A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT02716116
• Recruitment Status: Active, not recruiting
• First Posted: March 23, 2016
• Last Update Posted: October 18, 2023
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: March 14, 2016
• First Posted Date: March 23, 2016
• Last Update Posted Date: October 18, 2023
• Actual Study Start Date: June 16, 2016
• Estimated Primary Completion Date: March 28, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2022)

• Part 1, Dose Escalation Component: Recommended Phase 2 Dose (RP2D) of Orally Administered TAK-788 [ Time Frame: Cycle 1 (Cycle length is equal to [=] 28 days) ]
• Part 2, Expansion Cohorts 1, 2, 4, 5 and 7: Confirmed Objective Response Rate (ORR) Assessed by the Investigator [ Time Frame: Up to 36 months after first dose ]
• Part 2, Expansion Cohort 3: Intracranial ORR (iORR) Assessed by Independent Review Committee (IRC) [ Time Frame: Up to 36 months after first dose ]
• Part 2, Expansion Cohort 6: Confirmed ORR Assessed by IRC [ Time Frame: Up to 36 months after first dose ]
• Part 3, Extension Cohort: Confirmed ORR Assessed by IRC [ Time Frame: Up to 36 months after first dose ]

Original Primary Outcome Measures (submitted: March 17, 2016)

• 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.

Current Secondary Outcome Measures (submitted: March 22, 2022)

• Part 1, Dose Escalation Component: Dose Limiting Toxicities (DLTs) of TAK-788 [ Time Frame: Cycle 1 (Cycle length=28 days) ]
• Part 1, Dose Escalation Component: Maximum Tolerated Dose (MTD) of TAK-788 [ Time Frame: Cycle 1 (Cycle length=28 days) ]
• Parts 1 and 2, 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 for Parts 1 and 2) ]
• Parts 1 and 2, Dose Escalation and Expansion Cohorts: Tmax; Time of First Occurrence of Maximum Plasma Concentration (Cmax) of TAK-788 and its Metabolites [ Time Frame: Cycle 1 Day 1 and Cycle 2 Day 1 (cycle length=28 days for Parts 1 and 2) ]
• Parts 1 and 2, Dose Escalation and Expansion Cohorts: AUC 24; 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 for Parts 1 and 2) ]
• Parts 1 and 2, 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 for Parts 1 and 2) ]
• Parts 1 and 2, 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 for Parts 1 and 2) ]
• Parts 1 and 2, 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 for Parts 1 and 2) ]
• Part 2, Expansion Cohorts 1, 2, 3, 4, 5, and 7: Confirmed ORR as Assessed by IRC [ Time Frame: Up to 36 months after first dose ]
• Part 2, Expansion Cohorts: Best Overall Response as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Part 2, Expansion Cohorts: Best Target Lesion Response as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Parts 2 and 3, Expansion and Extension Cohorts: Duration of Response as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Parts 2 and 3, Expansion and Extension Cohorts: Disease Control Rate (DCR) as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Part 2 and 3, Expansion and Extension Cohorts: Time to Response as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Parts 2 and 3, Expansion and Extension Cohorts: Progression Free Survival (PFS) as Assessed by the Investigator and IRC [ Time Frame: Up to 36 months after first dose ]
• Parts 2 and 3, Expansion and Extension Cohorts: Overall Survival (OS) [ Time Frame: Up to 36 months after first dose ]
• Part 2, Expansion Cohort 3: Duration of Intracranial Response (iDOR) [ Time Frame: up to 36 months after first dose ]
• Part 2, Expansion Cohort 3: Intracranial PFS (iPFS) [ Time Frame: up to 36 months after first dose ]
• Part 2, Expansion Cohorts 6: Confirmed ORR as Assessed by the Investigator [ Time Frame: Up to 36 months after first dose ]
• Part 3, Extension Cohort: Confirmed ORR as Assessed by the Investigator [ Time Frame: Up to 36 months after first dose ]
• Part 3, Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and Health-related Quality of Life (HRQoL) Based on European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-core 30 (EORTC QLQ-C30) [ Time Frame: Up to 30 days after last dose of drug (approximately up to 37 months) ]
• Part 3, Extension Cohort: Number of Participants With Patient-reported Symptoms (Lung Cancer), Functioning, and health-related Global Quality of Life (HRQoL) Based on Quality of Life Questionnaire Lung Cancer Module-13 (QLQ-LC13) [ Time Frame: Up to 30 days after last dose of drug (approximately up to 37 months) ]

Original Secondary Outcome Measures (submitted: March 17, 2016)

• 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 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of TAK-788 in Adults With Non-Small Cell Lung Cancer
• 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
• Brief Summary: This study is about a medicine called TAK-788, also known as mobocertinib, given to adults with non-small cell lung cancer. The main aims of this study are to check if there are any side effects from TAK-788, to learn how TAK-788 is processed by the body, and to determine the best dose of TAK-788 to treat this condition. Participants will take TAK-788 capsules with chemotherapy. Participants will continue to take TAK-788 unless they or their doctor decide they should stop this treatment. Participants will take TAK-788 capsules with or without chemotherapy under antidiarrhea prevention to determine the safety of TAK-788 treatment. Non-Asian, non-White participants will take TAK-788 to determine the safety and tolerability of TAK-788 treatment.

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 (Part 1), expansion phase (Part 2), followed by an extension phase (Part 3).

The objectives of the dose escalation phase (Part 1), is to determine the safety profile of orally administered TAK-788, including the MTD, DLTs, RP2D, 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), without active 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, without active 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, without active CNS metastases; and
7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active, without active 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 enrolled 324 participants.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Carcinoma, Non-Small-Cell Lung

Intervention

Drug: TAK-788

TAK-788 capsules.

Other Name: AP32788

Study Arms

• Experimental: Part 1: Dose Escalation Component
  TAK-788 treatment for participants with advanced NSCLC.
  Intervention: Drug: TAK-788
• Experimental: Part 2: 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.
  Intervention: Drug: TAK-788
• Experimental: Part 2: Expansion Cohort 2
  TAK-788 treatment for NSCLC participants with HER2 exon 20 activating insertions or point mutations and no active, measurable CNS metastases.
  Intervention: Drug: TAK-788
• Experimental: Part 2: 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.
  Intervention: Drug: TAK-788
• Experimental: Part 2: 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), without active CNS metastases.
  Intervention: Drug: TAK-788
• Experimental: Part 2: 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 without active CNS metastases.
  Intervention: Drug: TAK-788
• Experimental: Part 2: 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 without active CNS metastases
  Intervention: Drug: TAK-788
• Experimental: Part 2: Expansion Cohort 7
  TAK-788 treatment for participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which TAK-788 is active without active CNS metastases.
  Intervention: Drug: TAK-788
• Experimental: Part 3: Extension Cohort
  TAK-788 treatment for participants with previously treated locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations.
  Intervention: Drug: TAK-788

Publications *

• Zhou C, Ramalingam SS, Kim TM, Kim SW, Yang JC, Riely GJ, Mekhail T, Nguyen D, Garcia Campelo MR, Felip E, Vincent S, Jin S, Griffin C, Bunn V, Lin J, Lin HM, Mehta M, Janne PA. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer: A Phase 1/2 Open-label Nonrandomized Clinical Trial. JAMA Oncol. 2021 Dec 1;7(12):e214761. doi: 10.1001/jamaoncol.2021.4761. Epub 2021 Dec 16. Erratum In: JAMA Oncol. 2022 Feb 24;: JAMA Oncol. 2022 Sep 1;8(9):1359.
• Han H, Li S, Chen T, Fitzgerald M, Liu S, Peng C, Tang KH, Cao S, Chouitar J, Wu J, Peng D, Deng J, Gao Z, Baker TE, Li F, Zhang H, Pan Y, Ding H, Hu H, Pyon V, Thakurdin C, Papadopoulos E, Tang S, Gonzalvez F, Chen H, Rivera VM, Brake R, Vincent S, Wong KK. Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib. Cancer Res. 2021 Oct 15;81(20):5311-5324. doi: 10.1158/0008-5472.CAN-21-1526. Epub 2021 Aug 11.
• Riely GJ, Neal JW, Camidge DR, Spira AI, Piotrowska Z, Costa DB, Tsao AS, Patel JD, Gadgeel SM, Bazhenova L, Zhu VW, West HL, Mekhail T, Gentzler RD, Nguyen D, Vincent S, Zhang S, Lin J, Bunn V, Jin S, Li S, Janne PA. Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial. Cancer Discov. 2021 Jul;11(7):1688-1699. doi: 10.1158/2159-8290.CD-20-1598. Epub 2021 Feb 25. Erratum In: Cancer Discov. 2023 Sep 6;13(9):2107.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: January 23, 2023): 334
• Original Estimated Enrollment (submitted: March 17, 2016): 105
• Estimated Study Completion Date: March 28, 2025
• Estimated Primary Completion Date: March 28, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

General Inclusion Criteria all cohorts: dose escalation, antidiarrhea prophylaxis, dose escalation combination, expansion, and extension:

1. Have histologically or cytologically confirmed locally advanced (and not a candidate for definitive therapy) or metastatic NSCLC disease (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 adult participants (aged 18 years or older, or as defined per local regulations).
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. With an EGFR exon 20 insertion: 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.
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 (greater than or equal to [ ≥ ]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.

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, without active 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.

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, without active 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.

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, without active CNS metastases.

1. Have a solid tumor that is not NSCLC, including, but not limited to, bladder/urinary tract cancer, breast cancer, gastric/esophageal cancer, biliary tract cancer, and head and neck cancer.
2. Is refractory to standard therapy.
3. Have EGFR or HER2 mutations, documented by a local test.

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. 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 or has not recovered from radiotherapy-related toxicities. Palliative radiation administered outside the chest and brain, stereotactic radiosurgery (SRS), and stereotactic body radiotherapy are allowed up to 7 days prior to the first dose
6. Received a moderate or strong CYP4503A inhibitor or moderate or strong CYP3A inducer within 10 days 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. Part 1 (dose escalation) and Expansion Cohorts 1 to 3 of Part 2 (expansion phase) only:

   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.

   Part 3 (extension cohort) and Expansion Cohorts 4 to 7 of Part 2 (expansion phase) only:

   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 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, 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: China, Germany, Italy, Japan, Korea, Republic of, Puerto Rico, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: France

Administrative Information

• NCT Number: NCT02716116
• Other Study ID Numbers: AP32788-15-101; U1111-1217-7205 ( Registry Identifier: WHO ); 2016-001271-68 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://vivli.org/ourmember/takeda/

• Current Responsible Party: Takeda
• Original Responsible Party: Ariad Pharmaceuticals
• Current Study Sponsor: Takeda
• Original Study Sponsor: Ariad Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: October 2023