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A Phase 1/2 Study of TAK-788 in Japanese Patients

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.
 
ClinicalTrials.gov Identifier: NCT03807778
Recruitment Status : Recruiting
First Posted : January 17, 2019
Last Update Posted : July 10, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to evaluate the safety, efficacy, tolerability and pharmacokinetics (PK) of TAK-788. At first, Phase 1 part of this study is designed to determine a recommended phase 2 dose (RP2D) of TAK-788 in Japanese participants with locally advanced or metastatic non-small cell lung cancer (NSCLC). After phase 1 study, the phase 2 part of this study will be conducted to evaluate the efficacy and safety of TAK-788 in treatment naive Japanese NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation.

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

Detailed Description:

The drug being tested in this study is called TAK-788. TAK-788 is being tested to treat Japanese participants with NSCLC. This study has two parts (Phase 1 part and Phase 2 part), Phase 1 part of this study will look at the safety, efficacy, tolerability and PK of TAK-788 orally administered once daily, and will determine a RP2D. Phase 2 study will look at the efficacy and safety of TAK-788 in treatment naive Japanese NSCLC patients with epidermal growth factor receptor (EGFR) exon 20 insertion mutation. All participants will be assigned to Phase 1 part or Phase 2 part and will be asked to take TAK-788 capsule as following dosage and regimen;

Phase 1 part; TAK-788, 40 mg as starting dose, once daily, and escalating up to 160 mg until a Maximum Tolerated Dose (MTD). An expansion phase may be followed at any dose to further confirm safety observations following identification of MTD/RP2D.

Phase 2 part; TAK-788, 160 mg, once daily

The study will enroll approximately 58-63 participants (Phase 1 part; 28-33 and Phase 2 part; 30).

This multi-center trial will be conducted in Japan. The overall time to participate in this study of Phase 1 part is approximately 3 years and Phase 2 part is approximately 4 years. Participants will make multiple visits to the clinic in the treatment period, and the post-treatment period including follow-up assessments after the last dose of the study drug.

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Study Type : Interventional
Estimated Enrollment : 63 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Study of the Oral EGFR/HER2 Inhibitor TAK-788 in Japanese Non-Small Cell Lung Cancer Patients
Actual Study Start Date : February 4, 2019
Estimated Primary Completion Date : November 28, 2020
Estimated Study Completion Date : March 31, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TAK-788, Phase 1 Part
TAK-788 40 milligrams (mg) (as the starting dose), capsules, orally, once daily on Days 1-28 of each 28-day treatment cycle for up to disease progression or intolerable toxicity, or another discontinuation criterion, and increasing until 160 mg, once daily (for up to approximately 10-12 cycles).
Drug: TAK-788
TAK-788 capsule

Experimental: TAK-788, Phase 2 Part
TAK-788 160 mg, once daily, for up to approximately 10-12 cycles.
Drug: TAK-788
TAK-788 capsule




Primary Outcome Measures :
  1. Phase 1 Part: Recommended Phase 2 Dose (RP2D) of Orally Administered TAK-788 [ Time Frame: Up to approximately 28 days ]
    The RP2D is the maximum tolerated dose (MTD) or less. 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.

  2. Phase 2 Part: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC) [ Time Frame: Up to approximately 1.5 years ]
    IRC assessed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in participants with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) mutations. ORR is defined as the percentage of participants achieving complete response (CR) and partial response (PR) per RECIST version 1.1. CR: Disappearance of all extranodal target lesions; PR: At least a 30% decrease in Sum of the Longest Diameters (SLD) of target lesions, taking as a reference the baseline SLD.


Secondary Outcome Measures :
  1. Phase 1 Part: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: Up to approximately 1.5 years ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant who has signed informed consent to participate in a study; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.

