A Study of U3-1402 in Subjects With Metastatic Breast Cancer

Overview

This study is to evaluate safety and efficacy of an antibody drug conjugate U3-1402 in patients with metastatic breast cancer (MBC) who have received no prior anti-HER2 therapy.

Full Title of Study: “A Phase II Study of U3-1402 in Patients With Metastatic Breast Cancer”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 30, 2023

Detailed Description

U3-1302 is an antibody drug conjugate comprising a recombinant fully human anti HER3 monoclonal antibody linked to a linker containing topoisomerase I inhibitor. This study is a phase II study of U3-1402 in subjects with MBC who have received no prior anti HER2 therapy. The study will be conducted in 2 parts (Part A and Part B). All enrolled subjects in part A will undergo pretreatment biopsies to determine if subjects with particular biomarker expression (ER/PR/HER2/HER3) show preliminary efficacy after an analysis is performed at 24 weeks. Part B will enroll subgroups of subjects that will be defined from part A based on ER/PR/HER2/HER3 expression and will be evaluated for efficacy analysis.

Interventions

  • Drug: U3-1402
    • All subjects will receive 5.6 mg/kg U3-1402 intravenously on day 1 of every 3 weeks

Arms, Groups and Cohorts

  • Experimental: Part A
    • Participants will receive 5.6 mg/kg U3-1402 intravenously on day 1 every 3 weeks. All participants will undergo pre-treatment biopsies. (An archival tissue sample taken within two months of treatment should be provided if it is not medically feasible to provide a pre-treatment biopsy). Up to 60 participants will be enrolled into this arm.
  • Experimental: Part B
    • Participants will receive 5.6 mg/kg U3-1402 intravenously on day 1 every 3 weeks. Part B will enroll additional 20 participants in each subgroup that will be defined from Part A (based on ER/PR/HER2/HER3 expression). A total of up to 60 participants (i.e., maximum of 3 subgroups) will be enrolled in Part B.

Clinical Trial Outcome Measures

Primary Measures

  • Overall response rate (ORR) of single agent U3-1402 in patients with MBC
    • Time Frame: Assessed every 6 weeks for the first 6 months then every 9 weeks thereafter until disease progression or death or up to 33 months.
    • ORR is defined as the proportion of patients with confirmed complete response (CR) or partial response (PR) (i.e., confirmation at least 4 weeks apart) according to RECIST Version 1.1 criteria. Per RECIST V1.1: A CR is defined as disappearance of all target and non-target lesions. A PR is defined as ≥30% decrease in the sum of diameters of target lesions from baseline sum.
  • Proportion of participants without disease progression at 6 month to determine six-months Progression Free survival (PFS-6) rate of single agent U3-1402 in patients with MBC
    • Time Frame: Every 6 weeks after day 1 for the first 6 months
    • PFS-6 is defined as the proportion of participants without disease progression (PD) at six months from the start of study drug according to RECIST version 1.1 criteria. Per RECIST V1.1, a PD is ≥20% increase in target lesions and ≥5mm from smallest sum, appearance of any new lesions, or unequivocal progression of non-target lesions

Secondary Measures

  • Proportion of patients with adverse events to assess the safety and tolerability of U3-1402 in patients with MBC
    • Time Frame: From day 1 until 40 days after end of treatment or up to 33 months
    • Safety is determined by proportion of participants who experience adverse events and serious adverse events when given U3-1402.
  • Determine the median Duration of Response (DOR)
    • Time Frame: Assessed every 6 weeks for the first 6 months then every 9 weeks thereafter until disease progression or death or up to 33 months.
    • Duration of response (DOR) is defined as the duration from the first documented response to the date of disease progression (PD) according to the RECIST V1.1 criteria or death due to any cause. Per RECIST V1.1, a PD is ≥20% increase in target lesions and ≥5mm from smallest sum, appearance of any new lesions, or unequivocal progression of non-target lesions
  • Determine the median progression free survival (PFS)
    • Time Frame: Assessed every 6 weeks for the first 6 months then every 9 weeks thereafter until disease progression or death or up to 33 months
    • Progression Free Survival (PFS) is defined as the time from start of study treatment to the date of the first documented disease progression (PD) according to the RECIST V1.1 criteria or death due to any cause. Per RECIST V1.1, a PD is ≥20% increase in target lesions and ≥5mm from smallest sum, appearance of any new lesions, or unequivocal progression of non-target lesions

