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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Phase 1, Multicenter, Open-label, Multiple Dose-escalation and Expansion Study of ARX788, as Monotherapy in Advanced Solid Tumors With HER2 Expression

Conditions
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Breast Neoplasms, Gastric Neoplasm, Solid Tumors

Intervention / Treatment
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* Drug: ARX788


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: This is a 2-part, Phase 1, open-label study will administer the IMP, ARX788 by IV infusion every 3, 4 or 6 weeks. Sequential dose escalation cohorts are planned using a 3+3 design. A cohort may be expanded to collect additional data if recommended by Safety Monitoring Committee based on comprehensive reviews of safety, tolerability and PK data to determine RP2D. 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+. Phase 1b will assess anticancer activity and safety in advanced cancer.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARX788 Phase 1a (Dose Escalation)<br>ARX788 will be administered every 3 weeks (Q3W) or every 4 weeks (Q4W) via intravenous (IV) infusion. Patients will be enrolled into escalating dose levels during Dose Escalation period. | Drug: ARX788<br>* An antibody drug conjugate<br>* Other names: antibody drug conjugate (ADC);|
| Experimental: ARX788 Phase 1b (Dose Expansion)<br>ARX788 will be administered every 3 weeks (Q3W) via intravenous (IV) infusion. Patients will receive the maximum tolerated dose during the Dose Expansion period of the study. | Drug: ARX788<br>* An antibody drug conjugate<br>* Other names: antibody drug conjugate (ADC);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects experiencing adverse events, frequency and seriousness of treatment emergent adverse events (TEAEs) | To assess the safety, tolerability, and immunogenicity profile | Day 1 through 30 days after last dose | 
| Phase 1b: Objective response rate (ORR: complete response + partial response) per imaging assessment based on RECIST version 1.1. | Number of subjects with objective response is assessed every 6-8 weeks from Cycle 1 Day 1 through disease progression. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with tumor response per imaging assessment based on RECIST version 1.1. | The objective response rate (ORR: CR+PR) based on RECIST v1.1 will be assessed as the primary endpoint to determine the anticancer activity of ARX788 as well as best overall response. | 18 months | 
| Area under the concentration-time curve (AUC) from first infusion to subject end of study. | Pharmacokinetic (PK) characteristics: ARX788 (intact ADC), total mAb, and metabolites | 36 months | 
| Half-life of ARX788 from first infusion to end of study. | Pharmacokinetic (PK) characteristics: ARX788 from first infusion to subject end of study | 36 months | 
| Immunogenicity profile of ARX788 | Number of subjects who develop anti-ARX788 antibody | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, antibody drug conjugate, breast cancer, gastric cancer, advanced solid tumors, HER2-overexpression, HER2-mutations