Lung Cancer Non-Small Cell Lung Cancer
Conditions
Interventions
All subjects (except cohort 3b) enrolled in Dose Expansion will receive HE3-DXd
for Injection 100 mg (lyophilized powder).
All subjects enrolled in Dose Expansion Cohort 4 will receive HE3-DXd CTM-3
Sponsors
Daiichi Pharmaceutical
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Inclusion Criteria for Dose Escalation 1. Male or female subjects aged 18 years and older. 2. Has histologically or cytologically documented adenocarcinoma NSCLC. 3.Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 4. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011): a. Historical confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q), OR b. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 or World Health Organization [WHO]) while on continuous treatment with an EGFR TKI. 5. Is currently receiving and able to discontinue erlotinib, gefitinib, afatinib, or osimertinib. 6. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening. 7. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib. 8.Has at least one measurable lesion per RECIST version 1.1 9. 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 1 lesion, not previously irradiated, amenable to core biopsy and is willing to undergo Screening tumor biopsy. 10. Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib. 11.Has Eastern Cooperative Oncology Group performance status of 0 or 1, with no deterioration over the previous 2 weeks For additional Inclusion criteria please refer to protocol Inclusion Criteria for Dose Expansion only: 1. Male of female subjects aged >=18 years (follow local regulatory requirements if the legal age of consent for study participation is >18 years old). 2. Has locally advanced or metastatic NSCLC not amenable to curative surgery or radiation. 3.Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen 4.Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease 5. Has at least 1 measurable lesion per RECIST v1.1. 6.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 For additional inclusion criteria please refer to protocol Additional Inclusion Criteria Specific to Cohorts 1, 3a, and 3b and 4 please refer to protocol Additional Inclusion Criteria Specific to Cohort 2 please refer to protocol Additional Inclusion criteria specific to Cohort 5 please refer to the protocol
Exclusion criteria
Exclusion criteria: Exclusion Criteria for Dose Expansion: 1. 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 2. Has previously documented evidence of anaplastic lymphoma kinase (ALK) fusion, ROS1 fusion, BRAF V600E mutation, RET rearrangement, HER2 mutation, MET amplification, or MET exon 14 skipping mutation. No new testing for these genomic alterations is required for Screening. 3.Treatment with any of the following: a. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI in Cohort 1 only), within 14 days prior to first dose of HE3-DXd b. Immune checkpoint inhibitor therapy within 21 days prior to dose of HE3-DXd c. Prior treatment with an anti-HER3 antibody d. Prior treatment with a topoisomerase I inhibitor e. Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) f. Major surgery (excluding placement of vascular access) within 4 weeks prior to first dose of HE3-DXd g. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks prior to first dose of HE3-DXd 4. Has history of other active malignancy within 3 years prior to first dose of HE3-DXd, except: a. Adequately treated non-melanoma skin cancer OR b. Superficial bladder tumors (Ta, Tis, T1) OR c. Curatively treated in situ disease 5. 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) 6. Has history of myocardial infarction within the past 6 months 7. Has symptomatic congestive heart failure[New York Heart Association (NYHA) Classes III-IV], unstable angina, or cardiac arrhythmia requiring antiarrhythmic treatment 8. Has left ventricular ejection fraction (LVEF) 250 milliseconds (ms) 10. 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 11. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval 12. 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, o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Dose Expansion Primary Endpoint (ie, Primary Outcome Measures) *ORR as assessed by Independent Central Review Committee (Central Review) based on RECIST v1.1 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints (ie, Secondary Outcome Measures) *Investigator assessed ORR based on RECIST v1.1, DCR, DOR, TTR, PFS, and OS *SAEs, TEAEs, physical examination findings (including ECOG PS), vital sign measurements, ophthalmologic findings, standard clinical laboratory parameters, ECG parameters (including *HR, *PR, *QTcF, and *QRS), and ECHO/ MUGA findings *Serum concentration of HE3-DXd, total anti-HER3 antibody, and free payload MAAA-1181a vs. time will be utilized. The serum PK parameters will include Cmax, Tmax, AUC8h, AUClast, and, if possible, Kel, t1/2, CL, Vz, and Vss ofHE3-DXd, anti-HER3 antibody, and MAAA 1181a. These PK parameters will be calculated both after the first dose and after multiple doses Exploratory Endpoints (ie, Exploratory Outcome Measures) *ADA measured in serum *To determine biomarkers that correlate with response or toxicity to HE3-DXd, the endpoints will include measured markers in tumor specimens (eg, HER3 IHC) and markers measured in plasma (eg, cfDNA, cfRNA) *Cohort 1 and 2 ONLY: Geometric mean ratios of AUClast and Cmax for HE3-DXd for Injection 50 mg/2.5 mL (frozen liquid) and HE3-DXd for Injection 100 mg (lyophilized powder) will be calculated after first dose (ie, Cycle 1) *Relation between HE3-DXd, total anti-HER3 antibody, or MAAA-1181a serum concentration and *QTcF Dose Expansion Cohort 4: Primary Endpoint (ie, Primary Outcome Measures) • Primary PK parameters: Cmax, area under the serum concentration-time curve from time 0 to infinite time (AUCinf), and AUClast for HE3-DXd, total anti HER3 antibody, and MAAA-1181a following the administration of the first dose of HE3-DXd drug product CTM-3. Secondary Endpoints (ie, Secondary Outcome Measures) • SAEs, TEAEs, adverse events of special interest (AESIs) (ie, ILD and elevation of aminotransferases and total bilirubin), physical examination findings (including ECOG PS), vital sign measurements, ophthalmologic findings, standard clinical laborator | — |
Countries
Netherlands
Outcome results
None listed