Clinical Trials /

A Trial of TAK-788 (AP32788) in Non-small Cell Lung Cancer (NSCLC)

NCT02716116

Description:

The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations, and to explore relationship between tumor and/or plasma biomarkers, and TAK-788 efficacy, safety, and/or cytochrome P450 3A (CYP3A) induction. The study will also determine the efficacy of TAK-788 in participants with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.

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

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Trial of TAK-788 (AP32788) in Non-small Cell Lung Cancer (NSCLC)
  • Official Title: A Phase 1/2 Study of the Safety, Pharmacokinetics, and Anti-Tumor Activity of the Oral EGFR/HER2 Inhibitor TAK-788 (AP32788) in Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: AP32788-15-101
  • SECONDARY ID: U1111-1217-7205
  • SECONDARY ID: 2016-001271-68
  • NCT ID: NCT02716116

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
TAK-788AP32788Dose Escalation Cohort

Purpose

The purpose of this phase 1/2 study is to evaluate the safety, recommended phase 2 dose (RP2D), dose limiting toxicities (DLTs), maximum tolerated dose (MTD), pharmacokinetics of oral TAK-788, anti-tumor activity of TAK-788 in participants with NSCLC with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) and anti-tumor activity of TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations, and to explore relationship between tumor and/or plasma biomarkers, and TAK-788 efficacy, safety, and/or cytochrome P450 3A (CYP3A) induction. The study will also determine the efficacy of TAK-788 in participants with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC.

Detailed Description

      This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of
      oral EGFR/HER2 Inhibitor TAK-788 in participants with NSCLC and anti-tumor activity of
      TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. The
      trial will be conducted in three parts: a dose escalation and expansion phase, followed by an
      extension phase.

      The objectives of the dose escalation phase are to determine the safety profile of orally
      administered TAK-788, including the MTD, DLTs, RP2D and pharmacokinetic profile. The primary
      goal of the expansion component of the trial is to evaluate the anti-tumor activity of
      TAK-788 in seven histologically and molecularly defined cohorts at the RP2D (determined based
      on dose escalation phase of the trial).

      The seven expansion cohorts will be:

        1. NSCLC participants with EGFR exon 20 activating insertions, who have either not received
           or not shown an objective response to an EGFR TKI, and who have no active, measurable
           CNS metastases;

        2. NSCLC participants with HER2 exon 20 activating insertions or point mutations and no
           active, measurable CNS metastases;

        3. NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating
           insertions or point mutations and active, measurable CNS metastases;

        4. NSCLC participants with other targets against which TAK-788 is active (examples include
           EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and
           other uncommon EGFR activating mutations), without active CNS metastases;

        5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an
           objective response to an EGFR TKI and subsequently progressed, without active CNS
           metastases;

        6. NSCLC participants with EGFR exon 20 activating insertions, who have not received prior
           systemic anticancer treatment for locally advanced or metastatic disease, without active
           CNS metastases; and

        7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which
           TAK-788 is active, without active CNS metastases.

      The extension phase will evaluate efficacy of TAK-788 in participants with locally advanced
      or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have been
      previously treated. The study will enroll approximately 341 participants.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation CohortExperimentalTAK-788 treatment for participants with advanced NSCLC.
  • TAK-788
Expansion Cohort 1ExperimentalTAK-788 treatment for NSCLC participants with EGFR exon 20 activating insertions, who have either not received or not shown an objective response to an EGFR tyrosine kinase inhibitors (TKI), and who have no active, measurable central nervous system (CNS) metastases.
  • TAK-788
Expansion Cohort 2ExperimentalTAK-788 treatment for NSCLC participants with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases.
  • TAK-788
Expansion Cohort 3ExperimentalTAK-788 treatment for NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases.
  • TAK-788
Expansion Cohort 4ExperimentalTAK-788 treatment for NSCLC participants with other targets against which TAK-788 is active (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations), without active CNS metastases.
  • TAK-788
Expansion Cohort 5ExperimentalTAK-788 treatment for NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed without active CNS metastases.
  • TAK-788
Expansion Cohort 6ExperimentalTAK-788 treatment NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease without active CNS metastases
  • TAK-788
Expansion Cohort 7ExperimentalTAK-788 treatment for participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active without active CNS metastases.
  • TAK-788
Extension CohortExperimentalTAK-788 treatment for participants with previously treated locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
  • TAK-788

Eligibility Criteria

        General Inclusion Criteria (all cohorts: dose escalation and expansion):

          1. Have histologically or cytologically confirmed locally advanced (and not a candidate
             for definitive therapy) or metastatic NSCLC disease (Stage IIIB or IV) or other solid
             tumors. For all cohorts except Expansion Cohort 7, the locally advanced or metastatic
             disease is NSCLC. For Expansion Cohort 7, the locally advanced or metastatic disease
             is any solid tumor other than NSCLC.

          2. Must have sufficient tumor tissue available for analysis.

          3. Must have measurable disease by response evaluation criteria in solid tumors (RECIST)
             v1.1.

          4. Male or female adult participants (aged 18 years or older, or as defined per local
             regulations).

          5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.