  2. Phase 1 Part: Number of Participants with First Cycle Dose-Limiting Toxicities (DLTs) [ Time Frame: Up to approximately 1.5 years ]
    Toxicity will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

  3. Phase 1 Part: DLTs of Orally Administered TAK-788 [ Time Frame: Up to approximately 28 days ]
    Toxicity will be evaluated according to the NCI CTCAE, Version 5.00. DLT will be defined as any of the events specified in the protocol that are considered by the investigator to be at least possibly related to therapy with study medications.

  4. Phase 1 Part: Maximum Tolerated Dose (MTD) of Orally Administered TAK-788 [ Time Frame: Up to approximately 28 days ]
    The MTD is the highest dose level at which the participant tolerates treatment without dose-limiting toxicities.

  5. Phase 1 Part: Cmax: Maximum Plasma Concentration for TAK-788 and its Active Metabolites after a Single Oral Dose [ Time Frame: Up to 24 hours; Pre-dose and multiple time points post-dose on Cycle 1 Day 1 (C1D1) ]
  6. Phase 1 Part: Tmax: Time to Cmax for TAK-788 and its Active Metabolites after a Single Oral Dose [ Time Frame: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 ]
  7. Phase 1 Part: AUC24: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for TAK-788 and its Active Metabolites after a Single Oral Dose [ Time Frame: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 ]
  8. Phase 1 Part: AUClast: Area Under the Plasma Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for TAK-788 and its Active Metabolites after a Single Oral Dose [ Time Frame: Up to 24 hours; Pre-dose and multiple time points post-dose on C1D1 ]
  9. Phase 1 Part: Cmax, ss: Maximum Plasma Concentration for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses [ Time Frame: Up to approximately 57 days; Pre-dose and multiple time points post-dose ]
  10. Phase 1 Part: Tmax, ss: Time to Cmax for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses [ Time Frame: Up to approximately 57 days; Pre-dose and multiple time points post-dose ]
  11. Phase 1 Part: AUC24, ss: Area Under the Plasma Concentration-Time Curve from Time 0 to 24 hours for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses [ Time Frame: Up to approximately 57 days; Pre-dose and multiple time points post-dose ]
  12. Phase 1 Part: Rac: Extent of Accumulation Ratio on Multiple Dosing for TAK-788 and its Active Metabolites at Steady State after Multiple Oral Doses [ Time Frame: Up to approximately 57 days; Pre-dose and multiple time points post-dose ]
  13. Phase 2 Part: Overall Response Rate (ORR) as Assessed by the Independent Review Committee (IRC) [ Time Frame: Up to approximately 4 years ]
    IRC assessed objective response rate (ORR) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 in participants with epidermal growth factor receptor (EGFR) or human epidermal growth factor 2 (HER2) mutations. ORR is defined as the percentage of participants achieving complete response (CR) and partial response (PR) per RECIST version 1.1. CR: Disappearance of all target lesions; PR: At least a 30% decrease in SLD of target lesions, taking as a reference the baseline SLD.

  14. Phase 2 Part: Duration of Response (DOR) [ Time Frame: Up to approximately 4 years ]
    Duration of response is defined as the time interval from the time that the measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that PD is objectively documented.

  15. Phase 2 Part: Time to Response [ Time Frame: Up to approximately 4 years ]
    Time to response is defined as the time interval from the date of randomization until the initial observation of CR or PR.

  16. Phase 2 Part: Disease Control Rate (DCR) [ Time Frame: Up to approximately 4 years ]
    DCR is defined as the percentage of participants who have achieved CR, PR, or stable disease (SD) (in the case of SD, measurements must have met the SD criteria at least once after study entry at a minimum interval of 42 days) after the initiation of study drug.

  17. Phase 2 Part: Progression Free Survival (PFS) [ Time Frame: Up to approximately 4 years ]
    PFS is defined as the time interval from the date of randomization until the first date at which the criteria for progressive disease (PD) according to RECIST version 1.1 are met or death, whichever occurs first.

  18. Phase 2 Part: Overall Survival (OS) [ Time Frame: Up to approximately 4 years ]
    OS is defined as the interval from the date of randomization until death.

