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

• ClinicalTrials.gov Identifier: NCT03255070
• Recruitment Status: Recruiting
• First Posted: August 21, 2017
• Last Update Posted: March 14, 2018
• Sponsor: Ambrx, Inc.
• Information provided by (Responsible Party): Ambrx, Inc.

Study Description

Brief Summary:

This is a 2-part, Phase 1, open-label study. Phase 1a of this study is designed to 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+ and Phase 1b is designed to assess anticancer activity and safety in 2 advanced breast cancer expansion cohorts: 1) for tumors that test as HER2 ISH positive or IHC3+ and, 2) for tumors that test as HER2 ISH negative with IHC 2+.

Condition or disease	Intervention/treatment	Phase
Breast Neoplasms; Stomach Neoplasm	Drug: ARX788	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

This is a 2-part, Phase 1, open-label study. Phase 1a is designed to 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+.

The IMP, ARX788, will be administered every 3 weeks or every 4 weeks via IV infusion. Five sequential dose escalation cohorts are planned. Cohort 1 and Cohort 2 will each enroll 3 subjects following a 3+3 design with possible expansion to 6 subjects as determined by the Safety Monitoring Committee based on dose-limiting toxicity assessment and comprehensive reviews of safety, tolerability and PK data. Cohort 3, Cohort 4 and Optional Cohort 5 will enroll 6 subjects each without planned expansion.

Phase 1b is designed to investigate the RP2D, from Phase 1a, to assess anticancer activity and safety in 2 advanced breast cancer expansion cohorts: 1) tested tumors HER2 ISH positive or IHC 3+ and 2) tested tumors HER2 ISH negative with IHC 2+.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Estimated Study Start Date: March 12, 2018
• Estimated Primary Completion Date: August 2020
• Estimated Study Completion Date: August 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1a: Cohort 1; Cohort 1 will administer Dose Level 1 of ARX788 every 4 weeks (Q4W) via intravenous infusion.	Drug: ARX788; An antibody drug conjugate
Experimental: Phase 1a: Cohort 2; Cohort 1 will administer Dose Level 1 of ARX788 every 3 weeks (Q3W) via intravenous infusion.	Drug: ARX788; An antibody drug conjugate
Experimental: Phase 1a: Cohort 3; Cohort 3 will administer Dose Level 2 of ARX788 every 4 weeks (Q4W) via intravenous infusion.	Drug: ARX788; An antibody drug conjugate
Experimental: Phase 1a: Cohort 4; Cohort 4 will administer Dose Level 2 of ARX788 every 3 weeks (Q3W) via intravenous infusion.	Drug: ARX788; An antibody drug conjugate
Experimental: Phase 1a: Optional Cohort 5 Q3W; Cohort 5 may administer Dose Level 3 of ARX788 every 3 weeks (Q3W) via intravenous infusion.	Drug: ARX788; An antibody drug conjugate

Outcome Measures

Primary Outcome Measures :

1. Number of subjects experiencing adverse events, frequency and seriousness of treatment emergent adverse events (TEAEs) [ Time Frame: Day 1 through 30 days after last dose ]
2. Phase 1b: Objective response rate (ORR: complete response + partial response) per imaging assessment based on RECIST version 1.1. [ Time Frame: 18 months ]
   Number of subjects with objective response is assessed every 6-8 weeks from Cycle 1 Day 1 through disease progression.

Secondary Outcome Measures :

1. Number of subjects with tumor response per imaging assessment based on RECIST version 1.1. [ Time Frame: 18 months ]
2. Area under the concentration-time curve (AUC) from first infusion to subject end of study. [ Time Frame: 18 months ]
   Pharmacokinetic (PK) characteristics: ARX788 (intact ADC), total mAb, and metabolites
3. Half-life of ARX788 from first infusion to end of study. [ Time Frame: 18 months ]
   Pharmacokinetic (PK) characteristics: ARX788 from first infusion to subject end of study
4. Immunogenicity profile of ARX788 [ Time Frame: 18 months ]
   Number of subjects who develop anti-ARX788 antibody

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Age >18 years and ≤75 years.
• Life expectancy >12 weeks.
• BMI 18 to 32 kg/m2.
• 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 and gastric cancer 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 pathologist's report.

• 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, GE junction or esophageal cancer, where applicable. Subjects with other types of cancer must have previously tested 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 1: advanced breast cancer, ISH positive or IHC 3+.
• Cohort 2: advanced breast cancer, ISH negative with IHC 2+.
• 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.
• 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.
• 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.
• 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 the IMP.
• History of interstitial lung disease, pneumonitis or other clinically significant lung diseases.
• Any CT imaging findings indicating radiation or drug-induced lung disorders at the time of screening
• Any known clinically significant prior radiation to the chest area that included lung parenchyma.
• History of ocular events related to keratitis or corneal disorders, or any current ongoing active ocular infections.
• History of seizure disorder.
• 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.
• History of congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia.
• Grade 2 to 4 peripheral neuropathy (NCI CTCAE v 4.03).
• Non-manageable electrolyte imbalances including hypokalemia, hypocalcemia, or hypomagnesemia (Grade 2 or greater based on NCI-CTCAE v 4.03).
• Any uncontrollable intercurrent illness, infection, 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 28 days before the first dose of the IMP. Hormonal therapy may be administered up to 7 days prior to the first dose of the IMP.
• Clinically significant surgical intervention within 21 days of the first dose of the IMP or with ongoing post-operative complications if more than 21 days.
• Radiotherapy administered 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.
• Pregnancy or breast feeding.
• Refusal to use effective methods of contraception (see inclusion criteria for details).
• Legal incapacity/limited legal capacity for providing informed consent.
• Known active HCV, HBV, and/or HIV infection.

Contacts and Locations

Contacts

Contact: Yong Jiang Hei, MD, PhD; 858-875-2400; yong.hei@ambrx.com

Locations

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Australia, Queensland

Mater Misericordiae Limited; Recruiting

South Brisbane, Queensland, Australia, 4101

Australia, Victoria

Monash Health; Recruiting

Clayton, Victoria, Australia, 3168

Sponsors and Collaborators

Ambrx, Inc.

More Information

• Responsible Party: Ambrx, Inc.
• ClinicalTrials.gov Identifier: NCT03255070
• Other Study ID Numbers: ARX788-1711
• First Posted: August 21, 2017
• Last Update Posted: March 14, 2018
• Last Verified: August 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ambrx, Inc.:

HER2; Breast Cancer; ADC; antibody drug conjugate; elevated HER2 expression; breast neoplasm; stomach neoplasm; gastrointestinal neoplasm; digestive system; breast diseases; digestive system neoplasm; digestive system diseases; stomach diseases

Additional relevant MeSH terms:

Breast Neoplasms; Stomach Neoplasms; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs