A Phase II Trial to Evaluate the Efficacy and Safety of Neoadjuvant Trastuzumab Deruxtecan for Patients with Stages II-III HER2-Amplified or HER2-Mutant Non-Small Cell Lung Cancers

JRCT ID: jRCT2031240530

Registered date:09/12/2024

Basic Information

• Recruitment status: Pending
• Health condition(s) or Problem(s) studied: Stage II-III HER2-Amplified or HER2-Mutant Non-Small Cell Lung Cancer
• Date of first enrollment: 01/09/2024
• Target sample size: 17
• Study type: Interventional

Intervention(s)

The study drug will be administered as an IV infusion over the course of 30 to 90 min every 3 weeks (plus or minus)2 days.
The initial dose of the study drug will be infused for 90 (plus or minus)10 min.

Outcome(s)

• Primary Outcome: Determine the MPR rate to neoadjuvant T-DXd, as assessed by central pathologic review

Secondary Outcome

- Determine the safety and tolerability of neoadjuvant T-DXd in patients with resectable stage II-IIIB (T3-4N2) HER2-amplified or HER2-mutant NSCLC
- Determine the proportion of patients with MPR (among evaluable patients) among the HER2-mutated and HER2-amplified subgroups
- Determine the ORR, as assessed by local radiologic review in accordance with Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1)
- Determine the metabolic response rate, as assessed by local radiologic review in accordance with modified PET Response Criteria in Solid Tumors (PERCIST)1

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1. Signed informed consent form
2. Age >= 18 years
3. Pathologically documented NSCLC
oStage II, IIIA, or selected IIIB, including T3N2 or T4 (by size criteria, not by mediastinal invasion), NSCLC (on the basis of the 8th edition of the AJCC NSCLC staging system)
Note: Patients may be enrolled on the basis of clinical stage, but documentation of nodal involvement by invasive mediastinal staging (e.g., endobronchial ultrasound (EBUS) or mediastinoscopy) is strongly encouraged
4. Molecular testing results on tissue and/or cfDNA from a CLIA-certified laboratory showing presence of a mutation or amplification of HER2
5. Molecular testing results used for patient eligibility should be obtained from a recent tumor biopsy (up to 6 months before enrollment). Alternatively, molecular testing results used to determine patient eligibility could have been obtained from a recent blood sample (up to 3 months before enrollment), as described in the study design
6. Measurable disease as defined by RECIST v1.1 (exceptions may be made in cases of PERCIST-measurable disease [e.g., T0N2 cancer otherwise appropriate for induction therapy])
7. NSCLC must have a solid or subsolid appearance on CT scan and cannot have a purely ground-glass-opacity appearance. For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured on the basis of the solid component only, exclusive of the ground-glass-opacity component
8. Evaluated by the attending surgeon before study enrollment to verify that the primary tumor and any involved lymph nodes are technically completely resectable and to verify that the patient is medically operable
9. Adequate pulmonary function to be eligible for surgical resection with curative intent
-Pulmonary function tests (PFTs) must be performed at screening and before surgery, in accordance with the preoperative calendar of events, and should include lung volumes, spirometry, and diffusion capacity
-Abnormal PFT results may be further evaluated with quantitative ventilation or perfusion scanning or cardiopulmonary exercise testing, at the discretion of the surgeon
-Postoperative percent predicted forced expiratory volume in 1 second and diffusion capacity must be >=40% and/or preoperative maximal oxygen consumption (VO2 max) must be >15 mL/kg/min
-It is acceptable to have the screening PFTs performed within 4 months of Cycle 1, Day 1, but they must be repeated before Cycle 1, Day 1, if clinically indicated
-The postinduction and preoperative PFTs must be performed at least 2 weeks after Cycle 2, Day 1
10. Echocardiogram demonstrating left ventricular ejection fraction (LVEF) >=50% within 28 days before enrollment. If clinically indicated, patients with underlying ischemic or valvular heart disease should be evaluated preoperatively by a cardiologist
11. ECOG Performance Status of 0 or 1
12. Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days before the first dose of study treatment:
- Absolute neutrophil count >=1500/uL (granulocyte-colony stimulating factor administration is not allowed within 1 week before Cycle 1, Day 1)
- Platelet count >=100,000/uL (platelet transfusion is not allowed within 1 week before Cycle 1, Day 1)
- International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time <=1.5 x the upper limit of normal (ULN)
- Hemoglobin >=9.0 g/dL
-AST and ALT <=3 x ULN
-Serum bilirubin <=1.5 x ULN (up to 3 x ULN for patients with Gilbert syndrome)
-Creatinine clearance >=30 mL/min (as calculated using the Cockcroft-Gault equation)
-Serum albumin >=2.5 g/dL
13. Men agree to use a highly effective contraceptive method or avoid intercourse during and upon completion of the study and for at least 4 months after the last dose of the study drug. Women of childbearing potential agree to use a highly effective contraceptive method or avoid intercourse during and upon completion of the study and for at least 7 months after the last dose of the study drug.
14.Determined by the responsible or subcontracted physician to be willing and able to comply with the requirements and limitations of the protocol.

