This study includes a Dose Escalation Part to identify the recommended combination dose (RCD) and a Dose Expansion Part to further evaluate efficacy and safety. The primary objectives: Dose Escalation: To assess the safety and tolerability of patritumab deruxtecan (U3-1402) and osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib, and to determine the recommended combination dose (RCD). Second-Line Dose Expansion Arm 1 and Arm 1b: To assess the preliminary antitumor activity of patritumab deruxtecan and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. Note: One or both of the study arms may open with one or two distinct dosing schedules. Second-Line Dose Expansion Arm 2: To assess the preliminary antitumor activity of patritumab deruxtecan monotherapy in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. First-Line Dose Expansion: To assess the safety and tolerability of patritumab deruxtecan and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation without prior systemic treatment for locally advanced or metastatic disease.
Name: Patritumab deruxtecan
Name: Patritumab deruxtecan
Name: Osimertinib
Name: Osimertinib
Name: Patritumab deruxtecan
Name: Patritumab deruxtecan
Name: Osimertinib
Description: A DLT is defined as any TEAE not attributable to disease or disease-related processes that occurs during the DLT evaluation period and is ≥Grade 3, with exceptions as defined in the protocol. A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. AEs will be coded using MedDRA and graded using NCI-CTCAE v5.0.
Measure: Dose Escalation: Incidence of Dose-limiting Toxicities (DLT), Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) Time: From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 9 monthsDescription: ORR is defined as the proportion of participants who achieved a best overall response of confirmed complete response (CR) or confirmed partial response (PR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version (RECIST) v1.1.
Measure: Second-line Dose Expansion: Objective Response Rate (ORR) Time: From start of study treatment until date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 monthsDescription: A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.
Measure: First-line Dose Expansion: Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) Time: From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 18 monthsDescription: ORR is defined as the proportion of participants who achieved a best overall response of confirmed CR or confirmed PR as assessed by BICR and Investigator per RECIST v1.1.
Measure: Dose Escalation and First-line Dose Expansion: Objective Response Rate (ORR) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: ORR is defined as the proportion of participants who achieved a best overall response of confirmed CR or PR as assessed by Investigator per RECIST v1.1.
Measure: Second-line Dose Expansion: Objective Response Rate (ORR) Time: From start of study treatment until the date of documented disease progression or other protocol-defined reason for discontinuation from the study (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 18 monthsDescription: DOR is defined as the time from the date of the first documentation of response (confirmed CR or confirmed PR) to the date of the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first. DoR as assessed by BICR and Investigator per RECIST v1.1
Measure: Dose Escalation, Second-line Dose Expansion, and First-Line Dose Expansion: Duration of Response (DoR) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: DCR is defined as the proportion of participants who achieved a best overall response of confirmed CR, confirmed PR, or stable disease (SD) as assessed by BICR and by Investigator per RECIST v1.1.
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Disease Control Rate (DCR) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: TTR is defined as the time from the start of study treatment to the date of the first documentation of response (confirmed CR or confirmed PR) in responding participants as assessed by BICR and by Investigator per RECIST v1.1.
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Time to Response (TTR) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: PFS is defined as the time from the start of study treatment to the date of the first documentation of objective PD as assessed by BICR and by Investigator per RECIST v1.1. or death due to any cause, whichever occurs first
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Progression-free Survival (PFS) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: OS is defined as the time from the start of study treatment to the date of death due to any cause
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Overall Survival (OS) Time: From start of treatment until date of disease progression or other reason for discontinuation (e.g, withdrawal of consent, lost to follow-up), whichever occurs first, up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: A TEAE is defined as an adverse event (AE) with a start or worsening date during the on-treatment period. A serious AE is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is an important medical event, or may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes noted. AESIs will also be assessed. Adverse events will be coded using MedDRA and will be graded using NCI-CTCAE v5.0.
Measure: Second-line Dose Expansion: Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) Time: From signing of informed consent form up to 40 (+7 days) days after the last dose of study drugs, up to approximately 18 monthsDescription: The immunogenicity of patritumab deruxtecan will be assessed.
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Proportion of Participants Who Are Anti-Drug Antibody (ADA)-Positive (Baseline and Post-Baseline) and Proportion of Participants Who Have Treatment-emergent ADA Time: From the start of study treatment until the end of treatment or study discontinuation (whichever occurs first), up to approximately 9 months (Dose Escalation) and 18 months (Dose Expansion)Description: Cmax will be assessed for patritumab deruxtecan, total anti-HER3 antibody, MAAA-1181a, osimertinib (except for Second-line Dose Expansion Arm 2), and AZ5104 (active metabolite of osimertinib; except for Second-line Dose Expansion Arm 2).
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Maximum Concentration (Cmax) Time: Patritumab deruxtecan: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)Description: Tmax will be assessed for patritumab deruxtecan, total anti-HER3 antibody, MAAA-1181a, osimertinib (except for Second-line Dose Expansion Arm 2), and AZ5104 (active metabolite of osimertinib; except for Second-line Dose Expansion Arm 2).
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) Time: Patritumab deruxtecan: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)Description: AUC up to the last quantifiable time (AUClast) and AUC during dosing interval (AUCtau) will be assessed for patritumab deruxtecan, total anti-HER3 antibody, MAAA-1181a, osimertinib (except for Second-line Dose Expansion Arm 2), and AZ5104 (active metabolite of osimertinib; except for Second-line Dose Expansion Arm 2).
Measure: Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Area Under the Concentration-Time Curve (AUC) Time: Patritumab deruxtecan: Cycles 1 and 3, Day 1 pre- and postdose, 4 hours (h), Days 8 and 15; Cycle 2, Day 1 pre- and postdose; Cycles 4, 6, 8, Day 1 pre- and postdose; Osimertinib: Cycles 1, 2, and 3, Day 1 pre- and postdose, 4 h (each cycle is 21 days)Allocation: Non-Randomized
Sequential Assignment
There is one SNP
The primary objectives: Dose Escalation: To assess the safety and tolerability of patritumab deruxtecan (U3-1402) and osimertinib in subjects with locally advanced or metastatic non-small cell lung cancer (NSCLC) with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib, and to determine the recommended combination dose (RCD). --- L858R ---
Second-Line Dose Expansion Arm 1 and Arm 1b: To assess the preliminary antitumor activity of patritumab deruxtecan and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. --- L858R ---
Second-Line Dose Expansion Arm 2: To assess the preliminary antitumor activity of patritumab deruxtecan monotherapy in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. --- L858R ---
First-Line Dose Expansion: To assess the safety and tolerability of patritumab deruxtecan and osimertinib in subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation without prior systemic treatment for locally advanced or metastatic disease. --- L858R ---
AUC up to the last quantifiable time (AUClast) and AUC during dosing interval (AUCtau) will be assessed for patritumab deruxtecan, total anti-HER3 antibody, MAAA-1181a, osimertinib (except for Second-line Dose Expansion Arm 2), and AZ5104 (active metabolite of osimertinib; except for Second-line Dose Expansion Arm 2).. Inclusion Criteria: Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion: - Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue - Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1) - Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting - Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting Inclusion Criteria Specific to First-line Dose Expansion: - The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US] sites), accredited (outside of the US), local laboratory or central laboratory. --- L858R ---
AUC up to the last quantifiable time (AUClast) and AUC during dosing interval (AUCtau) will be assessed for patritumab deruxtecan, total anti-HER3 antibody, MAAA-1181a, osimertinib (except for Second-line Dose Expansion Arm 2), and AZ5104 (active metabolite of osimertinib; except for Second-line Dose Expansion Arm 2).. Inclusion Criteria: Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion: - Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue - Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1) - Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting - Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting Inclusion Criteria Specific to First-line Dose Expansion: - The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US] sites), accredited (outside of the US), local laboratory or central laboratory. --- L858R --- --- L858R ---
Inclusion Criteria: Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion: - Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue - Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1) - Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting - Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting Inclusion Criteria Specific to First-line Dose Expansion: - The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US] sites), accredited (outside of the US), local laboratory or central laboratory. --- L858R ---
Inclusion Criteria: Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion: - Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue - Must have received osimertinib for locally advanced or metastatic disease at a dose of 80 mg once daily (QD) for at least 6 weeks and must not miss more than two doses during the 2 weeks prior to the first day of study treatment (Cycle 1, Day 1) - Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting - Has documentation of radiological disease progression following first-line treatment with osimertinib in the locally advanced or metastatic setting Inclusion Criteria Specific to First-line Dose Expansion: - The tumor tissue harbors one of the 2 common EGFR mutations occurring in NSCLC known to be associated with EGFR-TKI sensitivity (exon 19 deletion or L858R) as assessed by Clinical Laboratory Improvement Amendments (CLIA)-certified (United States [US] sites), accredited (outside of the US), local laboratory or central laboratory. --- L858R --- --- L858R ---
Non-Small Cell Lung Cancer (NSCLC) Lung Neoplasms Carcinoma, Non-Small-Cell Lung Dose Escalation: Population includes subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib. --- L858R ---
Dose Expansion: Two subject populations will be evaluated in the Dose Expansion Part: - Second-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib - First-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation, and without prior systemic therapy for advanced or metastatic disease. --- L858R ---
Dose Expansion: Two subject populations will be evaluated in the Dose Expansion Part: - Second-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation with tumor progression after treatment with osimertinib - First-Line: Subjects with locally advanced or metastatic NSCLC with an EGFR exon 19 deletion or L858R mutation, and without prior systemic therapy for advanced or metastatic disease. --- L858R --- --- L858R ---