U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This study is designed to evaluate safety and antitumor activity of U3-1402 in two parts: Dose Escalation and Dose Expansion. In Dose Escalation, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with epidermal growth factor receptor (EGFR) activating mutation after disease progression during/after EGFR tyrosine kinase inhibitor (TKI) therapy. In Dose Expansion, U3-1402 will be evaluated in participants with metastatic or unresectable NSCLC with EGFR activating mutation or squamous or non-squamous NSCLC (ie, without EGFR-activating mutations) with disease progression during/after systemic treatment for locally advanced or metastatic disease.

Detailed Description
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The primary objectives are: For Dose Escalation, to assess the safety and tolerability of U3-1402 in the study population and to determine the recommended dose for expansion (RDE) of U3-1402 in the study population For Dose Expansion, to investigate the antitumor activity of U3-1402 The number of treatment cycles is not fixed in this study. Participants will continue study treatment (for approximately 36 months) until they decide not to (withdraw consent), their disease gets worse [progressive disease (PD)], or side effects become unacceptable (unacceptable toxicity) or other stopping reasons have been met.

Official Title
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A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: U3-1402 (FL-DP)
* Drug: U3-1402 (CTM-1 Lyo-DP)
* Drug: U3-1402 (CTM-3 Lyo-DP)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for both Dose Escalation and Dose Expansion: Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation Has at least one measurable lesion per RECIST version 1.1 Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening Inclusion Criteria for Dose Escalation only: Has histologically or cytologically documented adenocarcinoma NSCLC Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011) Historical confirmation that the tumor harbors an epidermal growth factor receptor (EGFR) mutation known to be associated with EGFR tyrosine kinase inhibitor (TKI) sensitivity (including G719X, exon 19 deletion, L858R, L861Q) Has experienced clinical benefit from an EGFR TKI, followed by systemic progression of disease [Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] or World Health Organization (WHO)] while on continuous treatment with an EGFR TKI Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib Has been receiving erlotinib, gefitinib, afatinib, or osimertinib for at least 6 weeks with well-controlled related toxicities less than Grade 3 in severity at the time of Screening Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib Is willing to provide archival tumor tissue from a biopsy performed within 6 months of progression during treatment with erlotinib, gefitinib, afatinib, or osimertinib OR has at least one lesion, not previously irradiated, amenable to core biopsy and is willing to undergo screening tumor biopsy Demonstrates absence of EGFR T790M mutation if treated with erlotinib, gefitinib, or afatinib. No EGFR mutation testing is required if treated with osimertinib. Inclusion Criteria for all cohorts of Dose Expansion only: Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease For Cohorts 1, 2, 3a, and 3b: Is willing to provide archival tumor tissue from a biopsy performed within 6 months of consent and performed after progression during/after treatment with most recent cancer therapy regimen OR has at least 1 lesion, not previously irradiated, amenable to core biopsy and is willing to undergo tumor biopsy. Tumor tissue must be of sufficient quantity as defined in the laboratory manual and contain adequate tumor tissue content as confirmed by haematoxylin and eosin (H&S) staining at central laboratory. For Cohort 4: Neither archival tumor tissue nor core tumor biopsy will be collected Inclusion Criteria specific to Cohorts 1, 3a, 3b, and 4 of Dose Expansion: Has histologically or cytologically documented: Cohort 1: Adenocarcinoma NSCLC Cohorts 3a, 3b, and 4: NSCLC (including any histology other than small-cell or combined small cell and non-small cell) Has documentation of radiological disease progression following one or more lines of EGFR TKI treatment. Participants with EGFR T790M mutation following treatment with erlotinib, gefitinib afatinib, or dacomitinib must have received and have documentation of radiological disease progression following treatment with osimertinib unless unable or unwilling. Has documentation of EGFR-activating mutation(s) detected from tumor tissue: G719X, exon deletion 19, L858R, or L861Q. Participants with other EGFR-activating mutations may be eligible following discussion with the Sponsor. Inclusion Criteria specific to Cohort 2 of Dose Expansion: Has histologically or cytologically documented squamous or non-squamous NSCLC (ie, without EGFR-activating mutations). Has received prior treatment with anti-PD-1 or anti-PD-L1 antibody-based