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

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ClinicalTrials.gov Identifier: NCT02716116
Recruitment Status : Recruiting
First Posted : March 23, 2016
Last Update Posted : May 31, 2019
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Carcinoma, Non-Small-Cell Lung Drug: TAK-788 Phase 1 Phase 2

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), 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 TAK-788 is active, with or without active, measurable 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 341 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : April 30, 2016
Estimated Primary Completion Date : January 28, 2020
Estimated Study Completion Date : January 28, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose Escalation Cohort
TAK-788 treatment for participants with advanced NSCLC.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 1
TAK-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.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 2
TAK-788 treatment for NSCLC participants with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 3
TAK-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.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 4
TAK-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), with or without active, measurable CNS metastases.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 5
TAK-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, with or without active, measurable CNS metastases.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 6
TAK-788 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
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Expansion Cohort 7
TAK-788 treatment for participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, with or without active CNS metastases.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788

Experimental: Extension Cohort
TAK-788 treatment for participants with previously treated locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
Drug: TAK-788
TAK-788 capsules.
Other Name: AP32788




Primary Outcome Measures :
  1. Dose Escalation Cohort: RP2D of Orally Administered TAK-788 [ Time Frame: Day 1 to 28 (Cycle 1) ]
  2. Expansion Cohorts 1, 2, 4, 5, 6, and 7: Objective Response Rate (ORR) [ Time Frame: up to 36 months after first dose ]
  3. Expansion Cohort 3: Intracranial ORR (iORR) [ Time Frame: up to 36 months after first dose ]
  4. Extension Cohort: Confirmed ORR as per Independent Review Committee (IRC) [ Time Frame: up to 36 months after first dose ]

Secondary Outcome Measures :
  1. 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 ]
  2. 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) ]
  3. 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) ]
  4. Dose Escalation and Expansion Cohorts: AUC24: 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) ]
  5. 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) ]
  6. 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) ]
  7. 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) ]
  8. 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) ]
  9. 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) ]
  10. Expansion Cohorts: ORR as Assessed by IRC [ Time Frame: up to 36 months after first dose ]
  11. Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  12. Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  13. Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  14. Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  15. Expansion Cohort 3: Duration of Intracranial Response (iDOR) [ Time Frame: up to 36 months after first dose ]
  16. Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  17. Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC [ Time Frame: up to 36 months after first dose ]
  18. Expansion Cohort 3: Intracranial PFS (iPFS) [ Time Frame: up to 36 months after first dose ]
  19. Expansion and Extension Cohorts: Overall Survival (OS) [ Time Frame: up to 36 months after first dose ]
  20. Extension Cohort: Confirmed ORR as Assessed by the Investigator [ Time Frame: up to 36 months after first dose ]
  21. 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) ]
  22. 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) ]
  23. Extension Cohort: Change from Baseline in Global Quality of Life (QoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) [ Time Frame: Baseline up to 30 days after last dose of drug (approximately up to 37 months) ]
  24. Extension Cohort: Change from Baseline in Dyspnea Scale Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13) [ Time Frame: Baseline up to 30 days after last dose of drug (approximately up to 37 months) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 (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 participants greater than or equal to (>=) 18 years old. For participants in Japan, aged >=20 years.
  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 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]).

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

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, 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.

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, 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.

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, 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.

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. 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 prior to the first dose of TAK-788.
  3. 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. SRS and stereotactic body radiosurgery are allowed up to 7 days prior to the first dose.
  6. Received a strong CYP4503A inhibitor or strong CYP3A inducer within 2 weeks 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. 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 TAK-788.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02716116


Contacts
Layout table for location contacts
Contact: Takeda Study Registration Call Center +1-866-835-2233 globaloncologymedinfo@takeda.com

  Show 87 Study Locations
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Takeda

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT02716116     History of Changes
Other Study ID Numbers: AP32788-15-101
U1111-1217-7205 ( Registry Identifier: WHO )
2016-001271-68 ( EudraCT Number )
First Posted: March 23, 2016    Key Record Dates
Last Update Posted: May 31, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
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."

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
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

Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases