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    Summary
    EudraCT Number:2022-000528-39
    Sponsor's Protocol Code Number:TAK-676-1002
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-12-16
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2022-000528-39
    A.3Full title of the trial
    An Open-label, Dose Escalation, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-676 as a Single Agent and in Combination With Pembrolizumab in Adult Patients With Advanced or Metastatic Solid Tumors
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study of TAK-676 as Single Agent and TAK-676 in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors
    A.4.1Sponsor's protocol code numberTAK-676-1002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04420884
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1241-4427
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Development Center Americas, Inc. (TDC Americas)
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTakeda Development Center Americas, Inc. (TDC Americas)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc. (TDC Americas)
    B.5.2Functional name of contact pointTakeda Contact
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1877825-3327
    B.5.6E-mailmedinfoUS@takeda.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTAK-676
    D.3.2Product code TAK-676
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNn/a
    D.3.9.1CAS number n/a
    D.3.9.2Current sponsor codeTAK-676
    D.3.9.3Other descriptive nameTAK-676
    D.3.9.4EV Substance CodeSUB292275
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name KEYTRUDA
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePembrolizumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPembrolizumab
    D.3.9.2Current sponsor codePembrolizumab
    D.3.9.3Other descriptive nameKeytruda
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Cisplatin
    D.2.1.1.2Name of the Marketing Authorisation holder Hikma Farmacêutica (Portugal), S.A
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCisplatin
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.5
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCisplatin
    D.3.9.1CAS number 15663-27-1
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Carboplatin
    D.2.1.1.2Name of the Marketing Authorisation holderHikma Farmacêutica (Portugal), S.A.
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCarboplatin
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Fluorouracil
    D.2.1.1.2Name of the Marketing Authorisation holderHikma Farmacêutica (Portugal), S.A.
    D.2.1.2Country which granted the Marketing AuthorisationPortugal
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFluorouracil
    D.3.9.1CAS number 51-21-8
    D.3.9.4EV Substance CodeSUB07721MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Solid Neoplasms

    E.1.1.1Medical condition in easily understood language
    Advanced and Metastatic solid tumors are masses of abnormal tissue
    growth that originate in organs or soft tissues that have spread to other
    parts of body and cannot be controlled with treatment.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10065252
    E.1.2Term Solid tumor
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary Objectives:
    Dose escalation:
    To determine the safety and tolerability of escalating doses of TAK-676 administered as an SA or in combination with pembrolizumab in patients with advanced or metastatic solid tumors.
    Japan safety lead-in: To determine the safety and tolerability of TAK-676 in combination with pembrolizumab in Japanese patients with advanced or metastatic solid tumors.


    Expansion phase:
    To determine the safety and tolerability of TAK-676 in combination with pembrolizumab with or without chemotherapy in patients with previously untreated metastatic or unresectable, recurrent SCCHN.
    To determine the safety and tolerability of TAK-676 in combination with pembrolizumab in patients with previously treated recurrent locally advanced or metastatic MSI-H/dMMR CRC and MSS/pMMR CRC.


    E.2.2Secondary objectives of the trial
    Dose escalation:
    To determine PAD and RDE of TAK-676 and characterize the single- and multiple-dose PK of TAK-676 administered as an SA and in combination with pembrolizumab. To assess the preliminary antitumor activity of TAK-676 administered as an SA and in combination with pembrolizumab. Japan safety lead-in:To characterize the PK of TAK-676 administered as an SA and in combination with pembrolizumab in Japanese patients and to assess the preliminary antitumor activity of TAK-676-administered in combination with pembrolizumab in Japanese patients.

    Expansion phase:
    To confirm the RDE of TAK-676 and characterize the single- and multiple-dose PK of TAK-676 administered in combination with pembrolizumab with or without chemotherapy.
    To assess the preliminary antitumor activity of TAK-676 in combination with pembrolizumab with or without chemotherapy in previously untreated metastatic or unresectable, recurrent SCCHN patients.

