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A Trial of AP32788 in Non-Small Cell Lung Cancer

This study is currently recruiting participants.
Verified September 2017 by Ariad Pharmaceuticals
Sponsor:
ClinicalTrials.gov Identifier:
NCT02716116
First Posted: March 23, 2016
Last Update Posted: September 6, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Ariad Pharmaceuticals
March 14, 2016
March 23, 2016
September 6, 2017
April 2016
February 2018   (Final data collection date for primary outcome measure)
  • Recommended Phase 2 Dose (RP2D) of orally administered AP32788 in the Dose Escalation Cohort [ Time Frame: Day 1 to 28 (Cycle 1) ]
    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.
  • Overall Response Rate (ORR) in the Expansion Cohorts [ Time Frame: up to 24 months after first dose ]
    For Expansion Cohorts 1, 2, and 4, ORR is defined as Investigator-assessed overall response rate (using Response Evaluation Criteria in Solid Tumors version 1.1 [RECIST 1.1]). For Expansion Cohort 3, ORR is defined as the intracranial overall response rate.
Same as current
Complete list of historical versions of study NCT02716116 on ClinicalTrials.gov Archive Site
  • Safety analysis of AP32788 assessed by adverse events, toxicity grades, and laboratory test results [ Time Frame: up to 24 months after first dose ]
    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.
  • Identify DLTs and MTD of AP32788 in the Dose Escalation Phase [ Time Frame: Day 1 to 28 (Cycle 1) ]
  • Maximum plasma concentration (Cmax) of AP32788 and its metabolites [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • Time to Cmax (Tmax) [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • Terminal half-life (t½λz) of AP32788 [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • Apparent plasma clearance (CL/F) of AP32788 [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • Apparent volume of distribution (V/F) of AP32788 [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • Dose linearity for AP32788 exposure (Cmax and AUC) [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
  • The Accumulation Ratio of AP32788 (RAC) [ Time Frame: Up to 3 Cycles (each cycle 28 days) ]
    Extent of accumulation on multiple dosing
  • Overall response rate as assessed by Independent Review Committee [ Time Frame: up to 24 months after first dose ]
  • Best overall response [ Time Frame: up to 24 months after first dose ]
  • Best target lesion response [ Time Frame: up to 24 months after first dose ]
  • Duration of response [ Time Frame: up to 24 months after first dose ]
  • Duration of intracranial response in Expansion Cohort 3 [ Time Frame: up to 24 months after first dose ]
  • Disease control rate (DCR) [ Time Frame: up to 24 months after first dose ]
    The sum of complete responses (CR) + partial responses (PR) + stable disease (SD)
  • Progression free survival (PFS) [ Time Frame: up to 24 months after first dose ]
  • Intracranial PFS in Expansion Cohort 3 [ Time Frame: up to 24 months after first dose ]
  • Overall survival (OS) [ Time Frame: up to 24 months after first dose ]
Same as current
Not Provided
Not Provided
 
A Trial of AP32788 in Non-Small Cell Lung Cancer
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
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.

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.
Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Carcinoma, Non-Small-Cell Lung
Drug: AP32788
AP32788 capsules
  • Experimental: Dose Escalation Cohort
    AP32788 treatment for patients with advanced NSCLC.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 1
    AP32788 treatment for NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 activating insertions and no active, measurable central nervous system (CNS) metastases.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 2
    AP32788 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.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 3
    AP32788 treatment for NSCLC patients with EGFR exon 20 activating insertions or HER2 exon 20 activating insertions or point mutations and active, measurable CNS metastases.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 4
    AP32788 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.
    Intervention: Drug: AP32788
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
105
October 2019
February 2018   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact: Takeda Study Registration Call Center 844-662-8532 globaloncologymedinfo@takeda.com
United States
 
 
NCT02716116
AP32788-15-101
No
Not Provided
Plan to Share IPD: No
Ariad Pharmaceuticals
Ariad Pharmaceuticals
Not Provided
Not Provided
Ariad Pharmaceuticals
September 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP