Phase II Evaluation of Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Resistant to Trastuzumab, Pertuzumab, and Taxane Therapy

Trial ID: 2023-503627-26-00
Protocol: GEICAM/2021-08
Sponsor: Fundacion Grupo Espanol De Investigacion En Cancer De Mama

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Diseases & Conditions

Breast cancer metastatic HER2 positive breast cancer

Objectives

The primary objective of this Phase II clinical trial is to evaluate the **antitumor activity** of trastuzumab deruxtecan (T-DXd) in the first-line treatment of patients with HER2-positive locally advanced or metastatic breast cancer who are resistant to trastuzumab-pertuzumab-based therapy. This is clinically relevant as it addresses the need for effective treatment options in a patient population with limited therapeutic alternatives due to resistance to standard therapies.

Secondary objectives include:

Assessing other efficacy measures to provide a comprehensive understanding of the treatment's impact.
Evaluating the safety and tolerability of T-DXd in all enrolled patients, which is crucial for determining the risk-benefit profile of the treatment.
Evaluating health-related quality of life (HRQoL) to understand the treatment's effect on patients' overall well-being.

Participants

The clinical trial involves participants diagnosed with **metastatic breast cancer**, specifically targeting those with HER2-positive status who have shown resistance to trastuzumab-pertuzumab based therapy. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have a life expectancy of at least 12 weeks and must have recurrent breast cancer that is unresectable, locally advanced, or metastatic. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include adequate organ and marrow function, a left ventricular ejection fraction of at least 50%, and a willingness to comply with study procedures. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, although specific details regarding this aspect are not disclosed.

Plans and Procedures

The clinical trial is designed to evaluate the **antitumor activity** of **trastuzumab deruxtecan** in patients with HER2-positive **metastatic breast cancer** who are resistant to prior trastuzumab-pertuzumab based therapy. This is a Phase II, randomized, double-blind, controlled trial. The trial is expected to commence on September 21, 2023, and conclude by May 2, 2029. The study involves a series of visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as adequate organ function, HER2-positive status, and prior treatment history. Participants will be required to provide written informed consent before any study-specific procedures are conducted.

Following the screening, eligible participants will be randomized to receive the investigational product, DS-8201a, administered as a **solution for infusion** via the **intravenous** route. The maximum daily dose is 5.4 mg/kg, with a treatment period not exceeding 18 cycles. Study visits will include regular follow-up assessments to monitor the **objective response rate** (ORR), **progression-free survival** (PFS), and **overall survival** (OS), among other secondary endpoints. Safety and tolerability will be evaluated through the incidence and severity of adverse events, coded according to the MedDRA dictionary, and assessed using the NCI-CTCAE version 5.0.

The expected length of participant involvement is approximately 18 months, contingent upon individual response and tolerability. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The end-of-study visit will involve a comprehensive evaluation to document the final outcomes and any long-term effects of the treatment. The trial aims to provide valuable insights into the efficacy and safety of trastuzumab deruxtecan in this patient population, contributing to the advancement of therapeutic options for HER2-positive metastatic breast cancer.

Treatment

The clinical trial involves the administration of **trastuzumab deruxtecan**, commercially known as DS-8201a, which is a **HER2-targeted antibody and topoisomerase I inhibitor conjugate**. This experimental medication is provided in the form of a **solution for infusion**. The pharmaceutical formulation is designed for **intravenous** administration. The dosing regimen specifies a maximum daily dose of 5.4 mg/kg, with the same amount being the maximum total dose per administration. The treatment period is set to a maximum of 18 cycles, with each cycle corresponding to a specific time unit as defined in the study protocol. The active substance, trastuzumab deruxtecan, is a protein-based compound, classified under the category "Protein - Other". The medication is not formulated for pediatric use and is not designated as an orphan drug.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy and safety of the experimental drug, DS-8201a, in the target patient population. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to accurately assess the therapeutic outcomes of the treatment.