    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
    2. TAK-676 SA (dose escalation Part 1A):
    With histologically confirmed advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to these therapies.
    3. TAK-676 in combination with pembrolizumab (dose escalation Part 1B)
    With histologically confirmed advanced or metastatic solid tumors that have no standard therapeutic options or are intolerant to them, including:
    • Tumors that have relapsed or are refractory to anti-programmed cell death protein 1 (anti-PD-(L) 1)
    • Tumors that are naive to anti-PD-(L) 1 therapy
    4. For expansion phase only:
    • SCCHN (Part 2):
    • Participants with histologically confirmed (cytological diagnosis is acceptable) metastatic or recurrent, unresectable SCCHN that is considered incurable by local therapies. Participants should not have had prior systemic therapy administered in the recurrent or metastatic setting. Systemic therapy which was completed more than 6 months before signing consent if given as part of multimodal treatment of locally advanced disease is allowed.
    • Anatomic subsites to be included are oral cavity, oropharynx, hypopharynx, larynx, nasal cavity, and paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal). The exception to this is nasopharyngeal cancer and salivary gland tumors, which will not be included.
    • Participants with oropharyngeal cancer or tumors arising in the paranasal sinuses (maxillary, ethmoid, sphenoid, and frontal) must agree to provide archival tissue for human papilloma virus (HPV) testing
    • For Part 2A, tumors must have a PD-L1 combined positive score (CPS)
    ≥1. For Part 2B, any CPS is eligible.
    • For Part 2B, participants must be eligible to receive treatment with either cisplatin or carboplatin in combination with 5-fluorouracil (5FU) per the treating physician.
    5. CRC (Part 3):
    • Third-line or later MSI-H/dMMR CRC (Part 3A): Participants with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSI-H/dMMR CRC whose disease has progressed on or following therapy with 1) an anti PD -1 or PD-L1 antibody (ie, pembrolizumab) and 2) at least one line of combination chemotherapy including a fluoropyrimidine and irinotecan OR oxaliplatin with or without an anti- epidermal growth factor receptor (EGFR) or anti-vascular endothelial growth factor (VEGFR) monoclonal antibody (ie, cetuximab or bevacizumab). MSI-H/dMMR CRC participants must have received at least 6 weeks of prior treatment with an anti-PD-(L)1 .
    •Third-line MSS/pMMR CRC (Part 3B): Participants with histologically confirmed (cytological diagnosis is acceptable) recurrent locally advanced or metastatic MSS/pMMR CRC whose disease has progressed on or following therapy with 2 different lines of combination chemotherapy, including therapy with a fluoropyrimidine and irinotecan AND therapy with a fluoropyrimidine and oxaliplatin. Both lines of therapy may be given with or without an anti-EGFR or anti-VEGFR monoclonal antibody (ie, cetuximab or bevacizumab). Participants with MSS/pMMR CRC must have progressed on or after combination chemotherapy regimens
    containing BOTH irinotecan AND oxaliplatin.
    • Participants with MSI-H/dMMR or MSS/pMMR CRC must have MSI/MMR status assessed by certified/accredited lab immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) assay or NGS.
    • Participants with MSI-H/dMMR or MSS/pMMR CRC must have been treated with 2 prior lines of therapy in the recurrent locally advanced or metastatic setting.
    6. Adequate bone marrow, renal, hepatic and cardiac functions.
    7. Left ventricular ejection fraction (LVEF) >50%, as measured by echocardiogram or multiple-gated acquisition (MUGA) scan within 4 weeks before receiving the first dose of study drug.
    8. Clinically significant toxic effects of previous therapy have recovered to Grade 1 (per NCI CTCAE Version 5.0) or baseline
    9. In dose escalation Part 1, once peripheral evidence of TAK-676 pharmacodynamic stimulation of the innate and/or adaptive immune system is observed in the blood and/or clinical response/partial response (CR/PR) is observed in at least 1 participant, subsequent participants must:
    • Have at least 1 lesion amenable for biopsy.
    • Agree to have 2 tumor biopsies: 1 during the screening period and 1 while on TAK-676 treatment.
    10. Must have at least 1 RECIST v.1.1-evaluable (measurable) lesion. For the dose escalation phase (Part 1) only, nonmeasurable only disease is acceptable.
    11. Pharmacokinetic (PK)/pharmacodynamic blood must be drawn on a peripherally-inserted catheter. TAK-676 is preferentially administered through a central line, but peripheral infusion is acceptable. If a peripheral line is used for TAK-676 and/or pembrolizumab infusion, it must be separate than the one used for PK/pharmacodynamic collection.
    12. For Japan safety Lead-in: Japanese who are living in Japan.
    E.4Principal exclusion criteria
    1. Corrected QT interval by Fredericia (QTcF) greater than (>) 450 milliseconds (men) or >475 milliseconds (women) on a 12-lead electrocardiogram (ECG) during the screening period.
    2. Grade greater than or equal to (>=) 2 hypotension (that is, hypotension for which nonurgent intervention is required) at screening or during Cycle 1 Day 1 (C1D1) predose assessment.
    3. Oxygen saturation less than (<) 92 percent (%) on room air at screening or during C1D1 predose assessment.
    4. Treated with other STING agonists/antagonist and toll-like receptors agonists within the past 6 months.
    5. Active vaping within 90 days of C1D1 of study drug(s).
    6. Active smoking.
    7. Current history of pneumonitis, interstitial lung disease, severe chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, other
    restrictive lung diseases, acute pulmonary embolism, or Grade >=2 pleural effusion or ascites not controlled by tap or requiring indwelling catheters.
    8. History of brain and leptomeningeal metastasis unless:
    • Clinically and radiologically stable or improved (that is, >=6 weeks) after prior surgery, whole-brain
    radiation, or stereotactic radiosurgery, AND
    • Off corticosteroids.
    9. Ongoing Grade >= 2 infection or participants with Grade >=2 fever of
    malignant origin.
    10. Chronic, active hepatitis (example: participants with known hepatitis B
    surface antigen seropositive and/or detectable hepatitis C virus [HCV]RNA).
    11. For participants in the dose escalation SA Part 1A only: refusal of
    standard therapeutic options.
    12. For participants receiving pembrolizumab only: contraindication and/or
    intolerance to the administration of pembrolizumab.
    13. For participants receiving chemotherapy in Part 2B: contraindication and/or intolerance to the administration of both platinum agents (cisplatin and carboplatin) and/or 5-FU.
    14. Concurrent chemotherapy (except for Part 2B), immunotherapy (except for pembrolizumab in Part 1B, Part 2, and Part 3), biologic, or hormonal therapy (except for adjuvant endocrine therapy for a history of breast cancer). Concurrent use of hormones for noncancer-related conditions is acceptable (except for corticosteroid hormones), unless allowed per exclusion criterion 16.
    15. Radiation therapy within 14 days (42 days for radiation to the lungs) and/ or systemic treatment with radionuclides within 42 days before C1D1 of study drug(s). Participants with clinically relevant ongoing pulmonary complications from prior radiation therapy are not eligible.
    16. Use of systemic corticosteroids or other immunosuppressive therapy, concurrently or within 7 days of C1D1 of study drug(s), with the following exceptions:
    • Topical, intranasal, inhaled, ocular, intra-articular, and/or other nonsystemic corticosteroids.
    • Physiological doses of replacement steroid therapy (example: for adrenal insufficiency).
    • For participants enrolled in Part 2B, chemotherapy premedication with steroids can be administered according to local standards of care practice.
    17. Use of medications that are known clinical organic anion-transporting polypeptide B1 (OATP1B1) and/or OATP1B3 inhibitors, concurrently or within 14 days of C1D1 of study drug(s).
    18. Receipt of live attenuated vaccine (eg, tuberculosis Bacillus Calmette-Guerin vaccine, oral polio vaccine, measles, rotavirus, yellow fever) within 28 days of C1D1 of study drug(s).
    19. Recipients of allogeneic or autologous stem cell transplantation or organ transplantation.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints are:
    1. Frequency and severity of TEAEs.
    2. Number of patients with DLTs.
    3. Number and percentage of patients with 1 or more treatment-emergent SAE.
    4 Number and percentage of patients with 1 or more TEAE leading to dose modifications and treatment discontinuation.
    Safety endpoints will be evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analyses for the primary endpoint will be conducted after all patients enrolled in the study have had the opportunity to complete 24 months of treatment with TAK-676.

    Up to approximately 54 months.

    E.5.2Secondary end point(s)
    Dose escalation, Japan safety lead-in and expansion phases:
    1. PK parameters after administration of TAK-676:
    – Cmax.
    – Time of first occurrence of Cmax (tmax).
    – Area under the concentration-time curve from time 0 to time t (AUCt).
    – Area under the concentration-time curve from time 0 to infinity (AUC∞).
    – Terminal disposition phase half-life (t1/2z).
    – Total clearance after intravenous administration (CL).
    – Vss.
    – Renal clearance (CLR) and percentage of dose excreted in urine during 24 hours after dosing.
    – Renal clearance as a percentage of total clearance (CLR/CL [%]).
    - Percentage of dose excreted in feces during 24 hours after dosing.
    2. Response assessments per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 (Eisenhauer et al. 2009) by investigator.
    – ORR (confirmed complete response [cCR] + confirmed partial response [cPR]).
    – Disease control rate (DCR) (cCR + cPR + stable disease [SD] >6 weeks).
    – Duration of response (DOR).
    – Time to response (TTR).
    3. Upregulation of TAK-676–induced STING agonism gene expression signature in peripheral blood.
    4. Evaluation of T-cell infiltration upon TAK-676 treatment (parts 1A, 1B, 2 and 3).
    5. Genomic, transcriptomic and protein expression analyses of baseline and on-treatment tumor tissue (parts 1A, 1B, 2 and 3).

    Expansion phase only:
    1. Response assessments per RECIST v.1.1 by investigator
    – Progression-free survival (PFS)
    – OS
    – OS rate at 12 months
    – OS rate at 6 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Dose Escalation and Expansion Phases: Cycle 1 Days 1, 8 and 15: pre-infusion and at multiplepoints (up to 24 hours) post-infusion and at Day 1 for further cycles up to 54 months (Cycle length=21 days)]


    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial6
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Switzerland
    Puerto Rico
    Canada
    China
    Israel
    Japan
    United Kingdom
    United States
    Austria
    Belgium
    France
    Poland
    E.8.7Trial has a data monitoring committee No
    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
    The study will be completed at the time of primary analyses
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 128
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 230
    F.4.2.2In the whole clinical trial 368
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Eligible patients meeting the conditions set out in the protocol will have an option to continue to receive TAK 676 (TAK-676 alone or TAK-676 in combination with pembrolizumab) via Post Study Access as an extension phase of this study, in a separate open-label rollover study, or through a single-patient Investigational New Drug application or equivalent.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2023-03-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-11-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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