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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

Study Description
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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).

Condition or disease Intervention/treatment Phase
NSCLC Drug: Datopotamab deruxtecan Drug: Durvalumab Drug: Carboplatin Drug: Pembrolizumab Drug: Cisplatin Drug: Pemetrexed Drug: Paclitaxel Phase 3

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1280 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description: None (Open Label)
Primary Purpose: Treatment
Official Title: 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)
Actual Study Start Date : December 29, 2022
Estimated Primary Completion Date : February 22, 2027
Estimated Study Completion Date : February 22, 2027

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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.
 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.
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.

 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.


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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).

  9. Anti-Drug Antibody (ADA) for Dato-DXd [ Time Frame: Approximately 4 years ]
    The immunogenicity of Dato-DXd when combined with durvalumab and carboplatin.

  10. 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.

  11. 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.


Other Outcome Measures:
  1. 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).


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05687266


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

Locations
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Sponsors and Collaborators
AstraZeneca
Investigators
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Study Chair: Charu Aggarwal Perelman Center for Advanced Medicine
More Information
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT05687266    
Other Study ID Numbers: D926NC00001
2021-004606-21 ( EudraCT Number )
First Posted: January 18, 2023    Key Record Dates
Last Update Posted: April 9, 2024
Last Verified: April 2024
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 Vivli.org. 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)
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/

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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 Non-Small Cell Lung Cancer (NSCLC)
Datopotamab deruxtecan (Dato-DXd)
Durvalumab
Carboplatin
 Chemotherapy
Antibody-Drug Conjugate (ADC)
Trophoblast cell surface protein 2 (TROP2)
Additional relevant MeSH terms:
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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
Paclitaxel
Carboplatin
Pembrolizumab
 Pemetrexed
Durvalumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immune Checkpoint Inhibitors
Enzyme Inhibitors
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors