A Window-of-opportunity Study of U3-1402, a HER3-targeting Antibody-drug Conjugate in Operable Breast Cancer According to ERBB3 Expression

Last updated: June 21, 2023
Sponsor: SOLTI Breast Cancer Research Group
Overall Status: Active - Not Recruiting

Phase

1

Condition

Breast Cancer

Cancer

Treatment

U3 1402

Clinical Study ID

NCT04610528
SOLTI-1805
2019-004964-23
  • Ages > 18
  • All Genders

Study Summary

This is a prospective, multicenter, single arm, window-of-opportunity study evaluating the biological effect of U3-1402 in treatment naïve patients with early breast cancer, whose primary tumors are ≥1 cm by ultrasound evaluation.

The primary objective is to evaluate the biological activity of U3-1402, measured as the CelTIL score increase at post-treatment (C1D21) in HR+/HER2-negative BC included patients.

The study will consist of 2 parts enrolling ~115 patients.

  • Part A will target to treat, with 6.4 mg/kg dose, 80 patients with HR-positive/HER2-negative tumors and

  • Part B will target to treat with 5.6 mg/kg dose 20 patients with HR-positive/HER2-negative and 15 patients with TNBC tumors

Part A will test U3-1402 in patients with HR-positive/HER2-negative early breast cancer with a dose of 6.4 mg/kg. Part B will consist in testing 5.6 mg/kg dose of U3-1402 in patients with HR-positive/HER2-negative early breast cancer and in triple-negative early breast cancer and will be performed sequentially after Part A.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  1. Written ICF for all study procedures according to local regulatory requirements priorto beginning specific protocol procedures.
  2. Premenopausal or postmenopausal women and men, age ≥ 18 years.
  3. ECOG Performance Status 0 - 1.
  4. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breastuntreated and recently diagnosed, with all the following characteristics:
  • At least one lesion that can be measured in at least 1 dimension with ≥ 1 cm inlargest diameter measured by ultrasound.
  • Absence of distant metastasis (M0) as determined by institutional practice.
  • In the case of a multifocal tumor (defined as the presence of two or more foci ofcancer within the same breast quadrant), the largest lesion must be ≥ 1 cm anddesignated the "target" lesion for all subsequent tumor evaluations and biopsies.
  1. Patient must have biopsiable disease.
  2. Only for HR+/HER2-negative patients: Estrogen (ER)-positive and/or Progesterone (PgR)-positive and HER2-negative tumor by the most recent American Society of ClinicalOncology - College of American Pathologists (ASCO-CAP) guidelines: ER and PgR definedas IHC nuclear staining ≥1% and HER2 negative locally assessed. Only for TNBCpatients: Estrogen (ER)-negative and Progesterone (PgR)-negative and HER2-negativetumor by the most recent American Society of Clinical Oncology - College of AmericanPathologists (ASCO-CAP) guidelines: ER and PgR defined as IHC nuclear staining <1% andHER2 negative locally assessed
  3. Ki67% ≥ 10% locally assessed (Dowsset et al. Journal of the National Cancer Institute, 103 (22), 1656-1664. 2011).
  4. Available pre-treatment FFPE core needle biopsy evaluable for PAM50 and ERBB3 mRNAexpression. Minimal sample requirements are to have at least 2 tumor cylinders with aminimal tissue surface of 10 mm2 tissue, containing at least 50% tumor cells andhaving enough tissue to do at least 20 cuts of 4 μm each. Macrodissection is allowedwhen needed. If archival tissue is either insufficient or unavailable, a new biopsyfrom the pretreated tumor must be obtained. Patients whose tumor tissue is notevaluable for ERBB3 expression central testing are not eligible.
  5. Baseline LVEF ≥ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
  6. Adequate organ function, as determined by the following laboratory tests prior torandomization:
  • Hematological
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Platelet count ≥ 100 x 109/L
  • Hemoglobin ≥ 9 g/dL (red blood cell transfusion and/or erythropoietinallowed)
  • Renal o Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or 24-hour creatinineclearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note:Creatinine clearance does not need to be determined if the baseline serumcreatinine is within normal limits. Creatinine clearance should be calculated perinstitutional standard).
  • Hepatic
  • Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject withtotal bilirubin level > 1.5 x ULN
  • Aspartate aminotransferase (AST) ≤ 3 x ULN
  • Alanine aminotransferase (ALT) ≤ 3 x ULN
  • Coagulation International normalization ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN
  • Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN
  1. Absence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule; thoseconditions should be discussed with the patient before registration in the trial.
  2. Female subject of childbearing potential should have a negative urine or serumpregnancy test within 7 days prior to enrollment. If urine pregnancy test is positiveor cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancytesting does not need to be pursued in patients who are judged as postmenopausalbefore randomization, as determined by local practice, or who have undergone bilateraloophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearingpotential randomized to the treatment must use adequate contraception for the durationof protocol treatment and after 7 months after the study drug administration (seeAppendix B).

