Clinical Trial - NCT03260491

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

Recruiting

Sponsor: Daiichi Sankyo, Inc.

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03260491

Protocol Info

Short Description: Phase 1 U3-1402 in EGFR-Mutant NSCLC
Long Description: A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects with Metastatic or Unresectable EGFR-Mutant Non-Small Cell Lung Cancer
MGH Status: Open
Sponsor: Daiichi Sankyo Pharmaceuticals
Disease Program: Thoracic

Next Steps


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Purpose

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.
Condition Title Intervention Phase
Non-Small Cell Lung Cancer (NSCLC) U3-1402 Phase 1
Study Type Interventional
Official Title A Multicenter, Open-Label Phase 1 Study of U3-1402 in Subjects With Metastatic or Unresectable Non-small Cell Lung Cancer

Primary Outcome Measures

Dose-limiting toxicities (DLTs) in the dose escalation period [Time Frame: 21 days of Cycle 1] [Designated as safety issue: ]

Summary of adverse events in the dose escalation period [Time Frame: By the global end of trial date, approximately within 36 months] [Designated as safety issue: ]

Overall response rate (ORR) assessed by Blinded Independent Central Review (BICR) Committee in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]


Secondary Outcome Measures

Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

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 in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

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 in the dose escalation period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Overall response rate (ORR) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Disease control rate (DCR) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Duration of response (DOR) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Time to response (TTR) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Progression free survival (PFS) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Overall Survival (OS) in the dose escalation period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Summary of adverse events in the dose expansion period [Time Frame: By the global end of trial date, approximately within 36 months] [Designated as safety issue: ]

Maximum plasma concentration (Cmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Time of maximum concentration (Tmax) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

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 in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Terminal elimination rate constant (Kel) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Elimination half-life (t1/2) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Total body clearance (CL) of U3-1402, total anti-HER3 antibody, and MAAA 1181a in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

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 in the dose expansion period [Time Frame: During approximately the first 84 days after dosing] [Designated as safety issue: ]

Overall response rate (ORR) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Disease control rate (DCR) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Duration of response (DOR) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Time to response (TTR) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Progression free survival (PFS) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Overall Survival (OS) in the dose expansion period [Time Frame: Approximately within 36 months] [Designated as safety issue: ]

Estimated Enrollment: 216
Study Start Date: October 2017
Estimated Study Completion Date: December 2023
Estimated Primary Completion Date: December 2021
Arms Assigned Interventions

Experimental:Dose Escalation: Cohort 1, 3.2 mg/kg

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
U3-1402 consists of an antibody component (patritumab, U3-1287) covalently conjugated to a drug-linker (MAAA-1162a) containing a drug component (MAAA-1181a)

Experimental:Dose Escalation: Cohort 2, 6.4 mg/kg

Participants in Dose Escalation Cohort 2 will receive U3-1402 intravenously (IV) once every three weeks at 6.4 mg/kg.

Experimental:Dose Escalation: Cohort 3, 9.6 mg/kg

Participants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 9.6 mg/kg.

Experimental:Dose Escalation: Cohort 4, 12.8 mg/kg

Participants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 12.8 mg/kg.

Experimental:Dose Expansion: Cohort 1, EGFR mutant

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).

Experimental:Dose Expansion: Cohort 2, EGFR wild-type

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).

Experimental:Dose Expansion: Cohort 3a, EGFR mutant

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).

Experimental:Dose Expansion: Cohort 3b, EGFR mutant

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).

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

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. 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.

Inclusion Criteria specific to Cohort 1, Cohort 3a, and Cohort 3b of Dose Expansion:

1. Has histologically or cytologically documented:

1. Cohort 1: Adenocarcinoma NSCLC

2. Cohort 3a and 3b: 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 Cohort 1 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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03260491

Locations

  • United States, California
    • City of Hope Duarte, California, United States, 91010
    • University of California San Diego La Jolla, California, United States, 92093
    • Pacific Shores Medical Group Long Beach, California, United States, 90813
  • United States, Georgia
    • Winship Cancer Institute of Emory University Atlanta, Georgia, United States, 30322
  • United States, Massachusetts
    • Massachusetts General Hospital Boston, Massachusetts, United States, 02114
    • Dana-Farber Cancer Institute Boston, Massachusetts, United States, 02215
  • United States, Michigan
    • Karmanos Cancer Institute Detroit, Michigan, United States, 48201
    • Henry Ford Hospital Detroit, Michigan, United States, 48202
  • United States, New York
    • Memorial Sloan-Kettering Cancer Center New York, New York, United States, 10065
  • United States, Tennessee
    • Sarah Cannon Research Institute/Tennesse Oncology Nashville, Tennessee, United States, 37203
  • United States, Washington
    • Seattle Cancer Care Alliance Seattle, Washington, United States, 98109
  • Japan,
    • Kindai University Hospital Osaka, , Japan, 5898511
    • Shizuoka Cancer Center Shizuoka, , Japan, 4118777
    • The Cancer Institute Hospital of Japanese Foundation for Cancer Research (JFCR) Tokyo, , Japan, 1358550
  • Korea, Republic of,
    • Seoul National University Hospital Seoul, , Korea, Republic of, 03080
    • Asan Medical Center Seoul, , Korea, Republic of, 05505
  • Netherlands,
    • Netherlands Cancer Institute Amsterdam, , Netherlands, 1066 CX
  • Spain,
    • Hospital Universitario Vall d'Hebron Barcelona, , Spain, 08035
    • Hospital Universitario 12 de Octubre Madrid, , Spain, 28041
  • Taiwan,
    • Chung Shan Medical University Hospital Taichung, , Taiwan, 40705
    • National Cheng Kung University Hospital Tainan, , Taiwan, 00704
    • National Taiwan University Hospital Taipei, , Taiwan, 00100

Sponsors and Collaborators

Daiichi Sankyo, Inc.

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03260491
Other Study ID Numbers: 2017-000543-41
Study First Received:
Last Updated:
Health Authority:

Keywords provided by Daiichi Sankyo, Inc.:

Oncology

Advanced Non-small Cell Lung Cancer

Inoperable Non-small Cell Lung Cancer

Metastatic

Unresectable

Epidermal growth factor receptor

EGFR

Additional relevant MeSH terms:

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on November 12, 2020