U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer
- Conditions
- Non-Small Cell Lung Cancer (NSCLC)
- Interventions
- Drug: HER3-DXd (FL-DP)Drug: HER3-DXd (CTM-1 Lyo-DP)Drug: HER3-DXd (CTM-3 Lyo-DP)
- Registration Number
- NCT03260491
- Lead Sponsor
- Daiichi Sankyo
- Brief Summary
This study was designed to evaluate safety and antitumor activity of HER3-DXd in two parts: Dose Escalation and Dose Expansion.
In Dose Escalation, HER3-DXd was 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).
- Detailed Description
The primary objectives are:
* For Dose Escalation, to assess the safety and tolerability of HER3-DXd in the study population and to determine the recommended dose for expansion (RDE) of HER3-DXd in the study population
* For Dose Expansion, to investigate the antitumor activity of HER3-DXd
* For Cohort 5, investigate the antitumor activity of HER3-DXd in participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation after the failure of targeted therapy
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 309
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Escalation: Cohort 1, 3.2 mg/kg HER3-DXd (FL-DP) Participants in the Dose Escalation Cohort 1 will receive HER3-DXd intravenously (IV) once every three weeks at 3.2 mg/kg. Dose Escalation: Cohort 2, 4.8 mg/kg HER3-DXd (FL-DP) Participants in Dose Escalation Cohort 2 will receive HER3-DXd intravenously (IV) once every three weeks at 4.8 mg/kg. Dose Escalation: Cohort 3, 5.6 mg/kg HER3-DXd (FL-DP) Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 5.6 mg/kg. Dose Escalation: Cohort 4, 6.4 mg/kg HER3-DXd (FL-DP) Participants in Dose Escalation Cohort 3 will receive HER3-DXd intravenously (IV) once every three weeks at 6.4 mg/kg. Dose Expansion: Cohort 1, EGFR mutant HER3-DXd (CTM-1 Lyo-DP) Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE). Dose Expansion: Cohort 2, EGFR wild-type HER3-DXd (CTM-1 Lyo-DP) Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE). Dose Expansion: Cohort 3a, EGFR mutant HER3-DXd (CTM-1 Lyo-DP) Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive HER3-DXd IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE). Dose Expansion: Cohort 3b, EGFR mutant HER3-DXd (CTM-1 Lyo-DP) Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive HER3-DXd IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE). Dose Expansion: Cohort 4, EGFR mutant HER3-DXd (CTM-3 Lyo-DP) Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks. Dose Expansion: Cohort 5, KRAS-G12C mutant NSCLC HER3-DXd (CTM-3 Lyo-DP) Participants with locally advanced or metastatic NSCLC whose tumors harbor a KRAS-G12C mutation and that have progressed on the most recent line of therapy will receive HER3-DXd IV at 5.6 mg/kg every 3 weeks.
- Primary Outcome Measures
Name Time Method Dose-limiting toxicities (DLTs) during dose escalation 21 days of Cycle 1 Summary of adverse events during dose escalation By the global end of trial date, approximately within 36 months Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee during dose expansion (Dose Expansion Cohorts 1, 2, 3a, 3b, and Cohort 5) Approximately within 36 months ORR will be evaluated using RECIST v1.1.
Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4) During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Cohort 4) During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15.
- Secondary Outcome Measures
Name Time Method Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Time of maximum concentration (Tmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Area under the serum concentration-time curve from time 0 to 21 days (AUC[0-21]) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose escalation During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Overall response rate (ORR) during dose escalation Approximately within 36 months Evaluated using RECIST 1.1
Disease control rate (DCR) during dose escalation Approximately within 36 months Duration of response (DOR) during dose escalation Approximately within 36 months Time to response (TTR) during dose escalation Approximately within 36 months Progression free survival (PFS) during dose escalation Approximately within 36 months Overall Survival (OS) during dose escalation Approximately within 36 months Summary of adverse events during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) By the global end of trial date, approximately within 60 months Maximum serum concentration (Cmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-3 and Cohort 5) During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Time of maximum concentration (Tmax) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Area under the serum concentration-time curve from time 0 to 21 days (AUC[0-21]) and up to last quantifiable time (AUC[last]) of HER3-DXd, total anti-HER3 antibody, and MAAA-1181a during dose expansion (Dose Expansion Cohorts 1-3 and Cohort 5) During the first 5 cycles (each cycle is 21 days), including an intensive sampling schedule: pre-dose, end of infusion (EOI), 2 hour (hr), 4 hr, 8 hr post infusion, Day 8, and Day 15. Overall response rate (ORR) by Investigator during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Evaluated using RECIST 1.1
Disease control rate (DCR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Duration of response (DOR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Time to response (TTR) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Progression free survival (PFS) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Overall survival (OS) during dose expansion (Dose Expansion Cohorts 1-4 and Cohort 5) Approximately within 60 months Percentage of participants who are anti-drug antibody (ADA)-positive (baseline and post-baseline) and Percentage of participants who have treatment-emergent ADA during dose expansion (Cohort 4) Approximately within 60 months Mean Change from Baseline in the NSCLC-SAQ Total Score (Cohort 5) Approximately within 60 months The NSCLC-SAQ will assess symptom severity over the previous 7 days. Participants will respond using a 5-point verbal rating scale ranging from 0 "No (symptom) at all" to 4 "Very severe (symptom)" or from 0 "Never" to 4 "Always". NSCLC-SAQ total score is the sum of 5 domains (cough, pain, dyspnea, fatigue, and poor appetite) and ranges between 0 and 20. Higher scores indicate more severe symptomatology. Mean change from baseline in NSCLC-SAQ total score will be reported.
Proportions of Deteriorated, Stable, or Improved Symptoms from NSCLC-SAQ (Cohort 5) Approximately within 60 months Proportions of Deteriorated, Stable, or Improved Symptoms from PRO-CTCAE (Cohort 5) Approximately within 60 months
Trial Locations
- Locations (36)
City of Hope
🇺🇸Duarte, California, United States
University of California San Diego
🇺🇸La Jolla, California, United States
Pacific Shores Medical Group
🇺🇸Long Beach, California, United States
Winship Cancer Institute of Emory University
🇺🇸Atlanta, Georgia, United States
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Henry Ford Hospital
🇺🇸Detroit, Michigan, United States
NYU Langone Health - NYU Medical Oncology Associates
🇺🇸New York, New York, United States
Memorial Sloan-Kettering Cancer Center
🇺🇸New York, New York, United States
Gabrail Cancer Center (GCC) - Canton Facility
🇺🇸Canton, Ohio, United States
University of Pittsburgh Medical Center (UPMC) - Hillman Cancer Center (University of Pittsburgh Cancer Institute (UPCI)
🇺🇸Pittsburgh, Pennsylvania, United States
Sarah Cannon Research Institute/Tennesse Oncology
🇺🇸Nashville, Tennessee, United States
Fred Hutchinson Cancer Center
🇺🇸Seattle, Washington, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States
National Cancer Center Hospital East (NCCHE) - Kashiwa Campus
🇯🇵Kashiwa-Shi, Japan
Kurume University - Kurume University Hospital - Respiratory Diseases Center
🇯🇵Kurume-Shi, Japan
Kindai University Hospital
🇯🇵Osaka, Japan
Shizuoka Cancer Center
🇯🇵Shizuoka, Japan
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)
🇯🇵Tokyo, Japan
Netherlands Cancer Institute
🇳🇱Amsterdam, Netherlands
Clinica Universidad Navarra(Madrid)
🇪🇸Madrid, Spain
Clínica Universidad de Navarra (Pamplona)
🇪🇸Pamplona, Spain
Chung Shan Medical University Hospital
🇨🇳Taichung, Taiwan
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
NEXT Oncology - Hospital Quironsalud Barcelona
🇪🇸Barcelona, Spain
Hospital General Universitario Gregorio Maranon (HGUGM)
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Universitario Madrid Sanchinarro - Centro Integral Oncologico Clara Campal (CIOCC)
🇪🇸Madrid, Spain
Hospital Universitario Quirónsalud Madrid
🇪🇸Madrid, Spain
National Cheng Kung University Hospital
🇨🇳Tainan, Taiwan
National Taiwan University Hospital
🇨🇳Taipei, Taiwan