subjects with non-measurable disease are not eligible for Phase 1b).
* Histopathologic evidence of cancer based upon pathology report.
* Tumor tissue local laboratory HER2 testing results, adequate tumor sample available for confirmation of HER2 status. Subjects with other types of cancer must have previously tested locally for HER2 status by HER2 IHC or ISH assay.

  * Phase 1a: ISH positive or IHC 3+ advanced cancer (including breast or gastric/esophageal or other solid tumors).
  * Phase 1b: Cohort 8 advanced breast cancer (IHC 3+ or IHC 2+/ISH); Cohort 9 advanced breast cancer (IHC 2+ / ISH-); Cohort 10 advanced gastric cancer (IHC 3+ or IHC 2+/ISH+) or gastroesophageal junction adenocarcinoma; Cohort 11 other advanced solid tumor cancers with HER2-overexpression (HER2 IHC 3+ or IHC 2+/IHS+); Cohort 12 advanced solid tumor cancers with HER2 activating mutation.
* Eastern Cooperative Oncology Group Performance Status of 0 to 1.
* Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 1 as per the NCI-CTCAE v 4.03 (phase 1a) and v 5.0 ( Phase 1b).
* Adequate organ functions.
* Willing and able to understand and sign an informed consent inform and to comply with all aspects of the protocol.
* Female subjects must be surgically sterile, or have a monogamous partner who is surgically sterile, or at least 2 years postmenopausal, or who commits to use an acceptable form of birth control (defined as the use of an intrauterine device, a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 3 months following the last dose of study treatment.
* Male subjects must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study.

Exclusion Criteria:

* History of allergic reactions to any component of ARX788.
* History of ocular events, or any current ongoing active ocular infections.
* History of congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia within 12 months prior to enrollment
* Grade 2 to 4 peripheral neuropathy (NCI CTCAE v 5.0)
* History of unstable central nervous system (CNS) metastases
* Current severe, uncontrolled systemic disease (eg, clinical significant cardiovascular, pulmonary, or metabolic diseases)
* Any uncontrollable intercurrent illness, infection (including subjects with active, symptomatic Covid-19 infections), or other conditions that could limit study compliance or interfere with assessments.
* Exposure to any other investigational or commercial anticancer agents or therapies administered with the intention to treat malignancy within 14 days before the first dose of ARX788.
* Clinically significant surgical intervention (excluding diagnostic biopsy) within 21 days of the first dose of ARX788
* Radiotherapy administered less than 21 days prior to the first dose of ARX788, or localized palliative radiotherapy administered less than 7 days prior to the first dose of ARX788, or radiotherapy-induced toxicity of Grade 2 or greater based on NCI-CTCAE v 5.0.
* Pregnancy or breast feeding.
* Known active HCV, HBV, and/or HIV infection.