trastuzumab deruxtecan for Metastatic HER2-positive breast cancer

Inclusion criteria

• {"criterion_text":"- Must be competent and able to comprehend, sign, and date informed consent prior to any study specific procedures\n- Life expectancy > 12 weeks\n- Subjects with clinically inactive brain metastases may be included in the study\n- Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and study enrolment\n- LVEF ≥ 50% within 28 days before enrolment\n- Adequate organ and bone marrow function within 14 days before enrollment (as described in Table 1 of the protocol). All parameters must meet the inclusion criteria on the same day and must be the most recent results available\n- Adequate treatment washout period before enrolment (defined in Table 2 in the protocol)\n- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each administration of IMP. Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause.\n- Agree for periodically blood sample collection for liquid biopsy\n- Male or female subjects age ≥ 18 years\n- Subjects with histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either locally advanced disease not amenable to resection or radiation therapy with curative intent or metastatic disease not amenable to curative therapy\n- Subjects must have confirmed, per local testing on most recent tumor tissue sample available, an HER2-positive expression, as determined according to American Society of Clinical Oncology – College of American Pathologists guidelines (as defined in the 2013 American Society of Clinical Oncology (ASCO) recommendations for HER2 testing) with any ER and/or PgR tumor status\n- Subjects must have received no more than one line of treatment including trastuzumab plus or not pertuzumab associated to taxane in the advanced/metastatic setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane\n- Documented radiologic progression (during or after most recent treatment or within 6 months after completing adjuvant therapy)\n- Presence of at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1\n- Non measurable (evaluable) bone-only disease are eligible. Evaluable bone-only disease must include at least one lytic bone lesion or a mixed lytic-blastic bone lesion; blasticonly metastases are not allowed. Subjects who have had prior radiation to bone must have at least one evaluable lesion in a non-irradiated area. Patients with lesions identified only on radionucleotide bone scan are not eligible\n- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1"}

Exclusion criteria

• {"criterion_text":"- Prior treatment with an anti-HER2 Antibody Drug Conjugated (ADC)\n- Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 months prior to Cycle 1 Day 1 and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy (such as chemotherapy-induced neuropathy)\n- Current treatment with strong cytochrome P450 (CYP3A4) and any monoclonal antibodies treatment (washout period of ≥ 3 elimination half-lives of the inhibitor/antibody is required).\n- Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the study drug\n- History of severe hypersensitivity reactions to other monoclonal antibodies\n- Substance abuse or medical conditions such as clinically significant cardiac or pulmonary diseases or psychological conditions, that would, in the opinion of the investigator, increase the safety risk to the subject or interfere with the subject’s participation in the clinical study or evaluation of the clinical study results\n- Pregnant, breastfeeding, or planning to become pregnant.\n- Social, familial, or geographical factors that would interfere with study participation or follow-up.\n- Participation into a therapeutic clinical study within 4 weeks before study treatment or current participation in other investigational procedures.\n- Subject must not be an immediate family member of study site personnel or of Sponsor personnel\n- Otherwise considered inappropriate for the study by the investigator\n- Uncontrolled or significant cardiovascular disease, including any of the following: a. History of myocardial infarction (MI) within 6 months before enrolment. b. History of symptomatic congestive heart failure (New York Heart Association Class II to IV); c. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (male) based on average of Screening triplicate 12-lead ECG; d. Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to enrollment\n- History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.\n- 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 enrolment, severe asthma, severe 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 eCRF for patients who are included in the study. c. Prior pneumonectomy (complete)\n- Spinal cord compression or clinically active central nervous system (CNS) metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.\n- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals\n- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV prior to enrolment if required by local regulations or institutional review board (IRB)/ethics committee (EC).\n- Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-Dxd. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study treatment.\n- Multiple primary malignancies within 3 years, except adequately resected non melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral breast cancer"}

Primary endpoints

• {"endpoint_text":"- Concordance in progression between RECIST v1.1 and CTDNA at 1 year after the start of treatment. CTDNA will be categorised as either presence or no presence of circulating genomic alterations associated with pharmacological resistance and susceptibility to T-DXd.Genomic alterations will be considered as new appearance and/or increasing of existing alterations","definition_or_measurement_approach":"Assessment at 1 year after treatment start; CTDNA categorised as presence vs absence of circulating genomic alterations associated with resistance/susceptibility to T-DXd. Genomic alterations defined as new appearance and/or increase of existing alterations; progression per RECIST v1.1 compared to ctDNA findings."}

Secondary endpoints

• {"endpoint_text":"- Listing of circulating alterations during treatment and at progression: particularly those actionable at OncoKB level 3A/B or lower, particularly when ctDNA-only","definition_or_measurement_approach":"Cataloguing circulating genomic alterations detected by liquid biopsy during treatment and at progression; focus on OncoKB actionability levels."}
• {"endpoint_text":"- Liquid biopsy Lead Time Progression Free survival (PFS-LB) compared to medical imaging, Lead Time is defined as the time to progression by RECIST1.1 criteria (PFS-R) - (minus, subtraction) the time to progression by circulating tumor DNA, e.g. PFS-ctDNA. Days of Lead Time = days PFS-R - days PFS-ctDNA","definition_or_measurement_approach":"Lead Time measured as difference in days between progression by RECIST v1.1 (PFS-R) and progression by ctDNA (PFS-ctDNA); PFS-LB compared to imaging-based PFS."}
• {"endpoint_text":"- PFS assessed between two groups of patients in relation with HER2-2D: HER2 status lower vs higher detected by LB","definition_or_measurement_approach":"Progression-free survival comparison between patient groups defined by blood HER2-2D status (blood HER2-low vs blood HER2-high as detected by liquid biopsy)."}
• {"endpoint_text":"- Safety endpoint: Toxicity will be graded according to NCICTCAE vers. 5.0","definition_or_measurement_approach":"Adverse events/toxicities graded per NCI CTCAE version 5.0."}
• {"endpoint_text":"- Exploratory endpoint: Presence of tissue genomic alterations (from primary or last available tumor tissue) associated with pharmacological resistance and susceptibility to T-DXd to be compared with those found on liquid biopsy","definition_or_measurement_approach":"Comparison of genomic alterations detected in tissue (primary or last available tumor) with those detected by liquid biopsy; exploratory concordance analysis."}

Italy

Earliest CTIS Part Ii Submission Date

04-10-2024

Latest Decision Or Authorization Date

11-11-2024

Processing Time Days

38

Number Of Sites

1

Number Of Participants

22

Primary sponsor

Full Name

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Italy

Third parties

• {"country":"","full_name":"Astrazeneca","duties_or_roles":"Source of monetary support","organisation_type":""}