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

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

Tracking Information

• First Submitted Date: December 28, 2022
• First Posted Date: January 18, 2023
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: December 29, 2022
• Estimated Primary Completion Date: February 22, 2027 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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 (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: 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: 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: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Masking Description:

None (Open Label)

Primary Purpose: Treatment

• Condition: NSCLC

Intervention

• 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

• 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

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 2, 2024): 1280
• Original Estimated Enrollment (submitted: January 17, 2023): 1000
• Estimated Study Completion Date: February 22, 2027
• Estimated Primary Completion Date: February 22, 2027 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 130 Years (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: 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

Administrative Information

• NCT Number: NCT05687266
• Other Study ID Numbers: 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

• 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: AstraZeneca
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Charu Aggarwal; Perelman Center for Advanced Medicine

• PRS Account: AstraZeneca
• Verification Date: April 2024