Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab With or Without Carboplatin in Subjects With 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 19, 2022
• Sponsor: AstraZeneca
• Collaborator: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief Summary:

This study will assess safety, tolerability, and treatment activity of datopotamab deruxtecan (Dato-DXd) in combination with durvalumab in participants with advanced or metastatic non-small cell lung cancer (NSCLC).

Condition or disease	Intervention/treatment	Phase
Advanced or Metastatic NSCLC	Drug: Datopotamab deruxtecan; Drug: Durvalumab; Drug: Carboplatin	Phase 1

Detailed Description:

The primary objective of this study will assess the safety and tolerability of datopotamab deruxtecan (Dato-DXd) in combination with durvalumab with or without 4 cycles of carboplatin in participants with advanced or metastatic NSCLC who have either been previously treated or are treatment naïve in a metastatic setting.

Two dose levels of Dato-DXd (4.0 mg/kg and 6.0 mg/kg) will be studied in combination with fixed-dose durvalumab (1120mg), with or without 4 cycles of carboplatin in 4 study cohorts. This study will be conducted sequentially and dose escalation will occur according to lower dose to higher dose in the same combination regimen (4.0 mg/kg to 6.0 mg/kg) and from 2-drug combination (Dato-DXd and durvalumab) to 3-drug combination regimen (Dato-DXd, durvalumab, and carboplatin).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: Dose escalation and dose expansion model
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b, Multicenter, 2-Part, Open-Label Study of Datopotamab Deruxtecan (Data-DXd) in Combination With Durvalumab With or Without Carboplatin in Subjects With Advanced or Metastatic Non-Small Cell Lung Cancer (TROPION-Lung04)
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: March 15, 2023
• Estimated Study Completion Date: December 17, 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Datopotamab deruxtecan (Dato-DXd); Dose Escalation and Dose Expansion: Datopotamab deruxtecan (Dato-DXd) in combination with durvalumab with and without carboplatin in participants with advanced or metastatic NSCLC.

Drug: Datopotamab deruxtecan; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle (starting Datopotamab deruxtecan dose of 4.0 mg/kg); Other Name: Dato-DXd; Drug: Durvalumab; Intravenous infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle (fixed dose 1120 mg Q3W); Other Name: MEDI4736, Imfinzi; Drug: Carboplatin; Intravenous infusion Q3W on Day 1 or Day 2 of each 21-day cycle (AUC 5)

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-limiting Toxicities and Treatment-emergent Adverse Events (Dose Escalation) [ Time Frame: DLTs: Baseline up to Cycle 1 (Days 1 to 21); TEAEs: Baseline up to 90 days after last dose, up to approximately 42 months post-dose ]
   Dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) will be determined in the study population treated with Dato-DXd in combination with durvalumab.

Secondary Outcome Measures :

1. 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 42 months post-dose ]
2. 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 42 months post-dose ]
3. 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 42 months post-dose ]
4. 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 42 months post-dose ]
5. Progression-free Survival (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up progressive disease or death (whichever occurs first), up to approximately 42 months post-dose ]
6. 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 42 months post-dose ]
7. Percentage Change in the Sum of Diameters of Measurable Tumors (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to approximately 42 months post-dose ]
8. Overall Survival (Dose Escalation and Dose Expansion) [ Time Frame: Baseline up to death (any cause), up to approximately 42 months post-dose ]
9. Pharmacokinetic Parameter Maximum Plasma Concentration (Cmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: Dato-DXd, Cycle 1 and 3: Day 1 pre-dose, 30 minutes, 3 hours, 5 hours, 7 hours post-dose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre- and post-dose (each cycle is 21 days) ]
10. Pharmacokinetic Parameter Time to Maximum Plasma Concentration (Tmax) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: Dato-DXd, Cycle 1 and 3: Day 1 pre-dose, 30 minutes, 3 hours, 5 hours, 7 hours post-dose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre- and post-dose (each cycle is 21 days) ]
11. Pharmacokinetic Parameter Area Under the Plasma Concentration-Time Curve (AUC) of Dato-DXd, Total anti-TROP2 antibody, and MAAA-1181a (Dose Escalation and Dose Expansion) [ Time Frame: Dato-DXd, Cycle 1 and 3: Day 1 pre-dose, 30 minutes, 3 hours, 5 hours, 7 hours post-dose and Days 2, 4, 8, and 15; Cycle 2, 4 and 8, Day 1 pre- and post-dose (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.
12. Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) [ Time Frame: Dato-DXd: Cycle 1 Day 1 and Day 8 and Cycle 2 Day 1; Durvalumab: Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 21 days) ]
    The immunogenicity of datopotamab deruxtecan (Dato-DXd) and durvalumab will be assessed.
13. Proportion of Participants Who Have Treatment-emergent ADA [ Time Frame: Dato-DXd: Cycle 1 Day 1 and Day 8 and Cycle 2 Day 1; Durvalumab: Cycle 1 Day 1 and Cycle 2 Day 1 (each cycle is 21 days) ]
    The immunogenicity of datopotamab deruxtecan (Dato-DXd) and durvalumab will be assessed.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Subject ≥18 years old on the day of signing the ICF (local regulatory requirements to consent should be followed).
• Advanced or metastatic NSCLC, histologically confirmed at diagnosis of NSCLC, documented negative test results for EGFR and ALK genomic alterations, and no known genomic alterations in ROS1, NTRK, BRAF, RET, MET, or other actionable driver kinases with approved therapies (actionable genomic alterations).
• Is not a candidate for surgical resection or chemoradiation with curative intent.
• Documentation of radiological disease progression while on or after receiving the most recent treatment regimen, if any, for advanced or metastatic NSCLC.
• Must be treatment-naïve or have received only 1 prior line of systemic chemotherapy, without concomitant immune checkpoint inhibitors (ICIs) including anti- PD-1/PD-L1, anti-PD-L2, and anti-CTLA-4 for advanced or metastatic NSCLC.
• Willing and able to undergo a mandatory tumor biopsy. There is no requirement for PD-L1 protein expression for inclusion.
• Archival tumor tissue from initial diagnosis, to the extent that archival tumor tissue is available, for measurement of TROP2 expression levels or other biomarkers.
• Eastern Cooperative Oncology Group performance status (ECOG PS) 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.

Exclusion Criteria:

• Experienced grade 3 or higher immune-related adverse events with prior immunotherapy treatment.
• Received a live vaccine within 30 days prior to the first dose of study treatment.
• Active, known, or suspected autoimmune disease.
• Has a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of Cycle 1 Day 1.
• Prior allogenic organ transplantation.
• Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients (including but not limited to polysorbate 80) of Dato-DXd or durvalumab, and carboplatin for participants to be enrolled in relevant cohorts.
• Uncontrolled or significant cardiac disease.
• 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.
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Known human immunodeficiency virus (HIV) infection that is not well controlled.
• Active hepatitis or uncontrolled hepatitis B or C infection; is positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [anti-HBs], hepatitis B core antibody [anti-HBc, or hepatitis B virus [HBV] DNA) or hepatitis C (HCV antibody OR HCV RNA) infection.
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses.

• History of another primary malignancy, (beyond NSCLC) except for:

  1. Malignancy treated with curative intent and with no known active disease ≥3 years before the first dose of study treatment and of low potential risk for recurrence.
  2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
  3. Adequately treated carcinoma in situ without evidence of disease.
  4. Participants with a history of prostate cancer.
• Toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet improved to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 Grade ≤1 or baseline.

Contacts and Locations

Contacts

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

Locations

United States, California

Research Site; Recruiting

Santa Ana, California, United States, 92705

United States, Missouri

Research Site; Recruiting

Saint Louis, Missouri, United States, 63110

United States, New Jersey

Research Site; Recruiting

Hackensack, New Jersey, United States, 07601

United States, Ohio

Research Site; Recruiting

Cleveland, Ohio, United States, 44106

United States, Texas

Research Site; Recruiting

Dallas, Texas, United States, 75230

Research Site; Recruiting

San Antonio, Texas, United States, 78229

United States, Virginia

Research Site; Not yet recruiting

Fairfax, Virginia, United States, 22031

France

Research Site; Not yet recruiting

Paris Cedex 05, France, 75248

Japan

Research Site; Recruiting

Koto-ku, Japan, 135-8550

Research Site; Recruiting

Sunto-gun, Japan, 411-8777

Research Site; Recruiting

Yokohama-shi, Japan, 241-8515

Sponsors and Collaborators

AstraZeneca

Daiichi Sankyo, Inc.

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT04612751
• Other Study ID Numbers: D926FC00001; 2021-000274-28 ( EudraCT Number )
• First Posted: November 3, 2020
• Last Update Posted: May 19, 2022
• Last Verified: May 2022

Individual Participant Data (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; Statistical Analysis Plan (SAP); 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

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

Keywords provided by AstraZeneca:

Advanced or Metastatic NSCLC; Datopotamab deruxtecan (Dato-DXd); DS-1062a; Durvalumab

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carboplatin; Durvalumab; Antineoplastic Agents; Antineoplastic Agents, Immunological