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A Trial of AP32788 in Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT02716116
Recruitment Status : Recruiting
First Posted : March 23, 2016
Last Update Posted : September 17, 2018
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Takeda ( Ariad Pharmaceuticals )

March 14, 2016
March 23, 2016
September 17, 2018
April 30, 2016
July 30, 2021   (Final data collection date for primary outcome measure)
  • RP2D of Orally Administered AP32788 in the Dose Escalation Cohort [ Time Frame: Day 1 to 28 (Cycle 1) ]
  • Expansion Cohorts 1, 2, 4, 5, 6, and 7: Objective Response Rate (ORR) in the Expansion Cohorts [ Time Frame: up to 36 months after first dose ]
  • Expansion Cohort 3: Intracranial ORR (iORR) in Expansion Cohort [ Time Frame: up to 36 months after first dose ]
  • 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.
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 36 months after first dose ]
    Rates of adverse events (AEs), and serious AEs (SAEs) graded according to the NCI CTCAE v5.0; 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 in Cycle 1 (Cycle length is equal to [=] 28 days) ]
  • 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) ]
  • AUC24: Area Under the Concentration-time Curve From Time Zero to 24 hours for AP32788 and its Metabolites [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • AUCt: Area Under the Concentration-time Curve From Time Zero to Time t for AP32788 and its Metabolites [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • RAC (Cmax): Accumulation Ratio Based on Cmax [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • Ctrough: Observed Concentration at the End of a Dosing Interval [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • RAC (AUC): Accumulation Ratio Based on AUC [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • Cmax: Maximum Observed Concentration of AP32788 and its Metabolites [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • ORR as assessed by IRC [ Time Frame: up to 36 months after first dose ]
  • Best Overall Response [ Time Frame: up to 36 months after first dose ]
  • Best Target Lesion Response [ Time Frame: up to 36 months after first dose ]
  • Duration of Response [ Time Frame: up to 36 months after first dose ]
  • Duration of Intracranial Response (iDOR) in Expansion Cohort 3 [ Time Frame: up to 36 months after first dose ]
  • Disease Control Rate (DCR) [ Time Frame: up to 36 months after first dose ]
  • Progression Free Survival (PFS) [ Time Frame: up to 36 months after first dose ]
  • Intracranial PFS (iPFS) in Expansion Cohort 3 [ Time Frame: up to 36 months after first dose ]
  • Overall Survival (OS) [ Time Frame: up to 36 months after first dose ]
  • Cmax: Dose Linearity for AP32788 Exposure [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • AUC: Dose Linearity for AP32788 Exposure [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days) ]
  • 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 ]
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 participants with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2), and anti-tumor activity of AP32788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. 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 6 histologically and molecularly defined NSCLC cohorts and 1 cohort with solid tumor other than NSCLC. Approximately 250 participants will be enrolled total.

This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of oral EGFR/HER2 Inhibitor AP32788 in participants with NSCLC and anti-tumor activity of AP32788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. 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 MTD, DLTs, RP2D and pharmacokinetic profile.

The primary goal of the expansion component of the trial is to evaluate the anti-tumor activity of AP32788 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 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;
  5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, with or without active, measurable 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, with or without active, measurable CNS metastases; and
  7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which AP32788 is active, 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 participants with advanced NSCLC.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 1
    AP32788 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 CNS metastases.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 2
    AP32788 treatment for NSCLC participants with 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 participants 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 participants 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
  • Experimental: Expansion Cohort 5
    AP32788 treatment for NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an objective response to an EGFR TKI and subsequently progressed, with or without active, measurable CNS metastases.
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 6
    AP32788 treatment NSCLC participants with EGFR exon 20 activating insertions, who have not received prior systemic anticancer treatment for locally advanced or metastatic disease, with or without active, measurable CNS metastases
    Intervention: Drug: AP32788
  • Experimental: Expansion Cohort 7
    AP32788 treatment for participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which AP32788 is active, with or without active 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
250
105
July 30, 2021
July 30, 2021   (Final data collection date for primary outcome measure)

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 (Stage IIIB or IV) or other solid tumors.
  2. Must have sufficient tumor tissue available for analysis.
  3. Must have measurable disease by RECIST v1.1.
  4. Male or female participants >=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 organ function at baseline.
  8. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval corrected (Fridericia) (QTcF) of <=450 millisecond (ms) in males or <=470 ms in females.
  9. 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.
  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.

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 during treatment with that prior TKI.
  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]).

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

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, with or without active, measurable 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.
  4. Have or do not have active (untreated or progressing) CNS metastases.

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, with or without active, measurable 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.
  3. Have or do not have active (untreated or progressing) CNS metastases.

Expansion Cohort 7 Specific Inclusion Criteria:

Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which AP32788 is active, with or without active, measurable CNS metastases.

  1. Have a solid tumor that is not NSCLC and that is refractory to standard therapy.
  2. Have EGFR or HER2 mutations, documented by a local test.
  3. Have or do not have active (untreated or progressing) CNS metastases.

Exclusion Criteria:

  1. Previously received AP32788.
  2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy, and investigational agents,<=14 days prior to first dose of AP32788 (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 AP32788).
  3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days of the first dose of AP32788.
  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 AP32788. SRS and stereotactic body radiosurgery are allowed up to 7 days prior to the first dose.
  6. Received a strong cytochrome P450 (CYP)3A inhibitor or strong CYP3A inducer within 2 weeks prior to first dose of AP32788.
  7. 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.
  8. Have symptomatic CNS metastases (parenchymal or leptomeningeal) at screening or asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to the first dose of AP32788.
  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 AP32788.
  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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Older Adult)
No
Contact: Takeda Study Registration Call Center +1-866-835-2233 globaloncologymedinfo@takeda.com
United States
 
 
NCT02716116
AP32788-15-101
U1111-1217-7205 ( Registry Identifier: WHO )
No
Not Provided
Plan to Share IPD: Yes
Plan Description: "Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment."
Takeda ( Ariad Pharmaceuticals )
Ariad Pharmaceuticals
Takeda
Not Provided
Takeda
September 2018

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