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U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer

Trial Status: Active

This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, U3-1402 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, U3-1402 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.

Inclusion Criteria

  • Inclusion Criteria for both Dose Escalation and Dose Expansion: 1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation 2. Has at least one measurable lesion per RECIST version 1.1 3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: 1. Has histologically or cytologically documented adenocarcinoma NSCLC 2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) 1. Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) 2. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI 3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib 4. 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 5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib 6. 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 7. 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: 1. Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen 2. Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease 3. 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 Cohort 1, Cohort 3a, and Cohort 3b of Dose Expansion: 1. Has histologically or cytologically documented: 1. Cohort 1: Adenocarcinoma NSCLC 2. Cohort 3a and 3b: NSCLC (including any histology other than small-cell or combined small cell and non-small cell) 2. 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. 3. 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: 1. Has histologically or cytologically documented squamous or non-squamous NSCLC (ie, without EGFR-activating mutations). 2. Has received prior treatment with anti-PD-1 or anti-PD-L1 antibody-based regimen in the locally advanced or metastatic setting unless unable or unwilling. Participants with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (eg, ALK or ROS1 fusion) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy. Exclusion Criteria for Dose Escalation and 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. Treatment with any of the following: 1. 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 of the first dose of study treatment 2. Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment 3. Prior treatment with an anti-HER3 antibody (dose escalation only) 4. Prior treatment with a topoisomerase I inhibitor (dose escalation only) 5. Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) (dose escalation only) 6. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment 7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment, or stereotactic radiotherapy within 1 week prior to the first dose of U3-1402 3. Has history of other active malignancy within 3 years prior to enrollment, except: 1. Adequately treated non-melanoma skin cancer OR 2. Superficial bladder tumors (Ta, Tis, T1) OR 3. Curatively treated in situ disease 4. 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) 5. Has history of myocardial infarction within the past 6 months 6. 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 7. Has left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA) 8. 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) 9. 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 10. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval 11. 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. 12. 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 13. Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q

California

Duarte
City of Hope Comprehensive Cancer Center
Status: ACTIVE
San Diego
University of California San Diego
Status: ACTIVE

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: ACTIVE

Massachusetts

Boston
Brigham and Women's Hospital
Status: ACTIVE
Dana-Farber Cancer Institute
Status: ACTIVE
Massachusetts General Hospital Cancer Center
Status: WITHDRAWN

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Helena A. Yu
Phone: 646-888-4274
Email: yuh@mskcc.org

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: ACTIVE

The primary objectives are: - For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion (RDE) of U3-1402 in the study population - For Dose Expansion, to investigate the antitumor activity of U3-1402 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.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Daiichi Sankyo, Inc.

  • Primary ID U31402-A-U102
  • Secondary IDs NCI-2018-00060, 2017-000543-41, 194868
  • Clinicaltrials.gov ID NCT03260491