Participating in This Clinical Trial

Inclusion Criteria

Patients must meet the following criteria in order to be included in the research study: 1. Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling, or analyses 2. Women and men at least 18 years-of-age at the time of signature of the informed consent form (ICF) 3. Histologically documented locally advanced or metastatic breast cancer 4. Triple-negative breast cancer patients should have received at least 1 but no more than 3 prior lines of chemotherapy in the metastatic setting 5. HR+ breast cancer patients should have received prior treatment with endocrine therapy +CDK 4/6 inhibitor. No limit to prior endocrine therapy regimens but no more than 2 prior chemotherapy regimens in the metastatic setting 6. Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (bone-only disease excluded) 7. Patients who have received radiation or surgery for brain metastases are eligible if therapy was completed ≥4 weeks prior to initiation of study treatment (2 weeks for patients who received palliative radiation therapy), there is no evidence of central nervous system disease progression on a scan or mild neurologic symptoms, and there is no requirement for chronic corticosteroid therapy for the treatment of brain metastases 8. Willingness to undergo pre-treatment biopsy and on-treatment biopsies. Must have a tumor amenable to pre-treatment biopsy (unless archived tissue is available and was obtained within 2 months prior to starting treatment) and on-treatment biopsy (excludes bone lesions and previously irradiated lesions). 9. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1 10. Has adequate organ function within 7 days before the start of study treatment, defined as:

  • Platelet count ≥100 × 10^9/L – Hemoglobin (Hb) ≥9 g/dL (transfusion and/or growth factor support allowed) – Absolute neutrophil count ≥1.5 × 10^9/L – Prothrombin time (PT) and partial thromboplastin time (PTT) ≤1.5 × the upper limit of normal (ULN), except for patients on coumadin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-international normalized ratio (INR) within therapeutic range as deemed appropriate by the Investigator. – Serum creatinine ≤1.5 × ULN, or creatinine clearance ≥ 50 mL/min as calculated using the modified Cockcroft-Gault equation; confirmation of creatinine clearance is only required when creatinine is >1.5 × ULN. – AST/ALT ≤3 × ULN (if liver metastases are present, ≤5 × ULN) – Total bilirubin ≤1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert's syndrome or liver metastases – Serum albumin ≥ 2.5 g/dL 11. Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for at least 7 months following last dose. Male patients must also refrain from donating sperm during their participation in the study. Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry: 1. Treatment with any of the following:

  • Any systemic anti-cancer chemotherapy, small molecule, biologic, hormonal agent, or immune checkpoint inhibitor therapy from a previous treatment regimen or clinical study within 21 days prior to the first dose of U3-1402. – Prior treatment with any HER3 targeting agent – Prior treatment with an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g. DS-8201a, DS-1062a, and DS-7300a) – Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment – Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment – Chloroquine /hydroxychloroquine ≤14 days prior to the first dose of study drug treatment. 2. Patients with HER2-positive breast cancer per ASCO-CAP guidelines 3. Has any hypersensitivity to drug substances or inactive ingredients in drug product. 4. Has any history of ILD (including pulmonary fibrosis or radiation pneumonitis), has clinically significant ILD, or is suspected to have such disease by imaging during screening. If imaging findings are unlikely to indicate a history of pneumonitis, then the Investigator should discuss the considerations with the Medical Monitor about potential enrollment and record the reasoning in the source documentation. 5. Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: 1. any underlying pulmonary disorder (e.g., pulmonary emboli, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion) 2. any autoimmune, connective tissue or inflammatory disorder with pulmonary involvement (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) OR prior pneumonectomy 6. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or baseline at the time of starting study treatment. Note: patients with chronic Grade 2 toxicities who are asymptomatic or adequately managed with stable medication may be eligible with approval by the Medical Monitor. 7. Leptomeningeal metastases or spinal cord compression due to disease 8. Women who are pregnant, nursing, or plan to become pregnant while in the study and for at least 7 months after the last administration of study treatment 9. Men who plan to father a child while in the study and for at least 7 months after the last administration of study treatment 10. Any of the following cardiac criteria currently or within the last 6 months: – Mean resting corrected QT interval using Fridericia's formula (QTcF) prolongation to >470 ms for females and >450 ms for males in three successive screening measurements – Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third-degree heart block – Congestive heart failure (New York Heart Association ≥ Grade 2 [Appendix D]) – Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age – Patients with a left ventricular ejection fraction (LVEF) <50% 11. Has known clinically significant corneal disease from prior therapies such as drug-induced keratitis 12. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding diatheses, or active infection, including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required. 13. Presence of other active invasive cancers other than the one treated in this study within 3 years prior to screening, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix, or other local tumors considered cured by local treatment 14. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • SCRI Development Innovations, LLC
  • Collaborator
    • Daiichi Sankyo, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Erika Hamilton, MD, Study Chair, SCRI Development Innovations, LLC
  • Overall Contact(s)
    • Sarah Cannon Development Innovations, LLC, 8447106157, CANN.InnovationsMedical@sarahcannon.com

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