Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04)

• ClinicalTrials.gov Identifier: NCT04612751
• Recruitment Status: Recruiting
• First Posted: November 3, 2020
• Last Update Posted: May 9, 2024
• Sponsor: AstraZeneca
• Collaborator: Daiichi Sankyo
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: October 21, 2020
• First Posted Date: November 3, 2020
• Last Update Posted Date: May 9, 2024
• Actual Study Start Date: February 2, 2021
• Estimated Primary Completion Date: January 30, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 7, 2022)

Number of participants with DLTs; TEAEs and other safety parameters during the study. [ Time Frame: DLTs: within first cycle (21 days); TEAEs and other safety parameters: when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up (approximately 55 months) ]

DLTs, TEAEs, SAEs, AESIs, ECOG PS, vital sign measurements, standard clinical laboratory parameters (hematology, clinical chemistry, and urinalysis), ECG parameters, ECHO/MUGA scan findings, and ophthalmologic findings

Original Primary Outcome Measures (submitted: October 28, 2020)

• Dose-limiting Toxicities (Dose Escalation) [ Time Frame: Baseline up to Cycle 1 (Days 1 to 21) ]
  Dose-limiting toxicities and the maximum tolerated dose (MTD) will be determined in the study population treated with DS-1062a in combination with durvalumab.
• Treatment-emergent Adverse Events (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to 90 days after last dose, up to approximately 24 months postdose ]

Current Secondary Outcome Measures (submitted: December 15, 2023)

• ORR as assessed by investigator per RECIST Version 1.1 [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  ORR is defined as the proportion of participants with measurable disease at baseline who achieved a BOR of confirmed CR or confirmed PR.
• Duration of Response as assessed by investigator per RECIST version 1.1 [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Duration of Response is defined as the time from the date of the first documentation of objective response (confirmed CR or confirmed PR) to the date of the first documentation of objective PD, or death due to any cause, whichever occurs first.
• Disease Control Rate as assessed by the investigator per RECIST version 1.1 [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Disease Control Rate is defined as the proportion of participants who achieved a Best Overall Response of confirmed complete response, confirmed partial response, or stable disease.
• Progression-free Survival as assessed by the investigator per RECIST v1.1 [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Progression-free Survival is defined as the time interval from the date of the start of study treatment to the earlier of the dates of the first documentation of objective PD or death due to any cause, whichever occurs first
• Time to Response as assessed by investigator per RECIST Version 1.1 [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Time to Response is defined as the time from the date of the start of study treatment to the date of the first documentation of objective response (confirmed complete response or confirmed partial response)
• Best percentage change in the Sum of Diameters of measurable tumors [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  The best percentage change in the Sum of Diameters of measurable tumors is defined as the percentage change in the smallest Sum of Diameters from all postbaseline tumor assessments, taking as reference the baseline Sum of Diameters.
• Overall Survival [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Overall Survival is defined as the time from the date of the start of study treatment to the date of death due to any cause
• Pharmacokinetic Parameter Maximum Plasma/Serum Concentration (Cmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. Serum concentrations of durvalumab and MEDI5752, AZD2936, MEDI5752 and AZD7789. [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Cmax = Maximum concentration
• Pharmacokinetic Parameter Time to Maximum Plasma/Serum Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Tmax = time to reach maximum concentration.
• Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a. [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  Area under the plasma concentration-time curve up to last quantifiable time (AUClast) and area under the plasma concentration-time curve during dosing interval (AUCtau) will be assessed.
• Prevalence of Dato-Dxd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  ADA prevalence is defined as the proportion of all participants having ADA at any point in time (including pre-existing ADA at baseline and treatment-emergent ADA)
• Incidence of Dato-DXd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA [ Time Frame: At the time of the final analysis (when all participants have either discontinued the study or the last participant enrolled in the study has completed at least 9 months of follow-up, approximately 55 months). ]
  ADA incidence is defined as the proportion of participants having treatment-emergent ADA during the study period

Original Secondary Outcome Measures (submitted: October 28, 2020)

• Objective Response Rate (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to best overall response (confirmed complete response or partial response), up to approximately 24 months postdose ]
• Duration of Response (Dose Escalation and Dose Expansion) [ Time Frame: From first objective response (confirmed complete response or partial response) to progressive disease or death (whichever occurs first), up to approximately 24 months postdose ]
• Disease Control Rate (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to objective response (confirmed complete response, partial response, or stable disease), up to 24 months postdose ]
• Clinical Benefit Rate (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to objective response (confirmed complete response, partial response, or stable disease of at least 180 days), up to 24 months postdose ]
• Progression-free Survival (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up progressive disease or death (whichever occurs first), up to approximately 24 months postdose ]
• Time to Response (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to first objective response (confirmed complete response or partial response), up to approximately 24 months postdose ]
• Percentage Change in the Sum of Diameters of Measurable Tumors (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to approximately 24 months postdose ]
• Overall Survival (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to death (any cause), up to approximately 24 months postdose ]
• Pharmacokinetic Parameter Maximum Plasma Concentration (Cmax) of DS-1062a, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: DS-1062a, Cycle 1 and 3: Day 1 predose, 30 minutes, 3 hours (h), 5 h, 7 h postdose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre and postdose (each cycle is 21 days) ]
• Pharmacokinetic Parameter Time to Maximum Plasma Concentration (Tmax) of DS-1062a, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: DS-1062a, Cycle 1 and 3: Day 1 predose, 30 minutes, 3 hours (h), 5 h, 7 h postdose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre and postdose (each cycle is 21 days) ]
• Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of DS-1062a, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: DS-1062a, Cycle 1 and 3: Day 1 predose, 30 minutes, 3 hours (h), 5 h, 7 h postdose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre and postdose (each cycle is 21 days) ]
  Area under the plasma concentration-time curve up to last quantifiable time (AUClast) and area under the plasma concentration-time curve during dosing interval (AUCtau) will be assessed.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Phase 1b Study of Dato-DXd in Combination With Immunotherapy With or Without Carboplatin in Advanced or Metastatic Non-Small Cell Lung Cancer
• Official Title: A Phase 1b, Multicenter, 2-Part, Open-Label Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Immunotherapy With or Without Carboplatin in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer (Tropion-Lung04)
• Brief Summary: This study will assess safety, tolerability, and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Detailed Description

The primary objective is to assess the safety and tolerability of Dato-DXd in combination with immunotherapy with or without 4 cycles of carboplatin in participants with advanced or metastatic NSCLC.

Two dose levels of Dato-DXd will be studied in combination with immunotherapy (durvalumab, AZD2936, MEDI5752, or AZD7789) with or without 4 cycles of carboplatin in 14 study cohorts

Each cohort will start with Part 1 (dose escalation or confirmation), where 3 to 9 participants will be assessed for dose-limiting toxicities (DLT) in the first cycle of treatment. if the DLT incidence rate meets the criteria based on the modified toxicity probability interval-2 (mTPI-2), then Part 2 (dose expansion) may be opened.

• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Dose escalation and dose expansion model

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Advanced or Metastatic NSCLC

Intervention

• Drug: Datopotamab deruxtecan
  Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle
  Other Name: Dato-DXd
• Drug: Durvalumab
  Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle
  Other Name: Imfinzi
• Drug: Carboplatin
  Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle
• Drug: AZD2936
  Intravenous infusion prior to Dato-DXd
  Other Name: rilvegostomig
• Drug: MEDI5752
  Intravenous infusion prior to Dato-DXd
  Other Name: volrustomig
• Drug: AZD7789
  Intravenous infusion prior to Dato-DXd
  Other Name: sabestomig

Study Arms

• Experimental: Cohort 1
  Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Durvalumab
• Experimental: Cohort 2
  Datopotamab deruxtecan (Dato-DXd) + Durvalumab in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Durvalumab
• Experimental: Cohort 3
  Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Durvalumab
  • Drug: Carboplatin
• Experimental: Cohort 4
  Datopotamab deruxtecan (Dato-DXd) + Durvalumab + Carboplatin in NSCLC participants who are either treatment-naïve or have received only 1 prior line of systemic chemotherapy without concomitant ICI therapy
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Durvalumab
  • Drug: Carboplatin
• Experimental: Cohort 5
  Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: AZD2936
• Experimental: Cohort 6
  Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: AZD2936
• Experimental: Cohort 7
  Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Carboplatin
  • Drug: AZD2936
• Experimental: Cohort 8
  Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Carboplatin
  • Drug: AZD2936
• Experimental: Cohort 9
  Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Carboplatin
  • Drug: MEDI5752
• Experimental: Cohort 10
  Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: Carboplatin
  • Drug: MEDI5752
• Experimental: Cohort 11
  Datopotamab deruxtecan (Dato-DXd) + MEDI5752 in participants with treatment-naïve NSCLC
  Interventions:

  • Drug: Datopotamab deruxtecan
  • Drug: MEDI5752
• Experimental: Cohort 12
  Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC
  Intervention: Drug: AZD7789
• Experimental: Cohort 13
  Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC
  Intervention: Drug: AZD7789
• Experimental: Cohort 14
  Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with treatment-naïve NSCLC
  Intervention: Drug: AZD7789

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: December 15, 2023): 321
• Original Estimated Enrollment (submitted: October 28, 2020): 74
• Estimated Study Completion Date: January 30, 2026
• Estimated Primary Completion Date: January 30, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participant ≥18 years old on the day of signing the ICF (local regulatory requirement to consent should be followed).
• Histologically or cytologically confirmed diagnosis of advanced or metastatic NSCLC, without EGFR or ALK genomic alterations (testing not required for participants with documented squamous histology) and no known genomic alterations in other actionable driver kinases with approved therapies. Participants whose tumors harbor KRAS mutations are eligible for this study.
• For Cohorts 1 to 4, participants must be treatment-naïve or have received and radiologically progressed after only 1 prior line of systemic chemotherapy, without concomitant immune checkpoint inhibitors for advanced or metastatic NSCLC. For Cohorts 5 to 11 and 14, participants must be treatment-naïve for advanced or metastatic NSCLC. For Cohorts 12 to 13, participants must be CPI acquired resistant after 1 or 2 prior lines of systemic therapy for advanced or metastatic NSCLC, of which 1 should have contained an approved anti-PD-1/PD L1
• Willing and able to undergo a mandatory tumor biopsy. A tumor biopsy that was recently collected (within 3 months of screening) after completion of the most recent anticancer treatment regimen may be substituted for the biopsy collected during screening. For Cohorts 12 and 13, a tumor sample taken ≤24 months prior to screening is acceptable.
• Has measurable disease per RECIST1.1 within 28 days prior to Cycle 1 Day 1
• Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1 at screening
• Has adequate bone marrow reserve and organ function at baseline within 7 days prior to Cycle 1 day 1
• For Cohorts 5 to 14 only: Documented IHC PD-L1 expression per analytically validated Ventana PD-L1 (SP263) IHC assay, 22C3 PharmDx assay, or 28-8 PharmDx assay

Exclusion Criteria:

• Active or prior documented autoimmune or inflammatory disorders
• Uncontrolled or significant cardiac disease
• History of another primary malignancy with exceptions
• active or uncontrolled hepatitis B or C virus or uncontrolled HIV infection
• spinal cord compression or clinically active CNS metastases
• History of (non-infectious) ILD/pneumonitis that required steroids
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illness
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Clinically significant corneal disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: AstraZeneca Clinical Study Information Center; 1-877-240-9479; information.center@astrazeneca.com

• Listed Location Countries: Belgium, France, Italy, Japan, Korea, Republic of, Poland, Spain, Taiwan, Turkey, United States
• Removed Location Countries: Australia

Administrative Information

• NCT Number: NCT04612751
• Other Study ID Numbers: D926FC00001; 2021-000274-28 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Daiichi Sankyo
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Daiichi Sankyo
• Collaborators: Daiichi Sankyo
• Investigators: Not Provided
• PRS Account: AstraZeneca
• Verification Date: May 2024