Exclude criteria

1. NSCLC that is clinically T4 by virtue of mediastinal organ invasion or stage IIIB by virtue of N3 disease
2. Patients for whom the thoracic surgeon believes a total pneumonectomy is likely
3. Any previous therapy for lung cancer, including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, within 3 years
4. Patients with previous lung cancer that has been in remission for <3 years, with the exception of minimally invasive adenocarcinoma or incidental typical carcinoid tumors
5. History of (noninfectious) ILD or pneumonitis that required steroids or current ILD or pneumonitis or suspected ILD or pneumonitis that cannot be ruled out by imaging at screening
6. Lung-specific intercurrent clinically significant illnesses including but not limited to any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion)
7. Any autoimmune, connective tissue, or inflammatory disorders (e.g., rheumatoid arthritis, Sjogren's, sarcoidosis) where there is documentation or 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
8. Previous pneumonectomy (complete)
9. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Active primary immunodeficiency, known uncontrolled active HIV infection, or active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle, 1 Day 1. Participants with past or resolved hepatitis B virus infection who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-)
10. Corrected QT interval prolongation to >470 msec (women) or >450 msec (men) on the basis of the average of the screening triplicate 12-lead electrocardiogram (ECG)
11. Receipt of live, attenuated vaccine (mRNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days before 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 the study drug
12. Known allergy or hypersensitivity to the study treatment or any of the study drug excipients
13. History of severe hypersensitivity reactions to other monoclonal antibodies
14. Substance abuse or any other medical conditions that would increase the safety risk to the participant or interfere with participation of the participant or evaluation of the clinical study, in the opinion of the investigator
15. Major surgical procedure within 28 days before Cycle 1, Day 1
16. Malignancies other than the disease under study within 3 years before Cycle 1, Day 1, with the exception of patients with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, non-muscle invasive bladder cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or patients undergoing active surveillance per standard-of-care management (e.g., Rai stage 0 chronic lymphocytic leukemia, prostate cancer with Gleason score <=6, and prostate-specific antigen [<=10 ng/mL])
17. Treatment with an investigational agent for any condition within 4 weeks before Cycle 1, Day 1 (or within 5 half-lives of the investigational product, whichever is longer)
18. Medical history of myocardial infarction, symptomatic congestive heart failure (CHF; New York Heart Association class II-IV), unstable angina, or serious cardiac arrhythmia
19. Social, familial, or geographical factors that would interfere with study participation or follow-up
20. Concomitant medical condition that would increase the risk of toxicity, in the opinion of the investigator
21. Pregnant or lactating or intending to become pregnant during the study
Women of childbearing potential must have a negative serum pregnancy test result within 7 days before initiation of treatment
22. The investigator or subinvestigator determines that enrollment in this clinical trial is inappropriate

Related Information

• Primary Sponsor: Tsuboi Masahiro
• Source(s) of Monetary Support: Daiichi Sankyo Pharmaceutical Company Limited