regimen in the locally advanced or metastatic setting unless unable or unwilling. Participants with NSCLC known to harbor a genomic alteration(s) other than EGFR mutation(s) (eg, ALK or ROS1 fusion) for which treatment is available must have also received prior treatment with at least 1 genotype-directed therapy. Exclusion Criteria for Dose Escalation and Dose Expansion: Has any evidence of small cell histology, or combined small cell and non-small cell histology, in original tumor biopsy or in Screening biopsy performed after progression Treatment with any of the following: Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a previous cancer treatment regimen or clinical study (other than EGFR TKI in Cohorts 1, 3a, 3b, and 4 only), within 14 days of the first dose of study treatment Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment Prior treatment with an anti-HER3 antibody (dose escalation only) Prior treatment with a topoisomerase I inhibitor (dose escalation only) Prior treatment with an antibody-drug conjugate (ADC) that consists of an exatecan derivative that is a topoisomerase I inhibitor (eg, DS-8201a) (dose escalation only) Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug treatment, or palliative radiation therapy within 2 weeks of the first dose of study drug treatment, or stereotactic radiotherapy within 1 week prior to the first dose of U3-1402 Has history of other active malignancy within 3 years prior to enrollment, except: Adequately treated non-melanoma skin cancer OR Superficial bladder tumors (Ta, Tis, T1) OR Curatively treated in situ disease Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive brain metastases may be included in the study. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (1 week for stereotactic radiotherapy) Has history of myocardial infarction within the past 6 months Has symptomatic congestive heart failure[New York Heart Association (NYHA) Classes II-IV], unstable angina within the past 6 months, or cardiac arrhythmia requiring antiarrhythmic treatment Has left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA) Has any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG), eg, complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms) Has a mean corrected QT interval using Fridericia's Correction Formula (QTcF) prolongation to > 470 ms for females and > 450 ms for males in three successive Screening measurements Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval Has any factors that increase the risk of corrected QT (QTc) interval prolongation or risk of arrhythmic events, such as congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. Has any history of interstitial lung disease (ILD) (including pulmonary fibrosis or severe radiation pneumonitis), has current ILD/pneumonitis, or is suspected to have such disease by imaging during screening Has clinically significant corneal disease Additional Exclusion Criteria for Dose Expansion Cohort 2: 1. Has documentation of one or more of the following EGFR-activating mutations: G719X, exon 19 deletion, L858R, or L861Q Additional Exclusion Criteria for Dose Expansion Cohort 4: Evidence of any leptomeningeal disease Clinically severe respiratory compromise (based on Investigator's assessment) resulting from intercurrent pulmonary illnesses including, but not limited to: Any underlying pulmonary disorder Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement OR prior complete pneumonectomy Is receiving chronic systemic corticosteroids dosed at >10 mg/day prednisone or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to enrollment Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg Prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or confound the assessment of study results.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation: Cohort 1, 3.2 mg/kg<br>Participants in the Dose Escalation Cohort 1 will receive U3-1402 intravenously (IV) once every three weeks at 3.2 mg/kg. | Drug: U3-1402 (FL-DP)<br>* U3-1402 (frozen liquid drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a).<br>|
| Experimental: Dose Escalation: Cohort 2, 4.8 mg/kg<br>Participants in Dose Escalation Cohort 2 will receive U3-1402 intravenously (IV) once every three weeks at 4.8 mg/kg. | Drug: U3-1402 (FL-DP)<br>* U3-1402 (frozen liquid drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a).<br>|
| Experimental: Dose Escalation: Cohort 3, 5.6 mg/kg<br>Participants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 5.6 mg/kg. | Drug: U3-1402 (FL-DP)<br>* U3-1402 (frozen liquid drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a).<br>|
| Experimental: Dose Escalation: Cohort 4, 6.4 mg/kg<br>Participants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 6.4 mg/kg. | Drug: U3-1402 (FL-DP)<br>* U3-1402 (frozen liquid drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a).<br>|
| Experimental: Dose Expansion: Cohort 1, EGFR mutant<br>Participants with adenocarcinoma NSCLC with EGFR mutations in the Dose Expansion Cohort 1 will receive U3-1402 IV once every three weeks at the established recommended dose for expansion (RDE). | Drug: U3-1402 (CTM-1 Lyo-DP)<br>* U3-1402 (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the clinical manufacturing sites.<br>|
| Experimental: Dose Expansion: Cohort 2, EGFR wild-type<br>Participants with squamous or non-squamous NSCLC without EGFR-activating mutations in the Dose Expansion Cohort 2 will receive U3-1402 IV once every three weeks at the established recommended dose for expansion (RDE). | Drug: U3-1402 (CTM-1 Lyo-DP)<br>* U3-1402 (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the clinical manufacturing sites.<br>|
| Experimental: Dose Expansion: Cohort 3a, EGFR mutant<br>Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3a will receive U3-1402 IV once every three weeks at the established recommended dose for expansion (RDE) or, if applicable, adjusted RDE (aRDE). | Drug: U3-1402 (CTM-1 Lyo-DP)<br>* U3-1402 (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the clinical manufacturing sites.<br>|
| Experimental: Dose Expansion: Cohort 3b, EGFR mutant<br>Randomized participants with NSCLC and EGFR mutations in the Dose Expansion Cohort 3b will receive U3-1402 IV once every three weeks following an up-titration regimen (Cycle 1, Day 1: 57% of RDE or aRDE; Cycle 2, Day 1: 86% of RDE or, if applicable aRDE; Cycle 3 and subsequent cycles, Day 1: 114% of RDE or aRDE). | Drug: U3-1402 (CTM-1 Lyo-DP)<br>* U3-1402 (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the clinical manufacturing sites.<br>|
| Experimental: Dose Expansion: Cohort 4, EGFR mutant<br>Participants with NSCLC (including any histology other than small-cell or combined small-cell and non-small cell) with an EGFR-activating mutation will receive U3-1402 IV at 5.6 mg/kg every 3 weeks. | Drug: U3-1402 (CTM-3 Lyo-DP)<br>* U3-1402 (lyophilized drug product) consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a) that was manufactured by the commercial manufacturing sites.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicities (DLTs) during dose escalation |  | 21 days of Cycle 1 | 
| Summary of adverse events during dose escalation |  | By the global end of trial date, approximately within 36 months | 
| Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee during dose expansion | ORR will be evaluated using RECIST v1.1. | Approximately within 36 months | 
| Maximum serum concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion (Cohort 4) |  | Cycle 1: Day 1, pre-dose and end of infusion (EOI), 2 hours, 4 hours, 8 hours; Day 8, Day 15; Cycle 2: Day 1, pre-dose (each cycle is 21 days) | 
| Area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion (Cohort 4) |  | Cycle 1: Day 1, pre-dose and end of infusion (EOI), 2 hours, 4 hours, 8 hours; Day 8, Day 15; Cycle 2: Day 1, pre-dose (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum serum concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose escalation |  | During approximately the first 84 days after dosing | 
| Overall response rate (ORR) during dose escalation | Evaluated using RECIST 1.1 | Approximately within 36 months | 
| Disease control rate (DCR) during dose escalation |  | Approximately within 36 months | 
| Duration of response (DOR) during dose escalation |  | Approximately within 36 months | 
| Time to response (TTR) during dose escalation |  | Approximately within 36 months | 
| Progression free survival (PFS) during dose escalation |  | Approximately within 36 months | 
| Overall Survival (OS) during dose escalation |  | Approximately within 36 months | 
| Summary of adverse events during dose expansion |  | By the global end of trial date, approximately within 36 months | 
| Maximum serum concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]), from time 0 to Day 21 (AUC-21d), and up to last quantifiable time (AUC[last]) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Volume of distribution after a single-dose (Vz) and at steady-state after multiple doses (Vss) of U3-1402, total anti-HER3 antibody, and MAAA 1181a during dose expansion |  | During approximately the first 84 days after dosing | 
| Overall response rate (ORR) during dose expansion | Evaluated using RECIST 1.1 | Approximately within 36 months | 
| Disease control rate (DCR) during dose expansion |  | Approximately within 36 months | 
| Duration of response (DOR) during dose expansion |  | Approximately within 36 months | 
| Time to response (TTR) during dose expansion |  | Approximately within 36 months | 
| Progression free survival (PFS) during dose expansion |  | Approximately within 36 months | 
| Overall survival (OS) during dose expansion |  | Approximately within 36 months | 
| Percentage of participants who are anti-drug antibody (ADA)-positive (baseline and post-baseline) and Percentage of participants who have treatment-emergent ADA during dose expansion (Cohort 4) |  | Approximately within 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oncology, Advanced Non-small Cell Lung Cancer, Inoperable Non-small Cell Lung Cancer, Metastatic, Unresectable, Epidermal growth factor receptor, EGFR