A Dose-escalation Study of ARX788, IV Administered in Subjects With Advanced Cancers With HER2 Expression

A Phase 1, Multicenter, Open-label, Multiple Dose-escalation Study of ARX788, Intravenously Administered as a Single Agent in Subjects With Advanced Cancers With HER2 Expression

This is a 2-part, Phase 1 FIH study with Phase 1a designed to determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) in subjects with metastatic cancers with a human epidermal growth factor receptor 2 (HER2) test result that is in situ hybridization (ISH) positive (+) or immunohistochemistry (IHC) 3+ or 2+, and Phase 1b designed to assess anticancer activity and safety in three expansion cohorts: two different advanced breast cancer expansion cohorts (namely, for tumors that test as HER2 ISH positive or IHC3+ and for tumors that test as HER2 ISH negative with IHC 2+), and one advanced gastric cancer expansion cohort (for tumors that test as HER2 ISH positive or IHC3+).

Study Overview

• Status: Terminated
• Conditions: Stomach Neoplasms; Breast Neoplasms
• Intervention / Treatment: Drug: ARX788

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Mater Adult Hospital
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Richmond, Victoria, Australia, 3121
      • Epworth Healthcare
• New Zealand
  • Christchurch, New Zealand, 8140
    • Christchurch Hospital
  • Auckland
    • Grafton, Auckland, New Zealand, 1023
      • Auckland City Hospital
  • Wellington
    • Newtown, Wellington, New Zealand, 6022
      • Wellington Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Life expectancy >12 weeks.
2. BMI is between 18 to 32 kg/m2
3. Subjects whose advanced cancer has failed treatment or whose cancer has progressed following available standard therapy or for whom such therapy is not acceptable to the subject. Subjects whose tumor tissue local laboratory results are HER2 ISH positive or IHC3+ must have been previously treated with a HER2 targeting therapy (e.g. trastuzumab, in the country or region where such therapies are available and part of standard of care), or have failed SOC therapy. Subjects who have been previously treated with a HER2 targeting therapy such as trastuzumab or ado-trastuzumab emtansine are eligible.
4. Disease measurability: Phase 1a: measureable or non-measureable disease; Phase 1b: disease must be measureable (per RECIST v1.1) (subjects with non-measureable disease are not eligible for Phase 1b).
5. Histopathologic evidence of breast cancer based upon pathologist's report.
6. Tumor tissue local laboratory HER2 testing results (clinical pathology report) based on FDA or other regulatory agency approved, validated or commercially available IHC or ISH HER2 assay. Pre-screening for HER2 is allowed only for subjects with breast and gastric cancer, where applicable. Subjects with other types of cancer must have previously tested for HER2 status by HER2 IHC or ISH assay. 1) Phase 1a: ISH positive or IHC 2+ or 3+. 2) Phase 1b: Cohort 1: advanced breast cancer, ISH positive or IHC 3+; Cohort 2: advanced breast cancer, ISH negative with IHC 2+; and Cohort 3: advanced gastric cancer, ISH positive or IHC 3+.
7. Local pathology laboratory determination of HER2 status will be accepted, provided that the local laboratory is an accredited site for HER2 testing. In Phase 1b, if the local laboratory was not accredited at the time of testing, an adequate tumor tissue sample is required for central pathology laboratory HER2 testing. The tissue sample may be provided as 10 pre-cut unstained slides or a tumor block.
8. Eastern Cooperative Oncology Group Performance Status of 0 to 1.
9. 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.
10. The last dose of prior anticancer therapy must have been administered at least 28 days prior to the first dose of the IMP.
11. Adequate bone marrow function defined by absolute neutrophil count of ≥1.5×109/L, platelet count of ≥100.0×109/L, and hemoglobin of ≥9.0 g/dL.
12. Adequate hepatic function defined by serum total bilirubin ≤1.5 × upper limit of normal (ULN), aspartate aminotransferase/alanine aminotransferase ≤2.5 × ULN (or ≤5 × ULN in subjects with liver metastases).
13. Adequate renal function assessed by serum creatinine within reference lab normal limits and creatinine clearance (by Chronic Kidney Disease Epidemiology [CKD-EPI] Collaboration equation) ≥60 mL/min.
14. Adequate cardiac function as assessed by cardiac troponin I within normal range; left ventricular ejection fraction ≥ 50% or institutional lower limit of normal; cumulative anthracycline dose <360 mg/m2 doxorubicin or equivalent.
15. Willing and able to understand and sign an informed consent inform and to comply with all aspects of the protocol.
16. 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.
17. 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: Any subject who meets any of the following criteria should be excluded from the study:

