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Phase III, Open-label, First-line Study of Dato-DXd in Combination With Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations (AVANZAR)

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ClinicalTrials.gov Identifier: NCT05687266
Recruitment Status : Recruiting
First Posted : January 18, 2023
Last Update Posted : April 9, 2024
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE December 28, 2022
First Posted Date  ICMJE January 18, 2023
Last Update Posted Date April 9, 2024
Actual Study Start Date  ICMJE December 29, 2022
Estimated Primary Completion Date February 22, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 17, 2023)
  • Progression-Free Survival (PFS) in the TROP2 biomarker positive population [ Time Frame: Approximately 3 Years ]
    PFS is defined as time from randomisation until progression per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR), or death due to any cause.
  • Overall Survival (OS) in the TROP2 biomarker positive population [ Time Frame: Approximately 4 years ]
    OS is defined as the time from randomisation until the date of death due to any cause.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2024)
  • PFS in the Intent-to-Treat (ITT) population [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
  • OS in the ITT population [ Time Frame: Approximately 4 years ]
    OS is defined as the time from randomisation until the date of death due to any cause.
  • PFS in the TROP2 biomarker negative population [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
  • OS in the TROP2 biomarker negative population [ Time Frame: Approximately 4 years ]
    OS is defined as the time from randomisation until the date of death due to any cause.
  • Objective Response Rate (ORR) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    ORR is defined as the proportion of participants who have a confirmed Complete Response (CR) or confirmed Partial Response (PR), as determined by BICR and investigator per RECIST 1.1.
  • Duration of Response (DoR) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR and investigator assessment or death due to any cause.
  • PFS in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator assessment, or death due to any cause.
  • Pharmacokinetics of Dato-DXd when combined with durvalumab and carboplatin. [ Time Frame: Approximately 4 years ]
    Concentration of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma and pharmacokinetic (PK) parameters (such as peak and trough concentrations, as data allow; sparse sampling).
  • Anti-Drug Antibody (ADA) for Dato-DXd [ Time Frame: Approximately 4 years ]
    The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin.
  • Time to Second Progression or Death (PFS2) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    PFS2 is defined as the time from randomisation to the earliest of the progression events (following the initial progression), subsequent to first subsequent therapy, or death.
  • Clinical Outcome Assessments such as TTD in pulmonary symptoms (dyspnoea, cough and chest pain) as measured by the NSCLC-SAQ, and TTD in physical functioning as measured by PROMIS Physical Function short form 8c [ Time Frame: Approximately 4 years ]
    TTD is defined as the time from randomisation until the date of deterioration.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 17, 2023)
  • PFS in the Intent-to-Treat (ITT) population [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
  • OS in the ITT population [ Time Frame: Approximately 4 years ]
    OS is defined as the time from randomisation until the date of death due to any cause.
  • PFS in the TROP2 biomarker negative population [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
  • OS in the TROP2 biomarker negative population [ Time Frame: Approximately 4 years ]
    OS is defined as the time from randomisation until the date of death due to any cause.
  • Objective Response Rate (ORR) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    ORR is defined as the proportion of participants who have a confirmed Complete Response (CR) or confirmed Partial Response (PR), as determined by BICR and investigator per RECIST 1.1.
  • Duration of Response (DoR) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    DoR is defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1, as assessed by BICR and investigator assessment or death due to any cause.
  • PFS in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 3 years ]
    PFS is defined as time from randomisation until progression per RECIST 1.1 as assessed by investigator assessment, or death due to any cause.
  • Pharmacokinetics of Dato-DXd when combined with durvalumab and carboplatin. [ Time Frame: Approximately 4 years ]
    Concentration of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a in plasma and pharmacokinetic (PK) parameters (such as peak and trough concentrations, as data allow; sparse sampling).
  • Anti-Drug Antibody (ADA) for Dato-DXd [ Time Frame: Approximately 4 years ]
    The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin.
  • Time to Second Progression or Death (PFS2) in the TROP2 biomarker positive and ITT populations [ Time Frame: Approximately 4 years ]
    PFS2 is defined as the time from randomisation to the earliest of the progression events (following the initial progression), subsequent to first subsequent therapy, or death.
Current Other Pre-specified Outcome Measures
 (submitted: January 17, 2023)
Safety of Dato-DXd in combination with durvalumab and carboplatin [ Time Frame: Approximately 4 years ]
Safety and tolerability will be evaluated in terms of AEs (graded by CTCAE Version 5.0).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Phase III, Open-label, First-line Study of Dato-DXd in Combination With Durvalumab and Carboplatin for Advanced NSCLC Without Actionable Genomic Alterations
Official Title  ICMJE A Phase III, Randomised, Open-label, Multicentre, Global Study of Datopotamab Deruxtecan (Dato-DXd) in Combination With Durvalumab and Carboplatin Versus Pembrolizumab in Combination With Platinum-based Chemotherapy for the First-line Treatment of Patients With Locally Advanced or Metastatic NSCLC Without Actionable Genomic Alterations (D926NC00001; AVANZAR)
Brief Summary This is a Phase III, randomized, open-label, multicenter, global study to compare the efficacy and safety of Datopotamab Deruxtecan (Dato-DXd) in combination with durvalumab and carboplatin compared with pembrolizumab in combination with histology-specific platinum-based chemotherapy as first-line treatment of adults with stage IIIB, IIIC, or IV NSCLC without actionable genomic alterations (including sensitizing EGFR mutations, and ALK and ROS1 rearrangements).
Detailed Description

Participants with locally advanced or metastatic NSCLC without actionable tumor tissue genomic alterations and confirmed to meet all eligibility criteria will be randomized in a 1:1 ratio to Dato-DXd in combination with durvalumab and carboplatin versus pembrolizumab in combination with histology-specific platinum-based chemotherapy as first-line treatment.

The primary objectives of the study are to demonstrate superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum-based chemotherapy by assessment of Progression Free Survival (PFS) by BICR and Overall Survival (OS) in first-line treatment of TROP2 biomarker positive participants.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:
None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE NSCLC
Intervention  ICMJE
  • Drug: Datopotamab deruxtecan
    Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
    Other Name: Dato-DXd
  • Drug: Durvalumab
    Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle.
    Other Name: MEDI4736, Imfinzi
  • Drug: Carboplatin
    Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
  • Drug: Pembrolizumab
    Intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of each 21-day cycle for a maximum of 35 cycles or 2 years (whichever occurs first).
  • Drug: Cisplatin
    Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
  • Drug: Pemetrexed
    Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle.
  • Drug: Paclitaxel
    Intravenous (IV) infusion every 3 weeks on Day 1 of each 21-day cycle for up to 4 cycles.
Study Arms  ICMJE
  • Experimental: Dato-DXd + Durvalumab + Carboplatin
    Participants will be randomized to receive 6.0mg/kg Dato-DXd plus 1120 mg durvalumab plus carboplatin area under the curve [AUC] 5 mg/mL/minute.
    Interventions:
    • Drug: Datopotamab deruxtecan
    • Drug: Durvalumab
    • Drug: Carboplatin
  • Active Comparator: Histologic-specific therapy

    Non-squamous NSCLC participants will be randomized to receive 200 mg pembrolizumab plus 500 mg/m2 pemetrexed plus either AUC 5 mg/mL/minute carboplatin or 75 mg/m2 cisplatin.

    Squamous NSCLC participants will be randomized to receive 200 mg of pembrolizumab plus 200 mg/m2 paclitaxel plus AUC 5 or 6 mg/mL/minute carboplatin.

    Interventions:
    • Drug: Carboplatin
    • Drug: Pembrolizumab
    • Drug: Cisplatin
    • Drug: Pemetrexed
    • Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 2, 2024)
1280
Original Estimated Enrollment  ICMJE
 (submitted: January 17, 2023)
1000
Estimated Study Completion Date  ICMJE February 22, 2027
Estimated Primary Completion Date February 22, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion:

  • Participants ≥ 18 years at screening
  • Histologically or cytologically documented NSCLC that at the time of randomisation is Stage IIIB or IIIC disease not amenable to surgical resection or definitive chemoradiation or Stage IV metastatic disease
  • Lacks sensitising EGFR tumour tissue mutation and ALK and ROS1 rearrangements and has no documented tumour genomic alterations in NTRK, BRAF, RET, MET or other actionable driver oncogenes with approved and available therapies (actionable genomic alterations).

Testing is not required for tumors with squamous histology, with exceptions.

  • ECOG PS of 0 or 1
  • Archival tumour tissue
  • Has adequate bone marrow reserve and organ function within 7 days before randomization

Exclusion:

  • Mixed small-cell lung cancer and NSCLC histology; sarcomatoid variant of NSCLC
  • History of another primary malignancy with exceptions
  • Persistent toxicities caused by previous anti-cancer therapy not yet improved to Grade ≤ 1 or baseline, with exceptions.
  • Spinal cord compression or clinically or radiologically active brain metastases
  • History of leptomeningeal carcinomatosis.
  • Known active or uncontrolled hepatitis B or C virus infection.
  • Uncontrolled or suspected infection requiring IV antibiotics, antivirals, or antifungals.
  • Clinically significant corneal disease
  • History of non-infectious ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Listed Location Countries  ICMJE Austria,   Brazil,   Bulgaria,   Canada,   China,   Denmark,   France,   Germany,   Greece,   Hungary,   India,   Italy,   Japan,   Korea, Republic of,   Mexico,   Peru,   Poland,   Spain,   Sweden,   Taiwan,   Turkey,   United Kingdom,   United States,   Vietnam
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05687266
Other Study ID Numbers  ICMJE D926NC00001
2021-004606-21 ( EudraCT Number )
Has Data Monitoring Committee Yes
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  ICMJE
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 Vivli.org. 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)
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA/PhRMA Data-Sharing Principles. For details of our timelines, please refer 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 anonymized individual patient-level data via secure research environment Vivli.org. A Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.
URL: https://vivli.org/
Current Responsible Party AstraZeneca
Original Responsible Party Same as current
Current Study Sponsor  ICMJE AstraZeneca
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Charu Aggarwal Perelman Center for Advanced Medicine
PRS Account AstraZeneca
Verification Date April 2024

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP