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 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:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: AP32788-15-101
  • NCT ID: NCT02716116

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
AP32788Dose Escalation Cohort

Purpose

The purpose of this phase 1/2 study is to evaluate the safety, pharmacokinetics, and anti-tumor activity of oral AP32788 in patients with non-small cell lung cancer (NSCLC). The trial will be conducted in two parts: a dose escalation phase, followed by an expansion phase. The goal of the dose escalation phase is to determine the safety profile of orally administered AP32788, including the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phased 2 dose (RP2D) and pharmacokinetic profile. Once the RP2D is established, the expansion phase will assess the preliminary anti-tumor activity of AP32788 in 4 histologically and molecularly defined NSCLC cohorts. Approximately 105 patients will be enrolled.

Detailed Description

      This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of
      oral EGFR/HER2 Inhibitor AP32788 in patients with non-small cell lung cancer (NSCLC). The
      trial will be conducted in two parts: a dose escalation phase, followed by an expansion
      phase.

      The objectives of the dose escalation phase are to determine the safety profile of orally
      administered AP32788, including the maximum tolerated dose (MTD), dose limiting toxicities
      (DLTs), recommended phase 2 dose (RP2D) and pharmacokinetic profile.

      The primary goal of the expansion component of the trial is to evaluate the anti-tumor
      activity of AP32788 in four histologically and molecularly defined cohorts at the RP2D
      (determined based on dose escalation phase of the trial).

      The four expansion cohorts will be:

        1. NSCLC patients with EGFR exon 20 activating insertions and no active, measurable central
           nervous system (CNS) metastases;

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

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

        4. NSCLC patients with other targets against which AP32788 is active (examples include EGFR
           exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other
           uncommon EGFR activating mutations), with or without active, measurable CNS metastases.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation CohortExperimentalAP32788 treatment for patients with advanced NSCLC.
  • AP32788
Expansion Cohort 1ExperimentalAP32788 treatment for NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 activating insertions and no active, measurable central nervous system (CNS) metastases.
  • AP32788
Expansion Cohort 2ExperimentalAP32788 treatment for NSCLC patients with human epidermal growth factor receptor 2 (HER2) exon 20 activating insertions or point mutations and no active, measurable CNS metastases.
  • AP32788
Expansion Cohort 3ExperimentalAP32788 treatment for NSCLC patients with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases.
  • AP32788
Expansion Cohort 4ExperimentalAP32788 treatment for NSCLC patients with other targets against which AP32788 is active (examples include EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and other uncommon EGFR activating mutations), with or without active, measurable CNS metastases.
  • AP32788

Eligibility Criteria

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

          1. Have histologically or cytologically confirmed locally advanced (and not a candidate
             for definitive therapy) or metastatic NSCLC (Stage IIIB or IV).

          2. Must have sufficient tumor tissue available for analysis (see Study Reference Manual
             for specific requirements). For patients in the expansion cohorts, tumor tissue
             obtained after progression on the most recent prior therapy is preferred.

          3. Must have measurable disease by RECIST v1.1

          4. Male or female patients ≥18 years old.

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

          6. Minimum life expectancy of 3 months or more.

          7. Adequate renal and hepatic function as defined by the following criteria:

               1. Total serum bilirubin ≤2 × upper limit of normal (ULN);

               2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN
                  (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy);

               3. Estimated creatinine clearance ≥ 60 mL/min (calculated by using the
                  Cockcroft-Gault equation); and

               4. Serum albumin ≥2 g/dL.

          8. Adequate bone marrow function as defined by the following criteria:

             e. Absolute neutrophil count (ANC) ≥1.5 × 109/L; f. Platelet count ≥75 × 109/L; and g.
             Hemoglobin ≥9.0 g/dL.

          9. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval
             corrected (Fridericia) (QTcF) of ≤450 ms in males or ≤470 ms in females.

         10. All toxicities from prior therapy have resolved to ≤ grade 1 according to the NCI
             CTCAE v4.0, or have resolved to baseline, at the time of first dose of AP32788.

         11. For females of childbearing potential, a negative pregnancy test must be documented
             prior to enrollment.

         12. Female patients who are of childbearing potential and fertile male patients must agree
             to use a highly effective form of contraception with their sexual partners throughout
             study participation.

         13. Signed and dated informed consent indicating that the patient has been informed of all
             pertinent aspects of the study.

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

        Dose Escalation Cohort Specific Inclusion Criteria:

        1. Refractory to standard available therapies.

        Expansion Cohort 1 Specific Inclusion Criteria:

          1. Have a documented EGFR in-frame exon 20 insertion by a local test, including
             A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH,
             or any other in-frame exon 20 insertion mutation.

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

          3. Have not received a tyrosine kinase inhibitor (TKI) with activity against the specific
             documented EGFR exon 20 insertion.

          4. Not eligible for Expansion Cohort 3.

        Expansion Cohort 2 Specific Inclusion Criteria:

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

               1. A HER2 exon 20 insertion including A775_G776insYVMA, G776_V777insVC, or
                  P780_Y781insGSP, or any other in-frame exon 20 insertion mutation.

               2. An activating point mutation in HER2 including, but not limited to, L755S, G776V,
                  and V777L.

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

          3. Have not received a TKI with pan-HER activity (eg, afatinib, neratinib, or
             dacomitinib).

          4. Not eligible for Expansion Cohort 3.

        Expansion Cohort 3 Specific Inclusion Criteria:

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

               1. An EGFR exon 20 insertion: A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG,
                  D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion
                  mutation.

               2. A HER2 exon 20 insertion: A775_G776insYVMA, G776_V777insVC, P780_Y781insGSP, or
                  any other in-frame exon 20 insertion mutation.

               3. An activating point mutation in HER2 including, but not limited to, L755S, G776V,
                  and V777L.

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

          3. For patients with an EGFR exon 20 insertion: have not received a TKI with activity
             against the specific documented EGFR exon 20 insertion.

          4. For patients with a HER2 exon 20 insertion or HER2 activating point mutation: have not
             received a TKI with pan-HER activity (eg, afatinib, neratinib, or dacomitinib).

          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 (ie, measurable) intracranial CNS lesion (≥10 mm in longest
             diameter by contrast enhanced magnetic resonance imaging [MRI]). Lesions previously
             treated by stereotactic radiosurgery (SRS) or surgical resection should not be
             included as a target lesion. Lesions previously treated with whole brain radiation
             therapy (WBRT) may be included as a target lesion if (1) the last administration of
             WBRT was >3 months prior to the first dose of AP32788 and (2) unequivocal radiological
             progression of the lesion has been observed.

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

          3. For patients with a documented EGFR exon 19 deletion or exon 21 L858R substitution:
             resistant to at least one prior EGFR inhibitor (eg, erlotinib, gefitinib, or
             afatinib).

          4. For patients with a documented EGFR T790M mutation: have not received a TKI with
             activity against the EGFR T790M mutation.

          5. For patients with an uncommon activating mutation in EGFR: have not received a TKI
             with activity against the specific documented uncommon activating mutation.

          6. Have or do not have active (untreated or progressing) CNS metastases.

        Exclusion Criteria:

          1. Received systemic anticancer therapy (including cytotoxic chemotherapy,
             investigational agent, antineoplastic monoclonal antibodies, or immunotherapy) ≤14
             days prior to first dose of AP32788 (except for reversible EGFR TKIs [ie, erlotinib or
             gefitinib], which are allowed up to 7 days prior to the first dose of AP32788).

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

          3. Received radiotherapy ≤14 days prior to the first dose of AP32788 of study drug.

          4. Received a potent CYP3A inhibitor within 7 days or potent CYP3A inducer within 5 weeks
             prior to first dose of AP32788.

          5. Have undergone major surgery within 28 days prior to first dose of AP32788. Minor
             surgical procedures, such as catheter placement or minimally invasive biopsy, are
             allowed.

          6. Have brain metastases that are neurologically unstable or require an increasing dose
             of corticosteroids. Patients must be on a stable or decreasing dose of corticosteroids
             for 7 days prior to first dose of AP32788.

          7. Have symptomatic leptomeningeal carcinomatosis or spinal cord compression. Patients
             with asymptomatic leptomeningeal disease and no evidence of spinal cord compression
             are allowed.

          8. Have significant, uncontrolled, or active cardiovascular disease, including, but not
             restricted to:

               1. Myocardial infarction (MI) within 6 months prior to the first dose of study drug;

               2. Unstable angina within 6 months prior to first dose;

               3. Congestive heart failure (CHF) within 6 months prior to first dose;

               4. History of clinically significant (as determined by the treating physician)
                  atrial arrhythmia;

               5. Any history of ventricular arrhythmia; or

               6. Cerebrovascular accident or transient ischemic attack within 6 months prior to
                  first dose.

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

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

         11. 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.

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

         13. Are pregnant or breastfeeding.

         14. Have gastrointestinal illness or disorder that could affect oral absorption of AP32788
             (such as short gut syndrome, Crohn's disease, ulcerative colitis, or CTCAE grade 2 or
             greater diarrhea of any etiology at baseline).

         15. Have any condition or illness that, in the opinion of the investigator, might
             compromise patient 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:Recommended Phase 2 Dose (RP2D) of orally administered AP32788 in the Dose Escalation Cohort
Time Frame:Day 1 to 28 (Cycle 1)
Safety Issue:
Description:The RP2D will be the Maximum Tolerated Dose (MTD) or less. The MTD is defined as the highest dose at which ≤1 of 6 evaluable patients experience a dose-limiting toxicity (DLT) within the first 28 days of treatment. A DLT is a drug-related toxicity that is observed to occur within the first 28 days of treatment. Toxicity grades will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. An RP2D less than the MTD may be chosen if aspects of tolerability or efficacy not encompassed by the MTD determination suggest utilizing a lower dose.

Secondary Outcome Measures

Measure:Safety analysis of AP32788 assessed by adverse events, toxicity grades, and laboratory test results
Time Frame:up to 24 months after first dose
Safety Issue:
Description:Rates of adverse events (AEs), and serious AEs (SAEs) graded according to the NCI CTCAE v4.0; the frequency of occurrence of overall toxicity, categorized by toxicity grades (severity); listings of laboratory test results will also be generated, and descriptive statistics summarizing the changes in laboratory tests over time will be analyzed.
Measure:Identify DLTs and MTD of AP32788 in the Dose Escalation Phase
Time Frame:Day 1 to 28 (Cycle 1)
Safety Issue:
Description:
Measure:Maximum plasma concentration (Cmax) of AP32788 and its metabolites
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Time to Cmax (Tmax)
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Terminal half-life (t½λz) of AP32788
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve from time zero to 24 hours (AUC0-24) for AP32788 and its metabolites
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t) of AP32788 and its metabolites
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞) of AP32788 and its metabolites
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Apparent plasma clearance (CL/F) of AP32788
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Apparent volume of distribution (V/F) of AP32788
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:Dose linearity for AP32788 exposure (Cmax and AUC)
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:
Measure:The Accumulation Ratio of AP32788 (RAC)
Time Frame:Up to 3 Cycles (each cycle 28 days)
Safety Issue:
Description:Extent of accumulation on multiple dosing
Measure:Overall response rate as assessed by Independent Review Committee
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Best overall response
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Best target lesion response
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Duration of response
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Duration of intracranial response in Expansion Cohort 3
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Disease control rate (DCR)
Time Frame:up to 24 months after first dose
Safety Issue:
Description:The sum of complete responses (CR) + partial responses (PR) + stable disease (SD)
Measure:Progression free survival (PFS)
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Intracranial PFS in Expansion Cohort 3
Time Frame:up to 24 months after first dose
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:up to 24 months after first dose
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Ariad Pharmaceuticals

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

Last Updated

September 5, 2017