          6. Minimum life expectancy of 3 months or more.

          7. Adequate organ function at baseline.

          8. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval
             corrected (Fridericia) (QTcF) of less than or equal to (<=) 450 millisecond (ms) in
             males or <=470 ms in females.

          9. Willingness and ability to comply with scheduled visits and study procedures.

        Part 1: Dose Escalation Cohort Specific Inclusion Criteria:

        1. Refractory to standard available therapies.

        Part 2: Expansion Cohort 1 Specific Inclusion Criteria:

          1. Have a documented EGFR in-frame exon 20 insertion by a local test.

          2. Previously treated with one or more regimens of systemic therapy for locally advanced
             or metastatic disease.

          3. Prior treatment with an EGFR TKI is allowed unless the participants had an objective
             response and subsequent progression as assessed by the investigator or treating
             physician.

        Expansion Cohort 2 Specific Inclusion Criteria:

          1. Have one of the following documented by a local test:

               1. A HER2 exon 20 insertion;

               2. An activating point mutation in HER2.

          2. Previously treated with one or more regimens of systemic therapy for locally advanced
             or metastatic disease.

          3. Prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is
             allowed unless the participants had an objective response and subsequent progression
             as assessed by the investigator or treating physician.

        Part 2: Expansion Cohort 3 Specific Inclusion Criteria:

          1. Have one of the following documented by a local test:

               1. An EGFR exon 20 insertion;

               2. A HER2 exon 20 insertion;

               3. An activating point mutation in HER2.

          2. Previously treated with one or more regimen of systemic therapy for locally advanced
             or metastatic disease.

          3. For participants with an EGFR exon 20 insertion: prior treatment with an EGFR TKI is
             allowed unless the participants had an objective response and subsequent progression
             as assessed by the investigator or treating physician.

          4. For participants with a HER2 exon 20 insertion or HER2 activating point mutation:
             prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is
             allowed unless the participants had an objective response and subsequent progression
             as assessed by the investigator or treating physician during treatment with that prior
             TKI.

          5. Have either previously untreated intracranial CNS metastases or previously treated
             intracranial CNS metastases with radiologically documented new or progressing CNS
             lesions.

          6. Have at least one target (that is, measurable) intracranial CNS lesion (>=10
             millimeter [mm] in longest diameter by contrast enhanced magnetic resonance imaging
             [MRI]).

        Part 2: Expansion Cohort 4 Specific Inclusion Criteria:

          1. Have one of the following documented by a local test: an activating mutation in EGFR
             including exon 19 deletions or exon 21 L858R substitution (with or without T790M), or
             an uncommon activating mutation other than exon 20 insertion including, but not
             limited to, G719X (where X is any other amino acid), S768I, L861Q, or L861R.

          2. Treatment naive for locally advanced or metastatic disease or previously treated with
             one or more regimens of systemic therapy for locally advanced or metastatic disease.

        Part 2: Expansion Cohort 5 Specific Inclusion Criteria:

        NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an
        objective response to an EGFR TKI and subsequently progressed, without active CNS
        metastases.

          1. Have a documented EGFR in-frame exon 20 insertion by a local test.

          2. Previously treated with one or more regimens of systemic therapy for locally advanced
             or metastatic disease.

          3. Previously showed an objective response to an EGFR TKI, and subsequently progressed as
             assessed by the investigator or treating physician.

        Part 2: Expansion Cohort 6 Specific Inclusion Criteria:

        NSCLC participants with EGFR exon 20 activating insertions, who have not received prior
        systemic anticancer treatment for locally advanced or metastatic disease, without active
        CNS metastases.

          1. Have a documented EGFR in-frame exon 20 insertion by a local test.

          2. No prior systemic treatment for locally advanced or metastatic disease.

        Part 2: Expansion Cohort 7 Specific Inclusion Criteria:

        Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which
        TAK-788 is active, without active CNS metastases.

          1. Have a solid tumor that is not NSCLC, including, but not limited to, bladder/urinary
             tract cancer, breast cancer, gastric/esophageal cancer, biliary tract cancer, and head
             and neck cancer.

          2. Is refractory to standard therapy.

          3. Have EGFR or HER2 mutations, documented by a local test.

        Part 3: Extension Cohort Specific Inclusion Criteria:

          1. Have a documented EGFR in-frame exon 20 insertion by a local test and sufficient tumor
             tissue available for central analysis.

          2. Must have received at least 1 prior line of therapy for locally advanced or metastatic
             disease and no more than 2 regimens of systemic anticancer chemotherapies for locally
             advanced or metastatic disease.

               -  Prior treatment with an EGFR TKI is allowed unless the participant had an
                  objective response and subsequent progression as assessed by the investigator or
                  treating physician during treatment with that prior TKI.

        Exclusion Criteria:

          1. Previously received TAK-788.

          2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy, and
             investigational agents, <=14 days prior to first dose of TAK-788 (except for
             reversible EGFR TKIs [that is, erlotinib or gefitinib], which are allowed in the dose
             escalation and expansion cohorts up to 7 days prior to the first dose of TAK-788).

          3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days
             of the first dose of TAK-788.

