Clinical trial NCT05744375: Trastuzumab Deruxtecan in First-line HER2-positive Locally Advanced/MBC Patients Resistant to Trastuzumab+Pertuzumab
Official title: Phase II Trial of TRAstuzumab deruxtecaN in firSt-line Treatment of HER2-positive Locally advanCEd or Metastatic Breast caNcer (MBC) Patients Considered Resistant to Trastuzumab + Pertuzumab + Taxane Due to Early Relapse."TRANSCENDER Study"
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Locally Advanced Breast Cancer
Metastatic Breast Cancer
Keywords: Trastuzumab deruxtecan
HER2-positive
Advanced Breast Cancer
Metastatic Breast Cancer
resistant to prior (neo) adjuvant anti-HER2 therapy.
Lead sponsor: Spanish Breast Cancer Research Group
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2023-02-27
Enrollment: 2
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The goal of this national, multicenter single arm phase II clinical trial is to study the efficacy, safety and tolerability of the administration of Trastuzumab Deruxtecan (T-DXd) in HER2-positive locally advanced or metastatic breast cancer (MBC) patients resistant to trastuzumab plus pertuzumab plus taxane due to early relapse.

The main questions it aims to answer are:

* To evaluate the antitumor activity of T-DXd in the first-line treatment of HER2-positive breast cancer patients resistant to trastuzumab-pertuzumab based therapy.
* To assess other efficacy measures.
* To evaluate safety and tolerability in all patients enrolled in the study.
* To evaluate health-related quality of life (HRQoL). Forty-one evaluable patients will be treated with trastuzumab deruxtecan (T-DXd) 5.4 mg/kg IV every 3 weeks (± 3 days). Patients will receive T-DXd until unacceptable toxicity, progressive disease, informed consent withdrawal, or other discontinuation criterion is met.

Detailed description: This is a national, multicenter single arm phase II clinical trial to study the efficacy, safety and tolerability of the administration of Trastuzumab Deruxtecan (T-DXd) in HER2-positive locally advanced or MBC patients resistant to trastuzumab plus pertuzumab plus taxane due to early relapse.

Eligible patients will be enrolled and treated with T-DXd 5.4 mg/kg IV every 3 weeks.

The T-DXd dose will be recalculated in the event that patients experience body weight variations greater than 10% during the treatment period.

All patients enrolled will receive study therapy until radiographic or symptomatic progressive disease, unacceptable toxicity or withdraw of the informed consent, whatever occurs first.

Study population:

HER2-positive locally advanced or MBC patients who have not received prior chemotherapy or HER2 targeted therapy for advanced disease and with a Disease-Free Interval (DFI) of \<12 months from the end of prior (neo)adjuvant anti-HER2 therapy.

Study Duration: The start date of the study is the date of the first site activation. Recruitment period will occur during approximately 24 months from the first patient in.

The end date of the study is the date of the last visit of the last patient (LPLV), including follow-up. The duration of the study will be approximately 68 months from the first patient in.

Performing exploratory objectives will be independent of the date of the end of the study.

Eligibility criteria: Inclusion Criteria:

1. Written and signed informed consent obtained prior to any study-specific procedure.
2. Male or female patients of at least 18 years of age.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
4. Life expectancy ≥ 12 weeks.
5. Recurrent breast cancer that is unresectable locally advanced or metastatic.
6. Pathologically documented HER2-positive status by local laboratory determination, preferably on the most recent available Formalin-fixed paraffin-embedded (FFPE) tumor sample, according to the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) international guidelines valid at the time of the assay. In case of discordance in HER2 status in different biopsies, the result from the most recent biopsy will be used.
7. Pathologically documented Hormone Receptor (HR)-positive or -negative by local laboratory determination, preferably on the most recent available FFPE tumor sample, and according to ASCO/CAP international guidelines valid at the time of the assay. In case of discordance in HR status in different biopsies, the result from the most recent biopsy will be used.
8. Prior anti-HER2 based therapy (with trastuzumab plus pertuzumab plus taxane with or without trastuzumab-emtansine) in the (neo)adjuvant setting with a relapse while on therapy or within 12 months from the end of last anti-HER2 therapy.
9. Measurable disease assessed by the investigator based on RECIST version 1.1.
10. Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
11. Adequate organ and marrow function defined as follows:

    1. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L).
    2. Platelet count ≥ 100,000/mm3 (100x109/L).
    3. Hemoglobin ≥ 9g/dL (90g/L).
    4. Creatinine clearance ≥ 30 mL/min as calculated using the standard method for the institution.
    5. Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or \< 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
    6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3.0 x ULN (\< 5.0 × ULN in participants with liver metastases).
    7. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases are present).
    8. Serum albumin ≥ 2.5 g/dL
12. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
14. Negative serum pregnancy test with a sensitivity of at least 25 milliInternational Units per milliliter of urine (mIU/mL) (unless permanent previous sterilization procedure such as bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) for premenopausal women, and for women who have experienced menopause onset \< 12 months prior to first dose of therapy.

Exclusion Criteria:

1. Prior chemotherapy or HER2-targeted therapy for locally advanced or MBC (one prior endocrine therapy regimen for MBC without concurrent anti-HER2 therapy or radiotherapy is allowed).
2. Ineligible for treatment with T-DXd.
3. Any substance abuse or other medical conditions that, in the investigator's opinion, may interfere with patient's participation or study results.
4. Patients with spinal cord compression, leptomeningeal disease or clinically active central nervous system (CNS) metastases. Participants with clinically inactive brain metastases or treated brain metastases that are no longer symptomatic, and no needing corticosteroids or anticonvulsants may be enrolled in the study.
5. Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
6. Lung criteria:

   1. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe Chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.).
   2. Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the electronic Case Report Form (eCRF) for patients who are enrolled in the study.
   3. Prior pneumonectomy.
7. Medical history of myocardial infarction within 6 months before registration, symptomatic congestive heart failure (CHF), troponin levels consistent with myocardial infarction as defined according to American College of Cardiologists (ACC) guidelines, unstable angina, or serious cardiac arrhythmia requiring treatment. QT interval corrected using Fridericia's formula (QTcF) \> 470 msec (females) or \> 450 msec (males) based on average of the screening triplicate 12-lead ECG.
8. History of active primary immunodeficiency, known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).
9. Patients who received before treatment starts:

   1. Any investigational agent within 4 weeks.
   2. Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. \< 3 weeks for fluorouracil, doxorubicine, epirubicin or \< 1 week for weekly chemotherapy).
   3. Targeted therapy (e.g., antibodies): up to 4 weeks prior to starting study treatment.
   4. Endocrine therapy: tamoxifen or aromatase inhibitor within 2 weeks prior to starting study treatment.
   5. Radiotherapy within 2 weeks prior to starting study treatment. Patients who received prior radiotherapy to \>25% of bone marrow are not eligible regardless of when it was administered.
   6. Major surgery or other anti-cancer therapy not previously specified within 4 weeks prior to starting study treatment.

   In any case, resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI-CTCAE version 5.0 grade ≤ 1 (except alopecia or other toxicities not considered a safety risk for the patient at investigator´s discretion) is mandatory.Patients may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to \> grade 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as: chemotherapy-induced neuropathy or fatigue and immunotherapy-induced toxicities (e.g. endocrinopathies as hypothyroidism/hyperthyroidism, type 1 diabetes, hypoglycemia, adrenal insufficiency, adrenalitis and skin hypopigmentation \[vitiligo\]).
10. Have a diagnosis of any other malignancy within 3 years prior to inclusion, except for adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors curatively treated and contralateral breast cancer.
11. Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd.
12. Prior treatment with T-DXd or allergic reaction to trastuzumab.
13. Patient is pregnant or breastfeeding or planning to become pregnant within the projected duration of the trial, starting at screening and through 7 months after the last dose of the study treatment. Male patients whose partners plan to become pregnant within the duration of the trial, starting at screening and through 4 months after the last dose of the study treatment.

    ✓ For premenopausal women it is necessary an agreement to remain complete abstinent or use single or combined non-hormonal contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 7 months after the last dose of study treatment.
    * Examples of non-hormonal contraceptive methods with a failure rate of \< 1% per year include bilateral tubal litigation, male sterilization, and certain intrauterine devices (provided coils are copper banded).
    * Alternative, two methods (e.g. two barrier methods such as a condom and a cervical cap or combined with estrogen and progestogen) may be combined to achieve a failure rate of \< 1% per year. Barrier methods must always be supplemented with the use of a spermicide.

    Female patients must not donate, or retrieve for their own use, ova from the time of enrollment and throughout the study treatment period, and for at least 7 months after the final study drug administration. They should refrain from breastfeeding throughout this time. Preservation of ova may be considered prior to enrollment in this study.

    ✓ For men it is necessary an agreement to remain complete abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and to refrain from donating sperm during the same period, as defined below with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 4 months after the last dose of study treatment to avoid exposing the embryo.

    Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
14. Uncontrolled intercurrent illness including uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
15. Has substance abuse or any other medical/psychological conditions that may, in the opinion of the investigator, interfere with the patient's participation in the clinical study or evaluation of the clinical study results.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Through study treatment, and average of 18 months
Secondary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: Through study treatment, and average of 18 months
measure: Overall Survival (OS)
timeFrame: Through study, and average of 36 months
measure: Time to treatment response (TTR)
timeFrame: Through study treatment, and average of 18 months
measure: Duration of response (DoR)
timeFrame: Through study treatment, and average of 18 months
measure: The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment
timeFrame: Through study treatment, and average of 18 months
measure: Changes from baseline in the global health status score (GHS)
timeFrame: Through study treatment, and average of 18 months
measure: Time to deterioration (TTD) in quality of life (QoL)
timeFrame: Through study treatment, and average of 18 months
Other outcomes:
measure: Progression-Free Survival 2 (PFS2)
timeFrame: Through study, and average of 36 months
measure: Progression-Free Survival 3 (PFS3)
timeFrame: Through study, and average of 36 months
Locations:
city: Cádiz
country: Spain
facility: Hospital Universitario de Jeréz De La Frontera
state: Andalucía
city: Jaén
country: Spain
facility: Hospital Universitario de Jaén
state: Andalucía
city: Santander
country: Spain
facility: Hospital Universitario Marqués de Valdecilla
state: Cantabria
city: Fuenlabrada
country: Spain
facility: Hospital Universitario de Fuenlabrada
state: Madrid
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro de Majadahonda
state: Madrid
city: Palma De Mallorca
country: Spain
facility: Hospital Universitario Son Espases
state: Mallorca
city: Galdakao
country: Spain
facility: Hospital Galdakao-Usansolo
state: Vizcaya
city: A Coruña
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC)
city: Alicante
country: Spain
facility: Hospital San Juan de Alicante
city: Badajoz
country: Spain
facility: Hospital Universitario de Badajoz
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Cáceres
country: Spain
facility: Hospital Universitario San Pedro de Alcántara
city: Granada
country: Spain
facility: Hospital Universitario Clínico San Cecilio
city: Lleida
country: Spain
facility: Hospital Universitario Arnau de Vilanova de Lleida
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Marañón
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío
Study officials:
affiliation: Hospital General Universitario Gregorio Marañón. Madrid, Spain.
name: Study Director Study Director
role: STUDY_DIRECTOR
affiliation: Hospital del Mar. Barcelona, Spain.
name: Study Director Study Director
role: STUDY_DIRECTOR
References: