Metastatic Breast Cancer Resistant or Refractory MedDRA version: 20.0 Level: LLT Classification code 10027475 Term: Metastatic breast cancer System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.1 Level: PT Classification code 10055113 Term: Breast cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Sponsors
Ambrx, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years 2. Life expectancy > 3 months. 3. ECOG Performance Status = 1 4. Metastatic breast cancer subjected previously treated with T-DM1, and/or T-DXd, and/or tucatinib-containing regimens. Subjects must have been previously treated with one (or more) of these regimens to be eligible. Subjects must have been treated with trastuzumab plus taxane. Subjects who received prior pertuzumab, lapatinib, neratinib, margetuximab, and/or other available and accessible HER2-directed therapies or investigational therapies are eligible. 5. Presence of at least one measurable lesion per RECIST v 1.1 as determined by BICR. 6. A tumor block or formalin-fixed paraffin-embedded (FFPE) tissue from tumor biopsies as 10 pre-cut unstained slides must be collected for the HER2 status evaluation and biomarker analysis based on most recent tumor tissue sample. If insufficient tissue, a fresh tumor biopsy must be collected. All tumor tissue (including the pathology report and methods of pathology laboratory's tissue preparation/testing) needs to be sourced for central laboratory for HER2 testing. 7. Central laboratory-confirmed HER2-positive expression (estrogen receptor/progesterone receptor positive subjects may be enrolled if they are HER2-positive) according to 2018 American Society of Clinical Oncology – College of American Pathologists (ASCO-CAP) guidelines. See Laboratory Manual for details. 8. Subjects whose brain metastases have been treated may participate provided they show radiographic stability (defined as 1 brain MR image, obtained at least four weeks after treatment to the brain metastases, shows no evidence of intracranial progression). In addition, any neurologic symptoms (including seizures) that developed either as a result of the brain metastases or their treatment must have returned to baseline or resolved. Any steroids administered as part of this therapy must be completed at least three days prior to study medication. After approximately 20 such subjects [20% of the first 100 subjects] have been enrolled, subsequent subjects with any current or past history of brain metastases will be excluded. 9. Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved to Grade 0 or 1 as per the NCI-CTCAE v 5.0, except alopecia. 10. 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. 11. Adequate hepatic function, as defined by serum total bilirubin = 1.5 × ULN, serum aspartate aminotransferase and alanine aminotransferase = 2.5 × ULN. Subjects with known hepatic metastases or primary biliary cancer may have serum total bilirubin = 3.5 × ULN and transaminases = 5 × ULN. 12. Adequate renal function, defined as creatinine clearance = 30 mL/min, as calculated using the Cockcroft Gault equation: ([{140 -age in years} × {actual weight in kg}] divided by [{72 × serum creatinine in mg/dL} multiplied by 0.85 if female]). 13. Adequate cardiac function as assessed by left ventricular ejection fraction = 50% or institutional lower limit of normal; cumulative anthracycline dose < 360 mg/m2 doxorubicin or equivalent. 14. Willing and able to understand and sign an informed consent inform and to comply with all aspects of the protocol. 15. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and
Exclusion criteria
Exclusion criteria: 1. History of allergic reactions to any component of ARX788. 2. Prior history of interstitial lung disease, pneumonitis, or other clinically significant lung disease within 12 months prior to screening, with the exception of that directly attributable to the presence of lung metastases from their underlying cancer. Subjects with significant treatment-related lung injury, defined as any of the following, will be excluded: a) Any prior history of drug-induced immune-mediated pneumonitis. b) Prior history of radiation therapy to the chest of > 18 Gy with residual sequelae considered clinically significant by Investigator assessment. c) Radiographic evidence of radiation fibrosis involving > 15% of the lung parenchyma associated with clinical symptoms. 3. Any active ocular infections until resolved or any chronic corneal disorder unless approved by Medical Monitor. Keratopathy of grade =1 due to prior treatment with anti-HER2 ADC or chemotherapy are allowed. 4. History of congestive heart failure, unstable angina pectoris, unstable atrial fibrillation, or cardiac arrhythmia within 12 months prior to enrollment. Medical history of myocardial infarction within 6 months prior to enrollment. Baseline QTc, averaged over 3 screening ECGs must be = 470 msec (females) or = 450 msec (males). 5. Grade 3 to 4 peripheral neuropathy (NCI-CTCAE v 5.0). Patients with Grade 2 neuropathy can be enrolled at investigator’s discretion. 6. Non-manageable electrolyte imbalances including hypokalemia, hypocalcemia, or hypomagnesemia (Grade 2 or greater based on NCI-CTCAE v 5.0). 7. 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. 8. Exposure to any other investigational or commercial anticancer agents or therapies administered with the intention to treat malignancy within 2814 days before the first dose of ARX788. Anti-hormonal therapy may be administered up to 7 days prior to the first dose of ARX788. 9. Major surgical intervention within 21 days of the first dose of ARX788 or with ongoing post-operative complications. 10. 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. 11. Pregnant or breast feeding. 12. Known active HCV, HBV, and/or HIV infection. HIV test is not required for the screening, unless required by the local Health Authorities.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The confirmed objective response rate (ORR) of ARX788 by blinded independent central review (BICR) based on RECIST v1.1 in subjects with metastatic HER2-positive breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens.;Secondary Objective: - To evaluate duration of response (DOR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) - To evaluate the safety, tolerability, and immunogenicity profile of ARX788 - To determine the pharmacokinetics (PK) of ARX788, total anti-HER2 antibody, and pAF-AS269;Primary end point(s): Objective response rate (ORR) by blinded independent central review (BICR).;Timepoint(s) of evaluation of this end point: Monitored throughout the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - Efficacy: Anticancer activity of ARX788, including: o Duration of response (DOR) o Best overall response (BOR) (CR, PR, SD, or progressive disease) o Disease control rate o Progression-free survival (PFS) o Overall survival (OS) - Safety: The safety, tolerability, and immunogenicity profile assessed by AE, vital signs, ECG, LVEF, clinical laboratory tests, ADA assays, physical examination, medical history and prior and concomitant medication, and where applicable, changes from baseline . - Pharmacokinetics: Serum concentrations of ARX788, total antibody, and metabolite pAF-AS269 will. PK and PDx characteristics of ARX788 and its major metabolites - Immunogenicity: Presence of ADA and neutralizing ADA and their potential impact on the PK, efficacy, and safety of ARX788.;Timepoint(s) of evaluation of this end point: Monitored throughout the study | — |
Countries
Australia, Belgium, Brazil, Canada, Czechia, France, Germany, Hong Kong, Italy, Korea, Republic of, Portugal, Spain, Switzerland, Taiwan, United States
Contacts
Public ContactClinical Trial Information Desk
Ambrx, Inc.
Outcome results
None listed