E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small Cell Lung Cancer (NSCLSC) |
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E.1.1.1 | Medical condition in easily understood language |
Non-Small Cell Lung Cancer (NSCLSC) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059515 |
E.1.2 | Term | Non-small cell lung cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025054 |
E.1.2 | Term | Lung cancer non-small cell stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025055 |
E.1.2 | Term | Lung cancer non-small cell stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the efficacy of TAK-788, as evidenced by confirmed ORR, as assessed by the IRC, in patients with locally advanced or metastatic NSCLC harboring EGFR in-frame exon 20 insertion mutations and who have received at least 1 prior line of therapy for locally advanced or metastatic NSCLC. |
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E.2.2 | Secondary objectives of the trial |
1. To further characterize the efficacy of TAK-788 as shown by confirmed ORR, as assessed by the investigator, duration of response, progression free survival (PFS), disease control rate (DCR), time to response, and overall survival (OS) 2. To assess the safety and tolerability of TAK-788 3. To collect sparse plasma concentration-time data of TAK 788 and its active metabolites, AP32960 and AP32914, to contribute to population PK and exposure response analyses 4. To assess patient-reported symptoms (particular core symptoms of lung cancer), functioning, and health-related quality of life (HRQoL) with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC lung cancer module, QLQ-LC13 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General 1.Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) or metastatic disease (Stage IIIB or IV). For all cohorts except Expansion Cohort 7, the locally advanced or metastatic disease is NSCLC. 2.Must have sufficient tumor tissue available for analysis (see Laboratory Manual for specific requirements). For patients in the expansion cohorts and in the extension cohort, tumor tissue obtained after progression on the most recent prior therapy is preferred. 3.Must have measurable disease by RECIST v1.1 (Appendix B). 4.Male or female adult patients (aged 18 years or older, or as defined per local regulations). 5.Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix A). 6.Minimum life expectancy of 3 months or more. 7.Adequate renal and hepatic function as defined by the following criteria: a.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); b.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (or ≤5 × ULN if liver function abnormalities are due to underlying malignancy); c.Estimated creatinine clearance ≥30 mL/min (calculated by using the Cockcroft-Gault equation); d.Serum albumin ≥2 g/dL; and e.Serum lipase ≤1.5 × ULN; and f. Serum amylase ≤1.5 × ULN unless the increased serum amylase is due to salivary isoenzymes. 8.Adequate bone marrow function as defined by the following criteria: a.Absolute neutrophil count (ANC) ≥1.5 × 109/L; b.Platelet count ≥75 × 109/L; and c.Hemoglobin ≥9.0 g/dL. 9.Normal QT interval on screening electrocardiogram (ECG), defined as 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 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0 [18]), 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. 11.Female patients who: •Are postmenopausal 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, nonhormonal method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent 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. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) 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. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
Extension Phase specific 1.Have 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) assessed by a Clinical Laboratory Improvements Amendment (CLIA)-certified (United States [US] sites) or an accredited (outside of the US) local laborato and sufficient tumor tissue available for central analysis (see Laboratory Manual). The EGFR exon 20 insertion mutation can be either alone or in combination with other EGFR or HER2 mutations. Note: central confirmation is not required for enrollment. 2. 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. –Note: A systemic anticancer chemotherapy regimen will be counted if it is administered over at least 1 cycle. A new antineoplastic chemotherapy used as maintenance therapy will be counted as a new regimen. Neoadjuvant or adjuvant systemic anticancer chemotherapy will be counted as a prior regimen if completion of the (neo)adjuvant therapy occurred <12 months prior to enrollment. –Prior treatment with an EGFR TKI is allowed unless the patient had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI.
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E.4 | Principal 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 [ie, erlotinib or gefitinib], which are allowed 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 patients 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 criterion does not apply to Expansion Cohort 7. 5.Received radiotherapy ≤14 days prior to the first dose of TAK 788 or has not recovered from radiotherapy-related toxicities. Palliative radiation administered outside the chest and brain, SRS, and stereotactic body radiotherapy are allowed up to 7 days prior to the first dose. 6.Received a moderate or strong CYP3A inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of TAK 788 (see Appendix C). 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 at screening or asymptomatic disease requiring corticosteroids to control symptoms within 7 days prior to the first dose of TAK 788. 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. 9. Have currentut who receive prophylactic steroids or anticonvulsants are allowed. 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, including, but not restricted to: a.Myocardial infarction (MI) within 6 months prior to the first dose of study drug; b.Unstable angina within 6 months prior to first dose; c.Congestive heart failure (CHF) within 6 months prior to first dose; d.History of clinically significant (as determined by the treating physician) atrial arrhythmia; e.Any history of ventricular arrhythmia; or f.Cerebrovascular accident or transient ischemic attack within 6 months prior to first dose. 11.Have a known history of uncontrolled hypertension. Patients 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 (Appendix D). 13.(Parts 1 and 2 [dose escalation and expansion cohorts] only) 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. (Part 3 [extension cohort] only) Have an ongoing or active infection including, but not limited to, the requirement for IV antibiotics, or a known history of HIV. Testing is not required in the absence of history. (Part 3 [extension cohort] only) Hepatitis B surface antigen (HBsAg) positive patients are allowed to enroll if HBV DNA is below 1000 copies/mL in the plasma. Patients who are positive for anti-HCV antibody (HCVAb) can be enrolled but must not have detectable HCV RNA in the plasma. 14.Currently have or have a history of interstitial lung disease, radiation pneumonitis that required steroid treatment, or drug-related pneumonitis. 15.Female patients who are lactating and breastfeeding or have a positive urine or serum pregnancy test during the screening period. Note: Female patients 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 patient safety or interfere with the evaluation of the safety of the drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
Confirmed ORR, as assessed by the IRC, per RECIST v1.1 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the primary endpoint, confirmed ORR as assessed by the IRC, will be performed in the full analysis set when all ongoing patients have completed their Cycle 6 disease assessment. A futility analysis will be planned for the primary endpoint when approximately 20 patients have completed their Cycle 4 disease assessment. |
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E.5.2 | Secondary end point(s) |
1.Confirmed ORR, as assessed by the investigator, per RECIST v1.1 2.Duration of response, as assessed by the IRC and the investigator 3.Time to response, as assessed by the IRC and the investigator 4.DCR (the percentage of patients with best response of complete response [CR], partial response [PR], or SD), as assessed by the IRC and the investigator, per RECIST v1.1 5.PFS, as assessed by the IRC and the investigator 6.OS 7.Patient-reported symptoms (particular core symptoms of lung cancer), functioning, and HRQoL with the EORTC QLQ-C30 and QLQ-LC13
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Two-sided exact 95% binomial confidence intervals will be computed for all binary secondary endpoints, including confirmed ORR as assessed by the investigator and DCR as assessed by the IRC and the investigator. Kaplan Meier methods, including medians and confidence intervals, will be used to estimate PFS as assessed by the IRC and the investigator, duration of response as assessed by the IRC and the investigator, and OS. Descriptive statistics will be used to summarize time to response in responders and time on treatment. Patient-reported outcome assessments will be assessed at each cycle using descriptive summary statistics. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
China |
Japan |
Korea, Republic of |
Taiwan |
United States |
Spain |
Germany |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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End of study (completion) date is 3 years after the last patient has enrolled unless stopped earlier due to futility or sponsor decision.. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |