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

Non-Small Cell Lung Cancer (NSCLC) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03260491
• Other study ID #: U31402-A-U102
• Secondary ID: 2017-000543-4119
• Status: Active, not recruiting
• Phase: Phase 1
• Start date: October 30, 2017
• Est. completion date: December 31, 2024

Study information

• Verified date: September 2023
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 271
• Est. completion date: December 31, 2024
• Est. primary completion date: January 28, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria for both Dose Escalation and Dose Expansion:

1. Has locally advanced or metastatic NSCLC, not amenable to curative surgery or radiation

2. Has at least one measurable lesion per RECIST version 1.1

3. Has Eastern Cooperative Oncology Group performance status of 0 or 1 at Screening

Inclusion Criteria for Dose Escalation only:

1. Has histologically or cytologically documented adenocarcinoma NSCLC

2. Has acquired resistance to EGFR TKI according to the Jackman criteria (PMID: 19949011)

1. 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)

2. 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

3. Is currently receiving and able to discontinue erlotinib, gefinitib, afatinib, or osimertinib

4. 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

5. Has radiological documentation of disease progression while receiving continuous treatment with erlotinib, gefitinib, afatinib, or osimertinib

6. 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

7. 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:

1. Has received systemic therapy for locally advanced or metastatic disease including at least 1 platinum-based chemotherapy regimen

2. Has documented radiological disease progression during/after most recent treatment regimen for locally-advanced or metastatic disease

3. 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:

1. Has histologically or cytologically documented:

1. Cohort 1: Adenocarcinoma NSCLC

2. Cohorts 3a, 3b, and 4: NSCLC (including any histology other than small-cell or combined small cell and non-small cell)

2. 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.

3. 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:

1. Has histologically or cytologically documented squamous or non-squamous NSCLC (ie, without EGFR-activating mutations).

2. 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:

1. 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

2. Treatment with any of the following:

1. 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

2. Immune checkpoint inhibitor therapy within 21 days of the first dose of study treatment

3. Prior treatment with an anti-HER3 antibody (dose escalation only)

4. Prior treatment with a topoisomerase I inhibitor (dose escalation only)

5. 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)

6. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug treatment

7. 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

3. Has history of other active malignancy within 3 years prior to enrollment, except:

1. Adequately treated non-melanoma skin cancer OR

2. Superficial bladder tumors (Ta, Tis, T1) OR

3. Curatively treated in situ disease

4. 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)

5. Has history of myocardial infarction within the past 6 months

6. 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

7. Has left ventricular ejection fraction (LVEF) < 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)

8. 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)

9. 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

10. Unable or unwilling to discontinue concomitant drugs that are known to prolong the QT interval

11. 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.

12. 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

13. 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:

1. Evidence of any leptomeningeal disease

2. Clinically severe respiratory compromise (based on Investigator's assessment)

resulting from intercurrent pulmonary illnesses including, but not limited to:

1. Any underlying pulmonary disorder

2. Any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement OR prior complete pneumonectomy

3. 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

4. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg

5. 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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-Small Cell Lung Cancer (NSCLC)

Intervention

Drug:
• U3-1402 (FL-DP)
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).
• U3-1402 (CTM-1 Lyo-DP)
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.
• U3-1402 (CTM-3 Lyo-DP)
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.

Locations

Country	Name	City	State
Japan	Kindai University Hospital	Osaka
Japan	Shizuoka Cancer Center	Shizuoka
Japan	The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR)	Tokyo
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Netherlands	Netherlands Cancer Institute	Amsterdam
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Taiwan	Chung Shan Medical University Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Henry Ford Hospital	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of California San Diego	La Jolla	California
United States	Sarah Cannon Research Institute/Tennesse Oncology	Nashville	Tennessee
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Japan,  Korea, Republic of,  Netherlands,  Spain,  Taiwan, 

References & Publications (1)

Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA, Lynch T, Johnson BE, Miller VA. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010 Jan 10;28(2):357-60. doi: 10.1200/JCO.2009.24.7049. Epub 2009 Nov 30. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose-limiting toxicities (DLTs) during dose escalation		21 days of Cycle 1
Primary	Summary of adverse events during dose escalation		By the global end of trial date, approximately within 36 months
Primary	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
Primary	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)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall response rate (ORR) during dose escalation	Evaluated using RECIST 1.1	Approximately within 36 months
Secondary	Disease control rate (DCR) during dose escalation		Approximately within 36 months
Secondary	Duration of response (DOR) during dose escalation		Approximately within 36 months
Secondary	Time to response (TTR) during dose escalation		Approximately within 36 months
Secondary	Progression free survival (PFS) during dose escalation		Approximately within 36 months
Secondary	Overall Survival (OS) during dose escalation		Approximately within 36 months
Secondary	Summary of adverse events during dose expansion		By the global end of trial date, approximately within 36 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall response rate (ORR) during dose expansion	Evaluated using RECIST 1.1	Approximately within 36 months
Secondary	Disease control rate (DCR) during dose expansion		Approximately within 36 months
Secondary	Duration of response (DOR) during dose expansion		Approximately within 36 months
Secondary	Time to response (TTR) during dose expansion		Approximately within 36 months
Secondary	Progression free survival (PFS) during dose expansion		Approximately within 36 months
Secondary	Overall survival (OS) during dose expansion		Approximately within 36 months
Secondary	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