  19. Phase 2 Part: Patient-reported Symptoms, Functioning, and Health-related Quality of Life (HRQoL) as Assessed by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 [ Time Frame: Up to approximately 4 years ]
    EORTC QLQ-C30 is a cancer-specific questionnaire which comprises of 5 functional scales (physical, role, cognitive, emotional, and social functioning); 3 symptom scales (fatigue, pain, and nausea/vomiting); and a global health status/quality-of-life (QoL) scale. Six single-item scales are also included (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Raw scores will be converted into scale scores ranging from 0 to 100. For the functional scales and the global health status/QoL scale, higher scores represent better HRQoL, whereas for the symptom scales lower scores represent better HRQoL (i.e., a low level of symptomatology/problems).

  20. Phase 2 Part: Patient-reported Symptoms (particular core symptoms of lung cancer), Functioning, and HRQoL as Assessed by the EORTC lung cancer module QLQ-LC13 [ Time Frame: Up to approximately 4 years ]
    EORTC QLQ-LC13 contains 13 questions to assess for: dyspnea, and a series of single items including pain, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis. Score of each item will range from 0 to 100, where 0 indicates no symptoms and 100 indicates worst possible symptoms.



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.


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Ages Eligible for Study:   20 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

General Inclusion Criteria (Both in Phase 1 and Phase 2 Part);

  1. Male or female patients ≥20 years old.
  2. Must have measurable disease by RECIST v1.1. Previously irradiated lesions may not be used for target lesions, unless there is unambiguous radiological progression after radiotherapy.
  3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
  4. Minimum life expectancy of 3 months or more.
  5. Adequate renal and hepatic function as defined by the following criteria:

    •Total serum bilirubin ≤1.5 × upper limit of normal (ULN) (≤3.0 × ULN for patients with Gilbert syndrome or if liver function abnormalities are due to underlying malignancy);

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

    •Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation);

    •Serum albumin ≥2 g/dL; and

    •Serum lipase ≤1.5 × ULN; and

    •Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary isoenzymes.

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

    • Absolute neutrophil count ≥1.5 × 109/L;
    • Platelet count ≥75 × 109/L in Phase 1 Part and ≥100 × 109/L in Phase 2 Part; and
    • Hemoglobin ≥9.0 g/dL.
  7. Normal QT interval on screening ECG, defined as QTcF of ≤450 ms in males or ≤470 ms in females.
  8. Female patients who:

    • Are postmenopausal (natural amenorrhea and not due to other medical reasons) for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 1 highly effective non-hormonal method of contraception and 1 additional effective (barrier) method (see Section 8.7.1) at the same time, from the time of signing the informed consent form (ICF) through 30 days after the last dose of study drug, OR
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.

Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.

Male patients, even if surgically sterilized (ie, status postvasectomy), who:

  • Agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject.

Note: Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.

9.Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.

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

  • Phase-Specific Inclusion Criteria (Phase 1 part);

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

    2.Refractory to standard available therapies. 3.All toxicities from prior therapy have resolved to ≤ grade 1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0), or have resolved to baseline, at the time of first dose of TAK-788. Note: treatment-related grade >1 alopecia or treatment-related grade 2 peripheral neuropathy are allowed if deemed irreversible.

  • Phase-Specific Inclusion Criteria (Phase 2 part);

    1. Histologically or cytologically confirmed locally advanced not suitable for definitive therapy, recurrent, or metastatic (Stage IV) NSCLC.
    2. Not received prior systemic treatment for locally advanced or metastatic disease (with the exception below): Neoadjuvant or adjuvant chemotherapy/immunotherapy for Stage I to III or combined modality chemotherapy/radiation for locally advanced disease is allowed if completed >6 months before the development of metastatic disease.
    3. A documented EGFR in-frame exon 20 insertion (including A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH, or any other in-frame exon 20 insertion mutation) by a local test that has been analytically validated per local authority guidelines. The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations except EGFR common mutations (exon 19 del or L858R).
    4. Adequate tumor tissue available, either from primary or metastatic sites, for central laboratory confirmation of EGFR in-frame exon 20 insertion mutation. Note: confirmation of central test positivity is not required before the first dose of TAK-788.

