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Breast CancerEarly Phase 1TOT-HER3NCT04610528

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

A Early Phase 1 study testing U3 1402 in people with Breast Cancer, run by SOLTI Breast Cancer Research Group at 10 sites in Spain.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Breast Cancer
What is being tested?
U3 1402
Could I receive a placebo?
No, everyone receives an active treatment
How many people
80 participants
Where
10 sitesSpain
Study dates
22 Dec 2020to 30 Sep 2023
Phase
Early Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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
  • Platelet count ≥ 100 x 109/L
  • Hemoglobin ≥ 9 g/dL (red blood cell transfusion and/or erythropoietin allowed)
  • Renal
  • o Serum creatinine ≤ 1.5 x upper limit of normal (ULN), or 24-hour creatinine clearance ≥ 60 mL/min for subject with creatinine levels > 1.5 x ULN. (Note: Creatinine clearance does not need to be determined if the baseline serum creatinine is within normal limits. Creatinine clearance should be calculated per institutional standard).
  • Hepatic
  • Serum bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total 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
  • Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
  • Female subject of childbearing potential should have a negative urine or serum pregnancy test within 7 days prior to enrollment. If urine pregnancy test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Pregnancy testing does not need to be pursued in patients who are judged as postmenopausal before randomization, as determined by local practice, or who have undergone bilateral oophorectomy, total hysterectomy, or bilateral tubal ligation. Women of childbearing potential randomized to the treatment must use adequate contraception for the duration of protocol treatment and after 7 months after the study drug administration (see Appendix B).

Who cannot join

  • 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).
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  • 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).
  • Concurrent, serious, uncontrolled infections or current known infection with HIV or active hepatitis B and/or hepatitis C.
  • History of significant co-morbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with ICF.
  • Known hypersensitivity to either the drug substance components (including an antibody, a drug-linker, or a topoisomerase I inhibitor) or inactive ingredients in the drug product or history of severe hypersensitivity reactions to other monoclonal antibodies.
  • Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoid arthritis, Sjögren's syndrome, sarcoidosis etc.), or prior pneumonectomy.
  • Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, grade ≤1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per the discretion of the Investigator.

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

Spain10 sites

  • ICO Badalona

    Badalona, Barcelona

  • Hospital Universitari Vall d'Hebrón

    Barcelona, 08035

  • Hospital Clínic de Barcelona

    Barcelona, 08036

  • Hospital Universitario de Fuenlabrada

    Fuenlabrada, Madrid

  • Institut Català d'Oncologia Hospitalet

    L'Hospitalet de Llobregat, Barcelona

  • Centro Integral Oncológico Clara Campal (CIOCC)

    Madrid

  • Hospital Universitario 12 de Octubre

    Madrid

  • Hospital Universitario de Canarias

    Santa Cruz de Tenerife, Canary Islands, 38320

  • Hospital Universitario Virgen del Rocio

    Seville

  • Hospital Clinico Universitario de Valencia

    Valencia

Other trials in Spain

About this study

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.

Read more

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
Being tested
U3 1402
Keywords
HER3, antibody drug conjugate
Medical subject headings
Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • U3 1402Drug

    Also called Patritumab Deruxtecan

    6.4 mg/kg dose

  • U3 1402Drug

    Also called Patritumab Deruxtecan

    5.6 mg/kg dose

Study groups in NCT04610528
Study groupRoleWhat they receive
U3-1402ExperimentalU3-1402 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
Receives: Drug: U3 1402

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (8)

  1. CelTIL score

    Mean change in CelTIL score per central assessment in paired samples for each ERBB3 cohort

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

  2. ERBB3 levels vs. CelTIL score

    ERBB3 mRNA baseline levels and changes in CelTIL score for all patients and for each ERBB3 cohort

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

  3. HER3 IHC vs. CelTIL score

    HER3 IHC baseline levels and changes in CelTIL score for all patients and for each ERBB3 cohort

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

  4. PAM50 intrinsic subtypes vs. CelTIL score

    changes in CelTIL across the four PAM50 intrinsic subtypes.

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

  5. Complete Cell Cycle Arrest (CCCA)

    determined per central assessment by IHC Ki67< 2.7%

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

  6. ERBB3 mRNA expression vs. HER3 IHC

    Correlation coefficients between both biomarkers

    Measured: baseline

  7. safety and tolerability

    Type, incidence, severity (as graded by the NCI CTCAE v. 5.0), seriousness and attribution to the study medications of AEs and any laboratory abnormalities.

    Measured: through study completion, an average of 65 days each patient

  8. changes of HER3 expression.

    HER3 expression

    Measured: t baseline, at Day 3-Day 7 (optional), Cycle 1 Day 21

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted30 Oct 2020
  2. Study start22 Dec 2020
  3. Primary completion30 Jan 2022
  4. Study completion30 Sep 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
80 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04610528
Sponsor's protocol ID
SOLTI-1805
Other IDs
2019-004964-23, 2019
Acronym
TOT-HER3
Status last verified
Jun 2023
First submitted
27 Oct 2020
Last updated
23 Jun 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 33968735

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing U3 1402 in people with Breast Cancer, run by SOLTI Breast Cancer Research Group at 10 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 27 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 23 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

CelTIL score (time frame: baseline and after one dose of U3-1402 at Cycle 1 Day 21). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04610528, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2023.

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