Trastuzumab deruxtecan treatment for biomarker-selected (HER2 and ctDNA) patients with gastrooesophageal cancer
- Conditions
- Gastrooesophageal adenocarcinoma cancerCancer
- Registration Number
- ISRCTN15960722
- Lead Sponsor
- niversity of Southampton
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing
- Sex
- All
- Target Recruitment
- 25
1. Pathologically documented adenocarcinoma of the stomach (clinical stage before surgery of AJCC I-III), gastrooesophageal junction, or lower oesophagus (to include Type I Siewert only), with HER2 overexpression (IHC 3+ or IHC 2+/ISH+) based on local tissue testing results
2. ctDNA positive after surgery as per Signatera assay
3. Capable of giving signed informed consent prior to any mandatory study-specific procedures, sampling, or analyses and which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
4. Male and female participants must be at least 18 years of age at the time of signing the ICF
5. Treated with neoadjuvant chemotherapy before surgery for at least six weeks
6. Surgical resection with clear margins (R0)
7. Recovered from surgery in the opinion of the investigator
8. No previous treatment with trastuzumab or other HER2-directed therapy
9. No evidence of metastatic disease on post-surgical CT
10. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
11. Has LVEF = 50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before treatment
12. Has adequate organ and bone marrow function within 14 days before treatment allocation as below:
12.1. Platelet count = 100x109 (Platelet transfusion is not allowed within 1 week prior to screening assessment, use of thrombopoietin receptor agonists is not allowed within 2 weeks prior to screening assessment)
12.2. Hemoglobin = 80 g/L. Participants requiring transfusions or growth factor support to maintain hemoglobin = 80 g/L are not eligible. (Red blood cell transfusion is not allowed within 1 week prior to screening assessment)
12.3. Absolute neutrophil count = 1.5 x 109 (granulocyte-colony stimulating factor [G-CSF] administration is not allowed within 1 week prior to screening assessment)
12.4. ALT/ AST = 3 × ULN
12.5. Total bilirubin = 1.5 × ULN or < 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia)
12.6. Serum albumin = 2.5 g/dL
12.7. Creatinine clearance = 50 mL/min as calculated using the Cockcroft-Gault equation
12.8. Adequate clotting function International normalized ratio (INR) or prothrombin time and either partial thromboplastin or activated partial thromboplastin time (aPTT) = 1.5 ×
1. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs, or compromise the ability of the participant to give written informed consent.
2. Participants with a medical history of myocardial infarction within 6 months before treatment or symptomatic CHF (New York Heart Association Class II to IV), unstable angina pectoris, clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event, including myocardial infarction, unstable angina pectoris, and stroke. Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial-related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction.
3. Corrected QT interval (QTcF) prolongation to > 470 msec (females) or > 450 msec (males) based on an average of the screening triplicate 12-lead ECG.
4. History of (non-infectious) ILD/pneumonitis, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
5. Any of the following:
5.1. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, clinically significant pulmonary emboli within 3 months of treatment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, clinically significant pleural effusion etc.)
5.2. Any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's, sarcoidosis etc.), where there is documented, or suspicion of, pulmonary involvement at the time of Screening.
. 5.3. Prior pneumonectomy (complete)
6. Uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals.
7. Multiple primary malignancies within the prior 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumours curatively treated.
8. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt.
9. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade = 1 or baseline. The following exemption will apply; stable chronic G2 toxicity which in the opinion of the investigator is not reasonably expected to be exacerbated by treatment with study drugs.
10. Known allergy or hypersensitivity to T-DXd or any of the study drug excipients.
11. History of severe hypersensitivity reactions to other monoclonal antibodies.
12. Pregnant or breastfeeding female participants, or participants who are planning to become pregnant.
13. Involvement in the planning and/or conduct of the study
14. Has substance abuse or any other medical conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
15. Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of IMP
16. Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Percentage of people who are classed as ctDNA negative (ctDNA clearance yes/no) measured using the Signature ctDNA assay Signatera after 4 cycles of trastuzumab deruxtecan
- Secondary Outcome Measures
Name Time Method 1. ctDNA clearance measured using the Signature ctDNA assay Signatera after each cycle of trastuzumab deruxtecan<br>2. Disease-free survival. Time from surgery to recurrence of macroscopic disease on radiological imaging or death, expressed as Kaplan-Meier estimates of median DFS and percentage disease free at 12m and 24m<br>3. Overall survival after each cycle and follow-up visit. Time from surgery to death, expressed as Kaplan-Meier estimates of median OS and percentage alive at 12m, 18m and 24m <br>4. Symptoms and quality of life, as measured by the QLQ-C30, QLQ-OG25 and EQ-5D-5L questionnaires throughout the trial<br>5. Occurrence of adverse events (AEs), serious adverse events (SAEs), and changes from baseline in laboratory parameters, vital signs, and body weight throughout the trial