Clinical Trials /

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

NCT03260491

Description:

This study has two parts: dose escalation and dose expansion. 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 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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: U3-1402 in Metastatic or Unresectable Non-Small Cell Lung Cancer
  • 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 IDs

  • ORG STUDY ID: U31402-A-U102
  • SECONDARY ID: 2017-000543-41
  • SECONDARY ID: 194868
  • NCT ID: NCT03260491

Conditions

  • Non-Small Cell Lung Cancer (NSCLC)

Interventions

DrugSynonymsArms
U3-1402Dose Escalation: Cohort 1, 3.2 mg/kg

Purpose

This study has two parts: dose escalation and dose expansion. 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 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.

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation: Cohort 1, 3.2 mg/kgExperimentalParticipants in the Dose Escalation Cohort 1 will receive U3-1402 intravenously (IV) once every three weeks at 3.2 mg/kg.
  • U3-1402
Dose Escalation: Cohort 2, 6.4 mg/kgExperimentalParticipants in Dose Escalation Cohort 2 will receive U3-1402 intravenously (IV) once every three weeks at 6.4 mg/kg.
  • U3-1402
Dose Escalation: Cohort 3, 9.6 mg/kgExperimentalParticipants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 9.6 mg/kg.
  • U3-1402
Dose Escalation: Cohort 4, 12.8 mg/kgExperimentalParticipants in Dose Escalation Cohort 3 will receive U3-1402 intravenously (IV) once every three weeks at 12.8 mg/kg.
  • U3-1402
Dose Expansion: Cohort 1, EGFR mutantExperimentalParticipants 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).
  • U3-1402
Dose Expansion: Cohort 2, EGFR wild-typeExperimentalParticipants 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).
  • U3-1402
Dose Expansion: Cohort 3a, EGFR mutantExperimentalRandomized 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).
  • U3-1402
Dose Expansion: Cohort 3b, EGFR mutantExperimentalRandomized 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).
  • U3-1402

Eligibility Criteria

        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, with no
             deterioration over the previous 2 weeks

        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

        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 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),
                  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
             III-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 (pulmonary fibrosis or severe radiation
             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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicities (DLTs) in the dose escalation period
Time Frame:21 days of Cycle 1
Safety Issue:
Description:Evaluated using RECIST 1.1

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) 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
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve up to the 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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Volume of distribution after a single-dose (Vz) 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
Safety Issue:
Description:
Measure:Volume of distribution 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
Safety Issue:
Description:
Measure:Overall response rate (ORR) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:Evaluated using RECIST 1.1
Measure:Disease control rate (DCR) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Duration of response (DOR) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Time to response (TTR) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Progression free survival (PFS) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Overall Survival (OS) in the dose escalation period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Summary of adverse events in the dose expansion period
Time Frame:By the global end of trial date, approximately within 36 months
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve from time 0 to 8 hours (AUC[0-8]) 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
Safety Issue:
Description:
Measure:Area under the serum concentration-time curve up to the 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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Volume of distribution after a single-dose (Vz) 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
Safety Issue:
Description:
Measure:Volume of distribution 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
Safety Issue:
Description:
Measure:Overall response rate (ORR) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:Evaluated using RECIST 1.1
Measure:Disease control rate (DCR) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Duration of response (DOR) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Time to response (TTR) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Progression free survival (PFS) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:
Measure:Overall Survival (OS) in the dose expansion period
Time Frame:Approximately within 36 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

Trial Keywords

  • Oncology
  • Advanced Non-small Cell Lung Cancer
  • Inoperable Non-small Cell Lung Cancer
  • Metastatic
  • Unresectable
  • Epidermal growth factor receptor
  • EGFR

Last Updated

January 14, 2020