          4. Have been diagnosed with another primary malignancy other than NSCLC except for
             adequately treated non-melanoma skin cancer or cervical cancer in situ; definitively
             treated non-metastatic prostate cancer; or participants with another primary
             malignancy who are definitively relapse-free with at least 3 years elapsed since the
             diagnosis of the other primary malignancy.

             Note: This exclusion criteria does not apply to Expansion Cohort 7.

          5. Received radiotherapy <=14 days prior to the first dose of TAK-788 or has not
             recovered from radiotherapy-related toxicities. Palliative radiation administered
             outside the chest and brain, stereotactic radiosurgery (SRS), and stereotactic body
             radiotherapy are allowed up to 7 days prior to the first dose

          6. Received a moderate or strong CYP4503A inhibitor or moderate or strong CYP3A inducer
             within 10 days prior to first dose of TAK-788.

          7. Have undergone major surgery within 28 days prior to first dose of TAK-788. Minor
             surgical procedures, such as catheter placement or minimally invasive biopsy, are
             allowed.

          8. Part 1 (dose escalation) and Expansion Cohorts 1 to 3 of Part 2 (expansion phase)
             only:

             Have symptomatic CNS metastases at screening or asymptomatic disease requiring
             corticosteroids to control symptoms within 7 days prior to the first dose of TAK-788.

             Part 3 (extension cohort) and Expansion Cohorts 4 to 7 of Part 2 (expansion phase)
             only:

             Have known active brain metastases (have either previously untreated intracranial CNS
             metastases or previously treated intracranial CNS metastases with radiologically
             documented new or progressing CNS lesions). Brain metastases are allowed if they have
             been treated with surgery and/or radiation and have been stable without requiring
             corticosteroids to control symptoms within 7 days before the first dose of TAK-788,
             and have no evidence of new or enlarging brain metastases.

          9. Have current spinal cord compression (symptomatic or asymptomatic and detected by
             radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).

         10. Have significant, uncontrolled, or active cardiovascular disease.

         11. Have a known history of uncontrolled hypertension. Participants with hypertension
             should be under treatment on study entry to control blood pressure.

         12. Have prolonged QTcF interval, or being treated with medications known to be associated
             with the development of Torsades de Pointes.

         13. Have an ongoing or active infection, including but not limited to, the requirement for
             intravenous (IV) antibiotics, or a known history of human immunodeficiency virus
             (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in
             the absence of history.

         14. Currently have or have a history of interstitial lung disease, radiation pneumonitis
             that required steroid treatment, or drug-related pneumonitis.

         15. Female participants who are lactating and breastfeeding or have a positive urine or
             serum pregnancy test during the screening period.

             Note: Female participants who are lactating will be eligible if they discontinue
             breastfeeding.

         16. Have gastrointestinal illness or disorder that could affect oral absorption of
             TAK-788.

         17. Have any condition or illness that, in the opinion of the investigator, might
             compromise participant safety or interfere with the evaluation of the safety of the
             drug.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Escalation Cohort: RP2D of Orally Administered TAK-788
Time Frame:Day 1 to 28 (Cycle 1)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Dose Escalation and Expansion Cohorts: Safety Analysis of TAK-788 Assessed by Adverse Events, Toxicity Grades, and Laboratory Test Results
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Dose Escalation Cohort: Identify DLTs and MTD of TAK-788
Time Frame:Day 1 to 28 in Cycle 1 (Cycle length is equal to [=] 28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: Tmax: Time of First Occurrence of Maximum Plasma Concentration (Cmax)
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: AUC 24: Area Under the Concentration-time Curve from Time Zero to 24 hours for TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: AUCt: Area Under the Concentration-time Curve from Time Zero to Time t for TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: RAC (Cmax): Accumulation Ratio Based on Cmax of TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: Ctrough: Observed Concentration at the end of a Dosing Interval of TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: RAC (AUC): Accumulation Ratio Based on AUC of TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: Cmax: Maximum Observed Concentration of TAK-788 and its Metabolites
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion Cohort 3: Duration of Intracranial Response (iDOR)
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion Cohort 3: Intracranial PFS (iPFS)
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Expansion and Extension Cohorts: Overall Survival (OS)
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Extension Cohort: Confirmed ORR as Assessed by the Investigator
Time Frame:up to 36 months after first dose
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: Cmax: Dose Linearity for TAK-788 Exposure
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Dose Escalation and Expansion Cohorts: AUC: Dose Linearity for TAK-788 Exposure
Time Frame:Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days)
Safety Issue:
Description:
Measure:Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30)
Time Frame:up to 30 days after last dose of drug (approximately up to 37 months)
Safety Issue:
Description:
Measure:Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13)
Time Frame:up to 30 days after last dose of drug (approximately up to 37 months)
Safety Issue:
Description:
Measure:Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator
Time Frame:up to 36 months after first dose
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Millennium Pharmaceuticals, Inc.

Trial Keywords

  • NSCLC
  • EGFR
  • HER2
  • human epidermal growth factor receptor 2
  • exon 20 insertions
  • exon 19 deletions
  • exon 21 substitution
  • T790M
  • ErbB-2
  • Epidermal Growth Factor Receptor

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