Patritumab Deruxtecan in Combination With Osimertinib in Subjects With Locally Advanced or Metastatic EGFR-mutated Non-Small Cell Lung Cancer
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
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. The starting combination dose regimen is patritumab deruxtecan 3.2 mg/kg IV every 21 days (Q3W) and osimertinib 80 mg orally (PO) once daily. At least 3 to 6 subjects will be enrolled in each cohort.
Dose Expansion: Two subject populations will be evaluated in the Dose Expansion Part:
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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
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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. Note: The first line expansion will only be initiated if the RCD includes osimertinib 80 mg PO once daily.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose Escalation: Patritumab deruxtecan + osimertinib Participants in the Dose Escalation phase will receive patritumab deruxtecan IV Q3W + osimertinib PO once daily. The dose of patritumab deruxtecan in the first cohort will be 3.2 mg/kg Q3W. The dose of osimertinib in the first cohort will be 80 mg PO once daily. |
Drug: Patritumab deruxtecan
Intravenous infusion at a starting dose of 3.2 mg/kg Q3W
Other Names:
Drug: Osimertinib
Oral administration at 40 mg or 80 mg once daily
|
| Experimental: Second-line Dose Expansion: Patritumab deruxtecan + osimertinib (RCD) Participants in the Second-line Dose Expansion phase will be randomized to receive patritumab deruxtecan + osimertinib at the RCD 1 (and at RCD 2 if two provisional RCDs are selected in dose escalation) |
Drug: Patritumab deruxtecan
Intravenous infusion at RCD 1 (and at RCD 2 if two provisional RCDs are selected in dose escalation)
Other Names:
Drug: Osimertinib
Oral administration at RCD 1 (and at RCD 2 if two provisional RCDs are selected in dose escalation)
|
| Experimental: Second-line Dose Expansion: Patritumab deruxtecan Participants in the Second-line Dose Expansion phase will be randomized to receive patritumab deruxtecan 5.6 mg/kg IV Q3W |
Drug: Patritumab deruxtecan
Intravenous infusion 5.6 mg/kg Q3W
Other Names:
|
| Experimental: First-line Dose Expansion: Patritumab deruxtecan + osimertinib (RCD) If the RCD includes an osimertinib dose of 80 mg PO once daily, then participants will receive treatment with patritumab deruxtecan and osimertinib at the RCD or, if relevant, at one of the provisional RCDs once established in dose escalation |
Drug: Patritumab deruxtecan
Intravenous infusion at the selected RCD
Other Names:
Drug: Osimertinib
Oral administration at 80 mg once daily
|
Outcome Measures
Primary Outcome Measures
- Dose Escalation: Incidence of Dose-limiting Toxicities (DLT), Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) [From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 9 months]
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.
- Second-line Dose Expansion: Objective Response Rate (ORR) [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 months]
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.
- First-line Dose Expansion: Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) [From signing of informed consent form up to 40 days (+7 days) after the last dose of study drugs, up to approximately 18 months]
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.
Secondary Outcome Measures
- Dose Escalation and First-line Dose Expansion: Objective Response Rate (ORR) [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)]
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.
- Second-line Dose Expansion: Objective Response Rate (ORR) [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 months]
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.
- Dose Escalation, Second-line Dose Expansion, and First-Line Dose Expansion: Duration of Response (DoR) [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)]
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
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Disease Control Rate (DCR) [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)]
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.
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Time to Response (TTR) [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)]
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.
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Progression-free Survival (PFS) [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)]
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
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Overall Survival (OS) [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)]
OS is defined as the time from the start of study treatment to the date of death due to any cause
- Second-line Dose Expansion: Incidence of Treatment-emergent Adverse Events (TEAE), Serious Adverse Events (SAE), Adverse Events of Special Interest (AESI) [From signing of informed consent form up to 40 (+7 days) days after the last dose of study drugs, up to approximately 18 months]
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.
- 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 [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)]
The immunogenicity of patritumab deruxtecan will be assessed.
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Maximum Concentration (Cmax) [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)]
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).
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Time to Maximum Concentration (Tmax) [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)]
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).
- Dose Escalation, Second-line Dose Expansion, and First-line Dose Expansion: Pharmacokinetic Parameter Area Under the Concentration-Time Curve (AUC) [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)]
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).
Eligibility Criteria
Criteria
Inclusion Criteria:
Inclusion Criteria Specific to Dose Escalation and Second-Line Dose Expansion:
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Documentation of EGFR exon 19 deletion or L858R mutation detected from tumor tissue
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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)
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Must not have received any other prior systemic cancer therapies in the locally advanced/metastatic setting
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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:
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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. Only tissue-based testing will be accepted.
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Participants must have previously untreated locally advanced or metastatic NSCLC and must be eligible to receive first-line treatment with osimertinib, according to the judgment of the investigator. Prior adjuvant or neo-adjuvant therapy (chemotherapy, radiotherapy, investigational agents; except with osimertinib) is permitted.
All Participants:
Participants must meet all criteria to be eligible for inclusion in this study:
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Histologically or cytologically documented locally advanced or metastatic NSCLC not amenable to curative surgery or radiation.
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At least 1 measurable lesion as assessed by Investigator as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
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For Second-Line Dose Expansion (Arm 1, Arm 2, and Arm 1b) and First-Line Dose Expansion (Cohort 3), willing to provide required tumor tissue of sufficient quantity (as defined in the laboratory manual) with adequate tumor tissue content (as confirmed by hematoxylin and eosin staining at central laboratory). The pre-treatment biopsy is optional for participants enrolled in the Dose Escalation Part (all cohorts). Required tumor tissue can be provided as either:
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Pre-treatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to core biopsy OR
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Archival tissue collected from a biopsy performed within 3 months prior to signing of the tissue consent and since progression while on the most recent cancer therapy regimen.
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On-study tumor biopsy is optional in Dose Escalation.
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Has adequate bone marrow reserve and organ function based on local laboratory data within 14 days prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose Expansion) or within 14 days prior to randomization (Second-Line Dose Expansion):
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Platelet count: ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to Cycle 1, Day 1 to meet eligibility)
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Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
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Absolute neutrophil count ; 1500/mm3 or ≥1.5 × 109/L
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Serum creatinine (SCr) OR creatinine clearance (CrCl): SCr ≤1.5 × ULN, OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when creatinine is >1.5 × ULN
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Aspartate aminotransferase/ alanine aminotransferase: ≤3 × ULN (if liver metastases are present, ≤5 × ULN)
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Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver metastases)
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Serum albumin ; ≥2.5 g/dL
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Prothrombin time (PT) or PT-international normalized ratio (INR) and Activated partial thromboplastin time (aPTT) / Partial thromboplastin time (PTT): ≤1.5 × ULN, except for subjects on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator.
Exclusion Criteria:
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Any previous histologic or cytologic evidence of small cell OR combined small cell/non-small cell disease in the archival tumor tissue or pre-treatment tumor biopsy.
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Any history of interstitial lung disease (including pulmonary fibrosis or radiation pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease by imaging during screening.
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Clinically severe pulmonary compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to:
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Any underlying pulmonary disorder (eg, pulmonary emboli within three months of the study enrollment or randomization, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion);
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Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR prior complete pneumonectomy.
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Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose Expansion) or prior to randomization (Second-Line Dose Expansion). Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the study.
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Evidence of any leptomeningeal disease.
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Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive or treated brain metastases who are asymptomatic (ie, without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study.
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Inadequate washout period prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose
Expansion) or prior to randomization (Second-Line Dose Expansion) defined as:
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Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days;
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Any systemic anticancer (excluding osimertinib in all Dose Escalation Cohorts and in Second-Line Dose Expansion [Arm 1, Arm 2, and Arm 1b]), including investigational agents, <14 days or 5 half-lives, whichever is longer
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Immune checkpoint inhibitor therapy <5 half-lives
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Major surgery (excluding placement of vascular access) <4 weeks
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Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation < 28 days or palliative radiation therapy <14 days
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Chloroquine or hydroxychloroquine ≤14 days
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Medications or herbal supplemented known to be strong inducers of cytochrome P450 (CYP) 3A4 <21 days.
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Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per the discretion of the Investigator after consultation with the Sponsor Medical Monitor or designee.
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Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow osimertinib, or previous significant bowel resection that would preclude adequate absorption of osimertinib.
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Has any primary malignancy other than locally advanced or metastatic NSCLC within 3 years prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose Expansion) or within 3 years prior to randomization (Second-Line Dose Expansion), except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated.
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Uncontrolled or significant cardiovascular disease prior to Cycle 1, Day 1 (Dose Escalation and First-Line Dose Expansion) or prior to randomization (Second-Line Dose
Expansion) including:
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Mean corrected QT interval using Fridericia's formula (QTcF) prolongation interval of >470 ms for females and >450 ms for males in 3 successive screening measurements
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Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
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Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg
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Myocardial infarction within 6 months
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New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure within 28 days
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Uncontrolled angina pectoris within 6 months
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Has cardiac arrhythmia requiring antiarrhythmic treatment
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Complete left or right bundle branch block within 6 months
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History of second- or third-degree heart block or PR interval >250 ms within 6 months
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History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
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Has any factors that increase the risk of corrected QT (QTc) prolongation or risk of arrhythmic events, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives, or any concomitant medication known to prolong the QT interval
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Has clinically significant corneal disease
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Any evidence of severe or uncontrolled diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the subject to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Massachusetts General Hospital Cancer Center | Boston | Massachusetts | United States | 02114 |
| 2 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215-5450 |
| 3 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
| 4 | Virginia Cancer Specialists, PC | Fairfax | Virginia | United States | 22031 |
| 5 | National Cancer Center Hospital | Chuo Ku | Tokyo | Japan | 104-0045 |
| 6 | The Cancer Institute Hospital of JFCR | Tokyo | Japan | 135-8550 | |
| 7 | Kindai University Hospital | Ōsaka-sayama | Japan | 589-8511 |
Sponsors and Collaborators
- Daiichi Sankyo, Inc.
Investigators
- Study Director: Global Clinical Leader, Daiichi Sankyo, Inc.
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- U31402-A-U103
- 2020-003064-87