Efficacy

Efficacy in the clinical trial titled "Phase II trial of trastuzumab deruxtecan in first-line treatment HER2-positive locally advanced or metastatic breast cancer (MBC) patients considered resistant to trastuzumab + pertuzumab + taxane due to early relapse" will be assessed using several parameters. The primary endpoint is the **Objective Response Rate (ORR)**, which is defined as the rate of complete response (CR) plus partial response (PR) based on the investigator's assessment using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This will be evaluated among patients who have received at least one dose of the treatment.

Secondary efficacy endpoints include **Progression-Free Survival (PFS)**, which measures the time from enrollment to disease progression or death from any cause, and **Overall Survival (OS)**, which is the time from enrollment to death from any cause. Additionally, **Time to Treatment Response (TTR)** is defined as the time from enrollment to the first documentation of objective tumor response, and **Duration of Response (DoR)** is the time from the first documentation of objective tumor response to the first documented progressive disease or death. These assessments will also utilize RECIST version 1.1 criteria.

Safety and tolerability will be monitored through the incidence and severity of adverse events (AEs) and clinical lab abnormalities, with AEs graded according to the National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) version 5.0. Tolerability will also be evaluated by tracking the incidence of dose modifications, discontinuations due to AEs, number of administered cycles, and dose intensity. Patient-reported outcomes will be assessed using changes in mean scores and time to deterioration on the EORTC QLQ-C30 Global Health Status/Quality of Life from baseline.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written and signed informed consent obtained prior to any study-specific procedure
Male or female patients of at least 18 years of age.
Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
Life expectancy ≥ 12 weeks
Recurrent breast cancer that is unresectable locally advanced or metastatic
Pathologically documented HER2-positive status by local laboratory determination, preferably on the most recent available 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.
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.
Prior anti-HER2 based therapy (with trastuzumab plus pertuzumab plus taxane with or without trastuzumab-emtansine [T-DM1]) in the (neo)adjuvant setting with a relapse while on therapy or within 12 months from the end of last anti-HER2 therapy
Measurable disease assessed by the investigator based on RECIST version 1.1.
Left ventricular ejection fraction (LVEF) ≥ 50% measured by multiple-gated acquisition scan (MUGA) or echocardiogram (ECHO).
Adequate organ and marrow function defined as follows: a. Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/L). b. Platelet count ≥ 100,000/mm3 (100x109/L). c. Hemoglobin ≥ 9g/dL (90g/L). d. Creatinine clearance ≥ 30 mL/min as calculated using the standard method for the institution. e. Total serum bilirubin ≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline. f. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 3.0 x ULN (< 5.0 × ULN in participants with liver metastases). g. Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN if bone or liver metastases are present). h. Serum albumin ≥ 2.5 g/dL
International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
Negative serum pregnancy test with a sensitivity of at least 25 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.

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Exclusion Criteria

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).
Ineligible for treatment with T-DXd.
Any substance abuse or other medical conditions that, in the investigator's opinion, may interfere with patient's participation or study results.
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.
Active or prior documented interstitial lung disease (ILD)/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Lung criteria: a. 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.). b. 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. c. Prior pneumonectomy.
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.
History of active primary immunodeficiency, known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV).
Patients who received before treatment starts:a. Any investigational agent within 4 weeks. b. Chemotherapy within a period of time that is shorter than the cycle duration used for that treatment (e.g. < 3 weeks for fluorouracil, doxorubicine, epirubicine or < 1 week for weekly chemotherapy). c. Targeted therapy (e.g., antibodies): up to 4 weeks prior to starting study treatment. d. Endocrine therapy: tamoxifen or aromatase inhibitor within 2 weeks prior to starting study treatment. e. 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. f. 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]).
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.
Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd.
Prior treatment with T-DXd or allergic reaction to trastuzumab
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.
Uncontrolled intercurrent illness including uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
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.