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

NCT04610528 | Unknown Early Phase 1

• 2 other identifiers: SOLTI-18052019-004964-23
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 10

Brief 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.

Conditions

Breast Cancer

Keywords

HER3; antibody drug conjugate

Outcome Measures

Primary Outcomes (1)

• CelTIL score

  Mean change in CelTIL score per central assessment in paired samples. CelTIL score = -0.8 × tumor cellularity (in %) + 1.3 × TILs (in %). The minimum and maximum unscaled CelTIL scores will be -80 and 130. This unscaled CelTIL score will then be scaled to reflect a range from 0 to 100 points.

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

Secondary Outcomes (8)

• CelTIL score

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

• ERBB3 levels vs. CelTIL score

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

• HER3 IHC vs. CelTIL score

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

• PAM50 intrinsic subtypes vs. CelTIL score

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

• Complete Cell Cycle Arrest (CCCA)

  baseline and after one dose of U3-1402 at Cycle 1 Day 21

Study Arms (1)

U3-1402

EXPERIMENTAL

U3-1402 is an antibody drug conjugate (ADC) comprising a recombinant fully human anti-human epidermal growth factor receptor (HER) 3 immunoglobulin G1 (IgG1) monoclonal antibody (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a). MAAA-1181a is released after internalization and leads to apoptosis of the target tumor cells by the inhibition of topoisomerase I

Drug: U3 1402

Interventions

U3 1402 DRUG

6.4 mg/kg dose

Also known as: Patritumab Deruxtecan

U3-1402

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written ICF for all study procedures according to local regulatory requirements prior to beginning specific protocol procedures.
• Premenopausal or postmenopausal women and men, age ≥ 18 years.
• ECOG Performance Status 0 - 1.
• Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast untreated and recently diagnosed, with all the following characteristics:
• At least one lesion that can be measured in at least 1 dimension with ≥ 1 cm in largest 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 of cancer within the same breast quadrant), the largest lesion must be ≥ 1 cm and designated the "target" lesion for all subsequent tumor evaluations and biopsies.
• Patient must have biopsiable disease.
• 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 Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines: ER and PgR defined as IHC nuclear staining ≥1% and HER2 negative locally assessed. Only for TNBC patients: Estrogen (ER)-negative and Progesterone (PgR)-negative and HER2-negative tumor by the most recent American Society of Clinical Oncology - College of American Pathologists (ASCO-CAP) guidelines: ER and PgR defined as IHC nuclear staining \<1% and HER2 negative locally assessed
• Ki67% ≥ 10% locally assessed (Dowsset et al. Journal of the National Cancer Institute, 103 (22), 1656-1664. 2011).
• Available pre-treatment FFPE core needle biopsy evaluable for PAM50 and ERBB3 mRNA expression. Minimal sample requirements are to have at least 2 tumor cylinders with a minimal tissue surface of 10 mm2 tissue, containing at least 50% tumor cells and having enough tissue to do at least 20 cuts of 4 μm each. Macrodissection is allowed when needed. If archival tissue is either insufficient or unavailable, a new biopsy from the pretreated tumor must be obtained. Patients whose tumor tissue is not evaluable for ERBB3 expression central testing are not eligible.
• Baseline LVEF ≥ 50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan
• Adequate organ function, as determined by the following laboratory tests prior to randomization:
• Hematological
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

You may not qualify if:

• Inoperable locally advanced or inflammatory (i.e., inoperable Stage III) breast cancer.
• Metastatic (Stage IV) breast cancer.
• Bilateral invasive breast cancer.
• Patients in whom a primary tumor excisional biopsy was performed.
• Any prior treatment for primary actual invasive breast cancer.
• Prior treatment with a HER3 antibody, topoisomerase I inhibitor, with an ADC which consists of an exatecan derivative that is a topoisomerase I inhibitor (e.g., DS-8201) and with a govitecan derivative (e.g., IMMU-132).
• Medical history of symptomatic congestive heart failure (New York Heart Association classes II-IV) or serious cardiac arrhythmia requiring treatment; myocardial infarction within 6 months prior to randomization or unstable angina.
• QT interval corrected using Fridericia's formula to \> 450 millisecond (ms) in males and \> 470 ms in females.
• Any factors that increase the risk of corrected QT (QTc) interval prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
• Medical history of clinically significant lung diseases (e.g., interstitial pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who are suspected to have these diseases by imaging at screening period.
• Clinically significant corneal disease.
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization.
• Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.
• History of other malignancy within the last 3 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other malignancies with an expected curative outcome.
• Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).

Sponsors & Collaborators

• SOLTI Breast Cancer Research Group: lead
• Daiichi Sankyo: collaborator

Study Sites (10)

ICO Badalona

Badalona, Barcelona, Spain

Location

Institut Català d'Oncologia Hospitalet

L'Hospitalet de Llobregat, Barcelona, Spain

Location

Hospital Universitario de Canarias

Santa Cruz de Tenerife, Canary Islands, 38320, Spain

Location

Hospital Universitario de Fuenlabrada

Fuenlabrada, Madrid, Spain

Location

Hospital Universitari Vall d'Hebrón

Barcelona, 08035, Spain

Location

Hospital Clínic de Barcelona

Barcelona, 08036, Spain

Location

Centro Integral Oncológico Clara Campal (CIOCC)

Madrid, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Spain

Location

Hospital Clinico Universitario de Valencia

Valencia, Spain

Location

Related Publications (1)

• Pascual T, Oliveira M, Ciruelos E, Bellet Ezquerra M, Saura C, Gavila J, Pernas S, Munoz M, Vidal MJ, Margeli Vila M, Cejalvo JM, Gonzalez-Farre B, Espinosa-Bravo M, Cruz J, Salvador-Bofill FJ, Guerra JA, Luna Barrera AM, Arumi de Dios M, Esker S, Fan PD, Martinez-Saez O, Villacampa G, Pare L, Ferrero-Cafiero JM, Villagrasa P, Prat A. SOLTI-1805 TOT-HER3 Study Concept: A Window-of-Opportunity Trial of Patritumab Deruxtecan, a HER3 Directed Antibody Drug Conjugate, in Patients With Early Breast Cancer. Front Oncol. 2021 Apr 23;11:638482. doi: 10.3389/fonc.2021.638482. eCollection 2021.

  PMID: 33968735 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

patritumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 27, 2020
• First Posted: October 30, 2020
• Study Start: December 22, 2020
• Primary Completion: January 30, 2022
• Study Completion: September 30, 2023
• Last Updated: June 23, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

ES (10)