1. History of allergic reactions to any component of the ARX788.
2. 2. History of seizure disorder.
3. History of unstable central nervous system (CNS) metastases or seizure disorder related to the malignancy; however, those subjects who were treated for prior CNS metastases and who are asymptomatic may participate in the study as long as they are not receiving treatment with steroids.
4. History of congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia.
5. Grade 2 to 4 peripheral neuropathy (NCI CTCAE v 4.03).
6. Non-manageable electrolyte imbalances including hypokalemia, hypocalcemia, or hypomagnesemia (Grade 2 or greater based on NCI CTCAE v 4.03).
7. Any uncontrollable intercurrent illness, infection, or other conditions that could limit study compliance or interfere with assessments.
8. Exposure to any other investigational or commercial anticancer agents or therapies administered with the intention to treat malignancy within 28 days before the first dose of the IMP.
9. Significant surgical intervention within 21 days of the first dose of the IMP or with ongoing post-operative complications if more than 21 days.
10. Radiotherapy administrated less than 21 days prior to the first dose of the IMP, or localized palliative radiotherapy administered less than 7 days prior to the first dose of the IMP, or radiotherapy induced toxicity of Grade 2 or greater based on NCI CTCAE v 4.03.
11. Pregnancy or breast feeding.
12. Refusal to use effective methods of contraception (see inclusion criteria for details).
13. Legal incapacity/limited legal capacity for providing informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a: Dose-Escalation; Six cohorts with escalated dose levels of ARX788 at 0.33 mg/kg, 0.66 mg/kg, 1.3 mg/kg, 2.2 mg/kg, 2.9 mg/kg and 3.8 mg/kg will be administered every 3 weeks via intravenous infusion to determine the MTD.	Drug: ARX788; ARX788, an antibody drug conjugate
Experimental: Phase 1b: Dose-evaluation 1; Breast cancer subjects with high HER2 expression, categorized as ISH positive or IHC3+, will be administered with ARX788 at MTD every 3 weeks via intravenous infusion.	Drug: ARX788; ARX788, an antibody drug conjugate
Experimental: Phase 1b: Dose-evaluation 2; Breast cancer subjects with mid/low HER2 expression, categorized as ISH negative AND IHC2+, will be administered with ARX788 at MTD every 3 weeks via intravenous infusion.	Drug: ARX788; ARX788, an antibody drug conjugate
Experimental: Phase 1b: Dose-evaluation 3; Gastric cancer subjects with high HER2 expression, categorized as ISH positive or IHC3+, will be administered with ARX788 at MTD every 3 weeks via intravenous infusion.	Drug: ARX788; ARX788, an antibody drug conjugate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose of ARX788	Determine highest dose level at which less than 2 of 6 subjects experience a dose limiting toxicity.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with Adverse Events	Safety and tolerability of ARX788 as measured by all adverse events, hematology, blood chemistry, vital signs, electrocardiogram, and physical exam.	30 months
Area under the plasma concentration versus time curve (AUC) of ARX788 after infusion	Pharmakokinetic characteristics of ARX788 for infusion Cycle 1 and Cycle 3	30 months
Half-life of ARX788 after infusion	Pharmakokinetic characteristics of ARX788 for infusion Cycle 1 and Cycle 3	30 months
Number of participants with tumor response to ARX788 administration		18 months
Number of subjects developed anti-ARX788 antibody	Immunogenicity profile assessment	30 months

Collaborators and Investigators

• Sponsor: Zhejiang Medicine Co., Ltd.
• Collaborators: Ambrx, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: June 22, 2015
• First Submitted That Met QC Criteria: July 29, 2015
• First Posted (Estimate): July 30, 2015

Study Record Updates

• Last Update Posted (Actual): June 5, 2020
• Last Update Submitted That Met QC Criteria: June 3, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: breast cancer; HER2; ADC; antibody drug conjugate; elevated HER2 expression
• Additional Relevant MeSH Terms: Digestive System Diseases; Skin Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Breast Diseases; Neoplasms; Stomach Neoplasms; Breast Neoplasms
• Other Study ID Numbers: ZMC-ARX788-101; Universal Trial Number (UTN) (Other Identifier: U1111-1261-1912)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No