Exclusion

Exclusion Criteria:

  1. Inoperable locally advanced or inflammatory (i.e., inoperable Stage III) breastcancer.
  2. Metastatic (Stage IV) breast cancer.
  3. Bilateral invasive breast cancer.
  4. Patients in whom a primary tumor excisional biopsy was performed.
  5. Any prior treatment for primary actual invasive breast cancer.
  6. Prior treatment with a HER3 antibody, topoisomerase I inhibitor, with an ADC whichconsists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., DS-8201)and with a govitecan derivative (e.g., IMMU-132).
  7. Medical history of symptomatic congestive heart failure (New York Heart Associationclasses II-IV) or serious cardiac arrhythmia requiring treatment; myocardialinfarction within 6 months prior to randomization or unstable angina.
  8. QT interval corrected using Fridericia's formula to > 450 millisecond (ms) in malesand > 470 ms in females.
  9. Any factors that increase the risk of corrected QT (QTc) interval prolongation or riskof arrhythmic events, such as congenital long QT syndrome, family history of long QTsyndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
  10. Medical history of clinically significant lung diseases (e.g., interstitial pneumonia,pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who aresuspected to have these diseases by imaging at screening period.
  11. Clinically significant corneal disease.
  12. Major surgical procedure or significant traumatic injury within 28 days prior torandomization.
  13. Assessment by the investigator to be unable or unwilling to comply with therequirements of the protocol.
  14. History of other malignancy within the last 3 years, except for appropriately treatedcarcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer,or other malignancies with an expected curative outcome.
  15. Current severe, uncontrolled systemic disease (e.g. clinically significantcardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bonefractures).
  16. Concurrent, serious, uncontrolled infections or current known infection with HIV oractive hepatitis B and/or hepatitis C.
  17. History of significant co-morbidities that, in the judgment of the investigator, mayinterfere with the conduction of the study, the evaluation of response, or with ICF.
  18. Known hypersensitivity to either the drug substance components (including an antibody,a drug-linker, or a topoisomerase I inhibitor) or inactive ingredients in the drugproduct or history of severe hypersensitivity reactions to other monoclonalantibodies.
  19. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnessesincluding, but not limited to, any underlying pulmonary disorder (i.e. pulmonaryemboli within three months of the study enrollment, severe asthma, severe COPD,restrictive lung disease, pleural effusion etc.), and any autoimmune, connectivetissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoidarthritis, Sjögren's syndrome, sarcoidosis etc.), or prior pneumonectomy.
  20. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common TerminologyCriteria for Adverse Events (NCI-CTCAE) version 5.0, grade ≤1 or baseline. Subjectswith chronic grade 2 toxicities may be eligible per the discretion of theInvestigator.

Study Design

Total Participants: 80
Treatment Group(s): 1
Primary Treatment: U3 1402
Phase: 1
Study Start date:
December 22, 2020
Estimated Completion Date:
September 30, 2023

Connect with a study center

  • ICO Badalona

    Badalona, Barcelona
    Spain

    Site Not Available

  • Institut Català d'Oncologia Hospitalet

    Hospitalet de Llobregat, Barcelona
    Spain

    Site Not Available

  • Hospital Universitario de Canarias

    Tenerife, Islas Canarias 38320
    Spain

    Site Not Available

  • Hospital Universitario de Fuenlabrada

    Fuenlabrada, Madrid
    Spain

    Site Not Available

  • Hospital Clínic de Barcelona

    Barcelona, 08036
    Spain

    Site Not Available

  • Hospital Universitari Vall d'Hebrón

    Barcelona, 08035
    Spain

    Site Not Available

  • Centro Integral Oncológico Clara Campal (CIOCC)

    Madrid,
    Spain

    Site Not Available

  • Hospital Universitario 12 de Octubre

    Madrid,
    Spain

    Site Not Available

  • Hospital Universitario 12 de octubre

    Madrid,
    Spain

    Active - Recruiting

  • Hospital Universitario Virgen del Rocio

    Sevilla,
    Spain

    Site Not Available

  • Hospital Clinico Universitario de Valencia

    Valencia,
    Spain

    Site Not Available

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