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)

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)

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).

Study Overview

• Status: Recruiting
• Conditions: Advanced or Metastatic NSCLC
• Intervention / Treatment: Drug: Datopotamab deruxtecan; Drug: Durvalumab; Drug: Carboplatin; Drug: AZD2936; Drug: MEDI5752; Drug: AZD7789

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
• Enrollment (Estimated): 321
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: AstraZeneca Clinical Study Information Center; Phone Number: 1-877-240-9479; Email: information.center@astrazeneca.com

Study Locations

• Belgium
  • Hasselt, Belgium, 3500
    • Recruiting
    • Research Site
  • Mechelen, Belgium, 2800
    • Recruiting
    • Research Site
  • Roeselare, Belgium, 8800
    • Not yet recruiting
    • Research Site
• France
  • Paris Cedex 05, France, 75248
    • Withdrawn
    • Research Site
• Italy
  • Aviano, Italy, 33081
    • Not yet recruiting
    • Research Site
  • Meldola, Italy, 47014
    • Recruiting
    • Research Site
  • Milano, Italy, 20162
    • Recruiting
    • Research Site
  • Orbassano, Italy, 10043
    • Recruiting
    • Research Site
  • Roma, Italy, 00144
    • Recruiting
    • Research Site
• Japan
  • Koto-ku, Japan, 135-8550
    • Recruiting
    • Research Site
  • Sunto-gun, Japan, 411-8777
    • Recruiting
    • Research Site
  • Yokohama-shi, Japan, 241-8515
    • Recruiting
    • Research Site
• Korea, Republic of
  • Busan, Korea, Republic of, 49241
    • Not yet recruiting
    • Research Site
  • Cheongiu, Korea, Republic of, 28644
    • Not yet recruiting
    • Research Site
  • Hwasun-gun, Korea, Republic of, 58128
    • Not yet recruiting
    • Research Site
  • JinJoo, Korea, Republic of, 52727
    • Not yet recruiting
    • Research Site
  • Seoul, Korea, Republic of, 05505
    • Not yet recruiting
    • Research Site
  • Suwon, Korea, Republic of, 16247
    • Not yet recruiting
    • Research Site
  • Suwon-si, Korea, Republic of, 16499
    • Not yet recruiting
    • Research Site
• Poland
  • Gdańsk, Poland, 80-952
    • Recruiting
    • Research Site
  • Poland, Poland, 20-950
    • Recruiting
    • Research Site
  • Warszawa, Poland, 02-781
    • Not yet recruiting
    • Research Site
  • Łódź, Poland, 93-338
    • Recruiting
    • Research Site
  • Łódź, Poland, 92-213
    • Withdrawn
    • Research Site
• Spain
  • A Coruña, Spain, 15005
    • Recruiting
    • Research Site
  • Badalona, Spain, 08916
    • Recruiting
    • Research Site
  • Barcelona, Spain, 8036
    • Recruiting
    • Research Site
  • Barcelona, Spain, 8023
    • Withdrawn
    • Research Site
  • Madrid, Spain, 28034
    • Recruiting
    • Research Site
  • Madrid, Spain, 28046
    • Recruiting
    • Research Site
  • Madrid, Spain, 28050
    • Recruiting
    • Research Site
  • Pozuelo de Alarcon, Spain, 28223
    • Withdrawn
    • Research Site
  • Sevilla, Spain, 41015
    • Recruiting
    • Research Site
• Taiwan
  • Changhua, Taiwan, 50006
    • Withdrawn
    • Research Site
  • Hsinchu, Taiwan, 300
    • Recruiting
    • Research Site
  • Kaohsiung City, Taiwan, 83301
    • Withdrawn
    • Research Site
  • Taichung, Taiwan, 40705
    • Recruiting
    • Research Site
  • Tainan, Taiwan, 704
    • Recruiting
    • Research Site
  • Taipei, Taiwan, 100
    • Recruiting
    • Research Site
  • Taipei, Taiwan, 11217
    • Recruiting
    • Research Site
  • Taipei City, Taiwan, 110
    • Recruiting
    • Research Site
  • Taoyuan, Taiwan, 00333
    • Recruiting
    • Research Site
• Turkey
  • Adana, Turkey, 01060
    • Recruiting
    • Research Site
  • Ankara, Turkey, 06800
    • Recruiting
    • Research Site
  • Ankara, Turkey, 6200
    • Not yet recruiting
    • Research Site
  • Ankara, Turkey, 06620
    • Withdrawn
    • Research Site
  • Istanbul, Turkey, 34010
    • Recruiting
    • Research Site
  • Izmir, Turkey, 35330
    • Recruiting
    • Research Site
  • Konya, Turkey, 42080
    • Withdrawn
    • Research Site
  • Malatya, Turkey, 44280
    • Withdrawn
    • Research Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Withdrawn
      • Research Site
    • La Jolla, California, United States, 92093
      • Recruiting
      • Research Site
    • Santa Ana, California, United States, 92705
      • Completed
      • Research Site
  • Georgia
    • Tyrone, Georgia, United States, 30290
      • Recruiting
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Withdrawn
      • Research Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Withdrawn
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Research Site
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Research Site
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Recruiting
      • Research Site
  • New York
    • New York, New York, United States, 10065
      • Withdrawn
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Research Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Withdrawn
      • Research Site
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Completed
      • Research Site
    • Houston, Texas, United States, 77030
      • Completed
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Research Site
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

14

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Durvalumab; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Imfinzi
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	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Durvalumab; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Imfinzi
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	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Durvalumab; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Imfinzi; Drug: Carboplatin; Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle
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	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Durvalumab; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Imfinzi; Drug: Carboplatin; Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle
Experimental: Cohort 5; Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: AZD2936; Intravenous infusion prior to Dato-DXd; Other Names: rilvegostomig
Experimental: Cohort 6; Datopotamab deruxtecan (Dato-DXd) + AZD2936 in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: AZD2936; Intravenous infusion prior to Dato-DXd; Other Names: rilvegostomig
Experimental: Cohort 7; Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; 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 Names: rilvegostomig
Experimental: Cohort 8; Datopotamab deruxtecan (Dato-DXd) + AZD2936 + Carboplatin in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; 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 Names: rilvegostomig
Experimental: Cohort 9; Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Carboplatin; Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle; Drug: MEDI5752; Intravenous infusion prior to Dato-DXd; Other Names: volrustomig
Experimental: Cohort 10; Datopotamab deruxtecan (Dato-DXd) + MEDI5752 + Carboplatin in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: Carboplatin; Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle; Drug: MEDI5752; Intravenous infusion prior to Dato-DXd; Other Names: volrustomig
Experimental: Cohort 11; Datopotamab deruxtecan (Dato-DXd) + MEDI5752 in participants with treatment-naïve NSCLC	Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle; Other Names: Dato-DXd; Drug: MEDI5752; Intravenous infusion prior to Dato-DXd; Other Names: volrustomig
Experimental: Cohort 12; Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC	Drug: AZD7789; Intravenous infusion prior to Dato-DXd; Other Names: sabestomig
Experimental: Cohort 13; Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with CPI acquired resistant NSCLC	Drug: AZD7789; Intravenous infusion prior to Dato-DXd; Other Names: sabestomig
Experimental: Cohort 14; Datopotamab deruxtecan (Dato-DXd) + AZD7789 in participants with treatment-naïve NSCLC	Drug: AZD7789; Intravenous infusion prior to Dato-DXd; Other Names: sabestomig

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with DLTs; TEAEs and other safety parameters during the study.	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	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)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR as assessed by investigator per RECIST Version 1.1	ORR is defined as the proportion of participants with measurable disease at baseline who achieved a BOR of confirmed CR or confirmed PR.	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 as assessed by investigator per RECIST version 1.1	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.	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 as assessed by the investigator per RECIST version 1.1	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.	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 as assessed by the investigator per RECIST v1.1	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	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 as assessed by investigator per RECIST Version 1.1	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)	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).
Best percentage change in the Sum of Diameters of measurable tumors	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.	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	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	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).
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.	Cmax = Maximum concentration	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).
Pharmacokinetic Parameter Time to Maximum Plasma/Serum Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a.	Tmax = time to reach maximum concentration.	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).
Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a.	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.	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).
Prevalence of Dato-Dxd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA	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)	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).
Incidence of Dato-DXd, durvalumab, AZD2936, MEDI5752 and AZD7789 ADA	ADA incidence is defined as the proportion of participants having treatment-emergent ADA during the study period	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).

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo

Study record dates

Study Major Dates

• Study Start (Actual): February 2, 2021
• Primary Completion (Estimated): January 30, 2026
• Study Completion (Estimated): January 30, 2026

Study Registration Dates

• First Submitted: October 21, 2020
• First Submitted That Met QC Criteria: October 28, 2020
• First Posted (Actual): November 3, 2020

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Durvalumab; Advanced or Metastatic NSCLC; Datopotamab deruxtecan (Dato-DXd); DS-1062a; AZD2936; MEDI5752; AZD7789
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents; Antineoplastic Agents, Immunological; Carboplatin; Durvalumab
• Other Study ID Numbers: D926FC00001; 2021-000274-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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
• IPD Sharing 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.
• IPD Sharing 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No