      Exclusion Criteria:

      General Exclusion Criteria (Both in Phase 1 and Phase 2 Part);

    1. 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 patients with another primary malignancy who are definitively relapse-free with at least 3 years elapsed since the diagnosis of the other primary malignancy.
    2. 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.
    3. Have current spinal cord compression (symptomatic or asymptomatic and detected by radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
    4. Have significant, uncontrolled, or active cardiovascular disease, including, but not restricted to:
  • Myocardial infarction within 6 months prior to the first dose of study drug;
  • Unstable angina within 6 months prior to first dose;
  • Congestive heart failure within 6 months prior to first dose;
  • History of clinically significant (as determined by the treating physician) atrial arrhythmia;
  • Any history of ventricular arrhythmia; or
  • Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose.

    5.Have uncontrolled hypertension. Patients with hypertension should be under treatment on study entry to control blood pressure.

    6.Currently being treated with medications known to be associated with the development of Torsades de Pointes.

    7.Have an ongoing or active infection, including, but not limited to, the requirement for intravenous antibiotics. Have a known history of HIV infection. Testing of HIV is not required in the absence of history.Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if hepatitis B virus (HBV)-DNA is below 1000 copies/mL in the plasma.Patients who have positive hepatitis C virus (HCV) antibody can be enrolled but must have HCV-RNA undetectable in the plasma.

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

    9.Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period.

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

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

    11.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.

  • Phase-Specific Exclusion Criteria (Phase 1 part);

    1. Previously received TAK-788.
    2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy and investigational agents) within 14 days prior to the first dose of TAK-788 (except for reversible EGFR TKIs [ie, erlotinib or gefitinib] up to 7 days prior to the first dose of TAK-788).
    3. Received antineoplastic monoclonal antibodies including immunotherapy within 28 days prior to the first dose of TAK-788.
    4. Received radiotherapy within 14 days prior to the first dose of TAK-788, Stereotactic radiosurgery (SRS) and stereotactic body radiosurgery are allowed up to 7 days prior to the first dose.
    5. 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.

      Note: If a patient has worsening neurological symptoms or signs due to CNS metastases, the patient needs to complete local therapy and be neurologically stable (with no requirement for corticosteroids or use of anticonvulsants) for 7 days prior to the first dose of TAK-788. Patients with no prior history of signs or symptoms of CNS metastases but who receive prophylactic steroids or anticonvulsants are allowed.

    6. Received a strong cytochrome P450 (CYP)3A inhibitor or strong CYP3A inducer within 2 weeks prior to first dose of TAK-788.
  • Phase-Specific Exclusion Criteria (Phase 2 part);

    1. Received radiotherapy within 14 days before the first dose of TAK-788 or has not recovered from radiotherapy-related toxicities. Stereotactic radiosurgery, stereotactic body radiotherapy, or palliative radiation outside the chest and brain is allowed up to 7 days before the first dose of TAK-788.
    2. 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.
    3. Received a moderate or strong CYP3A inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of TAK-788.

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): NCT03807778


Contacts
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Contact: Takeda Study Registration Call Center +1-877-825-3327 medicalinformation@tpna.com

Locations
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Sponsors and Collaborators
Takeda
Investigators
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Study Director: Study Director Takeda
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03807778    
Other Study ID Numbers: TAK-788-1003
U1111-1223-2659 ( Other Identifier: WHO )
JapicCTI-194584 ( Registry Identifier: JapicCTI )
First Posted: January 17, 2019    Key Record Dates
Last Update Posted: July 10, 2020
Last Verified: July 2020
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 for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com 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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms