Brief Summary
This study will assess the effect of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in terms of progression-free survival (PFS).
Brief Title
A Study to Investigate the Efficacy and Safety of Dato-DXd With or Without Osimertinib Compared With Platinum Based Doublet Chemotherapy in Participants With EGFR-Mutated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
Detailed Description
This is a Phase III, open-label, 3-arm, multicenter study assessing the effects of Dato-DXd in combination with osimertinib or Dato-DXd monotherapy versus platinum-based doublet chemotherapy in participants with epidermal growth factor receptor gene mutation (EGFRm) locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on prior osimertinib treatment.
Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups:
1. Dato-DXd + osimertinib combination therapy
2. Dato-DXd monotherapy
3. Platinum-based doublet chemotherapy
Participants will receive study intervention until Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) -defined radiological progression by the investigator, unacceptable toxicity, or other discontinuation criterion is met.
After study intervention discontinuation, all participants will undergo an end of treatment (EoT) visit within 35 days of discontinuation and will be followed up for safety assessments 28 (+ 7) days after their last dose of study intervention.
Participants will be randomized in a 1:1:1 ratio to one of the following intervention groups:
1. Dato-DXd + osimertinib combination therapy
2. Dato-DXd monotherapy
3. Platinum-based doublet chemotherapy
Participants will receive study intervention until Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) -defined radiological progression by the investigator, unacceptable toxicity, or other discontinuation criterion is met.
After study intervention discontinuation, all participants will undergo an end of treatment (EoT) visit within 35 days of discontinuation and will be followed up for safety assessments 28 (+ 7) days after their last dose of study intervention.
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
1-877-240-9479
Central Contact Email
information.center@astrazeneca.com
Completion Date
Completion Date Type
Estimated
Conditions
Metastatic Non-small Cell Lung Cancer
Eligibility Criteria
Inclusion Criteria:
* Histologically or cytologically confirmed non-squamous NSCLC.
* Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomization.
Exclusion Criteria:
* Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.
* Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
* Has significant third-space fluid retention (example \[eg.\], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.
* History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.
* Unstable spinal cord compression and/or unstable brain metastases.
* Participants with symptomatic brain metastases (including leptomeningeal involvement).
* Clinically significant corneal disease.
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections.
* Has known human immunodeficiency virus (HIV) infection that is not well controlled.
* Histologically or cytologically confirmed non-squamous NSCLC.
* Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomization.
Exclusion Criteria:
* Use of chemotherapy, vascular endothelial growth factor inhibitor, immunotherapy or any anti-cancer therapy in the metastatic setting. Platinum-based chemotherapy in non-metastatic setting within 12 months prior to randomization.
* History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 2 years before the first dose of study intervention.
* Any evidence of severe or uncontrolled systemic diseases, including, but not limited to active bleeding diseases, active infection, active ILD/pneumonitis, cardiac disease.
* Has significant third-space fluid retention (example \[eg.\], ascites or pleural effusion) as judged by the investigator and is not amenable for required repeated drainage.
* History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids or drug-induced ILD, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
* Has severe pulmonary function compromise resulting from intercurrent pulmonary illnesses.
* Unstable spinal cord compression and/or unstable brain metastases.
* Participants with symptomatic brain metastases (including leptomeningeal involvement).
* Clinically significant corneal disease.
* Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, suspected infections or inability to rule out infections.
* Has known human immunodeficiency virus (HIV) infection that is not well controlled.
Inclusion Criteria
Inclusion Criteria:
* Histologically or cytologically confirmed non-squamous NSCLC.
* Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomization.
* Histologically or cytologically confirmed non-squamous NSCLC.
* Must have evidence of documented pre-existing EGFRm information (EGFRm known to be associated with (epidermal growth factor receptor \[EGFR\] tyrosine kinase inhibitor \[TKis\] sensitivity \[Ex19del, L858R, G719X, S768I, or L861Q\], either alone or in combination with other EGFR mutations, which may include T790M).
* Documented extra-cranial radiologic progression on prior osimertinib monotherapy (as most recent line of treatment) in the adjuvant, locally advanced, or metastatic setting.
* Less than or equal to (\<=2) prior lines of EGFR TKIs (osimertinib is the only permitted prior third generation EGFR TKI).
* At least one lesion, not previously irradiated, that qualifies as a RECIST v1.1 TL at baseline and can be accurately measured at baseline.
* World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
* Adequate bone marrow reserve and organ function within 7 days before randomization.
Gender
All
Gender Based
false
Keywords
Epidermal growth factor receptor gene mutation
Standard of Care
Locally, advanced carcinoma
Metastatic carcinoma
Non-small cell lung cancer
Dato-dxd
Datopotamab deruxtecan
Osimertinib
Tagrisso
Pemetrexed
Carboplatin
Cisplatin
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT06417814
Org Class
Industry
Org Full Name
AstraZeneca
Org Study Id
D516KC00001
Overall Status
Recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase III, Open-label, Sponsor-blind, Randomized Study of Dato-DXd With or Without Osimertinib Versus Platinum-based Doublet Chemotherapy for Participants With EGFR-mutated Locally Advanced or Metastatic Non-small Cell Lung Cancer Whose Disease Has Progressed on Prior Osimertinib Treatment (TROPION-Lung15)
Primary Outcomes
Outcome Description
PFS is defined as the time from randomization to Blinded Independent Central Review (BICR)-assessed progression using RECIST v1.1 or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinical progression.
Outcome Measure
Progression free Survival (PFS)
Outcome Time Frame
Up to 2.5 years
Secondary Ids
Secondary Id
2024-511362-37-00
Secondary Outcomes
Outcome Description
OS is defined as time from randomization until the date of death due to any cause.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Overall Survival (OS)
Outcome Description
CNS PFS is defined as the time from randomization to BICR confirmed progression in the CNS or death due to any cause, regardless of whether the participant withdraws from study therapy, receives other anti-cancer therapy, or clinically progresses prior to BICR confirmed CNS modified RECIST v1.1 progression.
Outcome Time Frame
Up to 2.5 years
Outcome Measure
Central Nervous System Progression-free Survival (CNS PFS)
Outcome Description
ORR is defined as the percentage of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by BICR per RECIST v1.1.
Outcome Time Frame
Up to 2.5 years
Outcome Measure
Objective Response Rate (ORR)
Outcome Description
DoR is defined as the time from the date of first documented response until date of documented progression per RECIST v1.1, as assessed by BICR or death due to any cause.
Outcome Time Frame
Up to 2.5 years
Outcome Measure
Duration of Response (DoR)
Outcome Description
PFS2 is defined as the time from randomization to the earliest of the progression event (following the initial investigator assessed progression), after first subsequent therapy, or death.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Progression-free Survival-2 (PFS-2)
Outcome Description
ORR is defined as the percentage of participants who have a confirmed CR or confirmed PR, using CNS modified RECIST v1.1.
Outcome Time Frame
Up to 2.5 years
Outcome Measure
Objective Response Rate (ORR) Using CNS Modified RECIST v1.1
Outcome Description
DoR is defined as the time from the date of first documented response until date of documented progression or death due to any cause using CNS modified RECIST v1.1.
Outcome Time Frame
Up to 2.5 years
Outcome Measure
Duration of Response (DoR) Using CNS Modified RECIST v1.1
Outcome Description
Time to deterioration (in pulmonary symptoms \[dyspnea, cough, and chest pain\]) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Time to Deterioration in Pulmonary Symptoms
Outcome Description
Time to deterioration in physical functioning as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function short form 8c will be evaluated. Time to deterioration (in physical functionating) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Time to Deterioration in Physical Functioning
Outcome Description
Time to deterioration in GHS/QoL as measured by the GHS/QoL scale from EORTC IL172 will be reported. Time to deterioration (in GHS/QoL) is defined as the time from randomization until the date of deterioration. Deterioration is defined as change from baseline that reaches a meaningful change threshold.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Time to Deterioration in Global Health Status (GHS)/Quality of Life (QoL)
Outcome Description
Concentration of Dato-DXd, total anti-TROP2 antibody and DXd in plasma.
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Pharmacokinetics (PK) of Dato-DXd
Outcome Description
Presence of antidrug antibody (ADAs) for Dato-DXd (confirmatory results: positive or negative, titers).
Outcome Time Frame
Up to 3.5 years
Outcome Measure
Immunogenicity of Dato-DXd
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Balazs Halmos
Investigator Email
bahalmos@montefiore.org