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About
This study is designed to evaluate safety and antitumor activity of HER3-DXd in two parts: Dose Escalation and Dose Expansion.
In Dose Escalation, HER3-DXd will be evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy.
In Dose Expansion, HER3-DXd will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.
In addition, HER3-DXd will be evaluated in participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation after progression on the most recent line of therapy (Cohort 5).
Full description
The primary objectives are:
The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.
Enrollment
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Inclusion and exclusion criteria
Inclusion Criteria for both Dose Escalation and Dose Expansion:
Inclusion Criteria for Dose Escalation only:
Has histologically or cytologically documented adenocarcinoma NSCLC
Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)
Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib
Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening
Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib
Is willing to provide archival tumor tissue from a biopsy performed within 6 months of progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy
Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib.
Inclusion Criteria for all cohorts of Dose Expansion only:
Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen
Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease
For Cohorts 1, 2, 3a, and 3b: Is willing to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after progression during/after treatment with most recent cancer therapy regimen OR has at least 1 lesion, not previously irradiated, amenable to core biopsy and is willing to undergo tumor biopsy. Tumor tissue must be of sufficient quantity as defined in the laboratory manual and contain adequate tumor tissue content as confirmed by haematoxylin and eosin (H&S) staining at central laboratory.
Inclusion Criteria specific to Cohorts 1, 3a, 3b, and 4 of Dose Expansion:
Has histologically or cytologically documented:
Has documentation of radiological disease progression following one or more lines of EGFR TKI treatment. Participants with EGFR T790M mutation following treatment with erlotinib, gefitinib afatinib, or dacomitinib must have received and have documentation of radiological disease progression following treatment with osimertinib unless unable or unwilling.
Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. Participants with other EGFR-activating mutations may be eligible following discussion with the Sponsor.
Inclusion Criteria specific to Cohort 2 of Dose Expansion:
Inclusion Criteria for Cohort 5:
Exclusion Criteria for Dose Escalation and Dose Expansion:
Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression
Treatment with any of the following:
Has history of other active malignancy within 3 years prior to enrollment, except:
Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants 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 whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy)
Has history of myocardial infarction within the past 6 months
Has symptomatic congestive heart failure[New York Heart Association (NYHA) Classes II-IV], unstable angina within the past 6 months, or cardiac arrhythmia requiring antiarrhythmic treatment
Has left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)
Has any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms)
Has a mean corrected QT interval using Fridericia's Correction Formula (QTcF) prolongation to > 470 ms for females and > 450 ms for males in three successive Screening measurements
Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval
Has any factors that increase the risk of corrected QT (QTc) interval prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or severe radiation pneumonitis), has current ILD/pneumonitis, or is suspected to have such disease by imaging during screening
Has clinically significant corneal disease
Additional Exclusion Criteria for Dose Expansion Cohort 2:
Additional Exclusion Criteria for Dose Expansion Cohort 4:
Evidence of any leptomeningeal disease
Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
Is receiving chronic systemic corticosteroids dosed at >10 mg/day prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to enrollment
Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results.
Exclusion Criteria for Cohort 5:
Primary purpose
Allocation
Interventional model
Masking
309 participants in 10 patient groups
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Central trial contact
(US sites) Daiichi Sankyo Contact for Clinical Trial Information; (Japan sites) Daiichi Sankyo Contact for Clinical Trial Information
Data sourced from clinicaltrials.gov
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