(6S,9AS)-8-((6-(3-(4-ETHYL-1-PIPERAZINYL)-1-AZETIDINYL)-2-PYRIDINYL)METHYL)-6-((2-FLUORO-4-HYDROXYPHENYL)METHYL)HEXAHYDRO-4,7-DIOXO-N-(PHENYLMETHYL)-2-(2-PROPEN-1-YL)-2H-PYRAZINO(2,1-C)(1,2,4)TRIAZINE-1(6H)-CARBOXAMIDE for Hepatocellular carcinoma|Colorectal cancer|Endometrial cancer|Solid tumor

Inclusion criteria

• {"criterion_text":"-For HCC subjects only Subjects with confirmed diagnosis of unresectable HCC with any of the following criteria: a. Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors b. Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or chronic hepatitis B or C infection (see Appendix 11) For other ST subjects (ie, except for HCC subjects) Subjects with histologically or cytologically confirmed diagnosis of solid tumor for which no alternative standard therapy or no effective therapy exists"}
• {"criterion_text":"-Adequate liver function"}
• {"criterion_text":"-Adequate serum mineral level"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-At least one measurable lesion based on modified RECIST (mRECIST; for HCC Subparts in Dose Escalation Part [see Appendix 5]) or on RECIST 1.1 (see Appendix 4) for Other ST Subparts in Dose Escalation Part and all subparts in Expansion and Dose Optimization Parts) meeting following criteria: – At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 using computerized tomography (CT)/magnetic resonance imaging (MRI) – Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation, or transarterial chemoembolization (TACE)/transarterial embolization (TAE) must show evidence of disease progression based on RECIST 1.1 to be deemed a target lesion"}
• {"criterion_text":"-For HCC subjects only: Child-Pugh score A. Note: If Child-Pugh score 7 or more was observed during Screening or Baseline, the subject is ineligible and re-assessment of the Child-Pugh score is not permitted."}
• {"criterion_text":"-For HCC subjects only: Subjects categorized to stage B (not amenable to locoregional therapy or refractory to locoregional therapy, and not amenable to a curative treatment), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system."}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-For HCC Subpart in Expansion Part only: prior systemic therapy for locally advanced or metastatic disease is as defined below a. Subjects who have received only 1 prior line of IO-based regimen and have progressed on or after prior treatment with IO-based regimen, or IO ineligible subjects who have received no prior systemic therapy. Subjects who previously received lenvatinib treatment are ineligible"}
• {"criterion_text":"-For CRC Subpart in Expansion Part only: subjects must have received at least 2 prior regimens (not exceeding 4 prior regimens) or could not tolerate standard treatment and must have received the following prior therapies in the metastatic setting if approved and locally available (progressed on at least 1 prior regimen in the metastatic setting or could not tolerate standard treatment): Note: Adjuvant chemotherapy counts as prior systemic treatment if there is documented disease progression within 6 months of treatment completion. Note: If a subject is determined to be intolerant to prior standard treatment, the subject must have received at least of 2 cycles of that therapy. Note: Subjects who have received oral tyrosine kinase inhibitor (eg, regorafenib) are ineligible. a. Fluoropyrimidine, irinotecan and oxaliplatin with or without an anti-VEGF monoclonal antibody (mAb) (eg, bevacizumab) Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior treatment. Note: Subjects who have previously received fluoropyrimidine, oxaliplatin, and irinotecan as part of the same and only chemotherapy regimen, eg, FOLFOXIRI or FOLFIRINOX, may be eligible after discussion with the Sponsor. b. Chemotherapy with anti-EGFR mAb (cetuximab or panitumumab) for subjects with RAS (KRAS/NRAS) wild type (WT) CRC Note: RAS (KRAS/NRAS) WT subjects with right or left CRC lesions who may have not been treated with anti-EGFR mAb based on local guidelines are eligible. c. BRAF inhibitor (in combination with cetuximab ± binimetinib) for BRAF V600E mutated tumors d. Immune checkpoint inhibitor for subjects with microsatellite instability-high (MSI-H) CRC"}
• {"criterion_text":"-For EC Subpart in Expansion Part only: Subjects must have EC that has progressed after prior platinum-based chemotherapy and an anti-programmed cell death (ligand) 1 (PD-(L)1)-directed therapy for EC (subjects ineligible for IO therapy who have progressed after prior platinum-based chemotherapy are eligible). Up to 3 prior systemic therapies, of which up to 2 for metastatic or locally advanced disease, are permitted. Note: There is no restriction regarding prior hormonal therapies. For Dose Optimization Part only: Subjects must have EC that has progressed after prior platinum-based chemotherapy and an anti-PD-(L)1-directed therapy for EC. Up to 3 lines of prior therapy, regardless of setting, are allowed. Note: Prior hormonal therapy and radiation are allowed and do not count as prior lines of therapy. Subjects must be eligible for treatment with either single-agent paclitaxel or single-agent doxorubicin as determined by the investigator, with consideration of previous therapies received for EC. (Revised per Amendment 14)"}
• {"criterion_text":"-Life expectancy of ≥12 weeks"}
• {"criterion_text":"-Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (see Appendix 2)."}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-All AEs due to previous anti-cancer therapy have either returned to Grade 0–1 except for alopecia or up to Grade 2 peripheral neuropathy (renal/bone marrow/liver function should meet the inclusion criteria)"}
• {"criterion_text":"-Adequate washout period before study drug administration: a. Chemotherapy and radiotherapy: 3 weeks or 5 times the half-life, whichever is shorter b. Any antitumor therapy with antibody: 4 weeks or more c. Any investigational drug or device: 4 weeks or more d. Blood/platelet transfusion or granulocyte colony-stimulating factor (G-CSF): 2 weeks or more Note: Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not had radiation pneumonitis"}
• {"criterion_text":"-Adequately controlled blood pressure (BP)"}
• {"criterion_text":"-Adequate renal function"}
• {"criterion_text":"-Adequate bone marrow function"}

Exclusion criteria

• {"criterion_text":"-Any of cardiac conditions as follows: - Heart failure New York Heart Association (NYHA) Class II or above - Prolongation of corrected QT (QTcF) interval to >480 ms - Left ventricular ejection fraction (LVEF) <50%"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-Any of bone disease/conditions as follows: – T-score of <–3.0 at the left or right total hip, left or right femoral neck or lumbar spine (L1-L4) as determined by dual energy x-ray absorptiometry (DXA) scan. Subjects with T-score <-2.5 to -3.0 can only be included if treatment with a bisphosphonate (eg, zoledronic acid) or denosumab has been started at least 14 days and no more than 6 months prior to the first dose of study drug – Metabolic bone disease, such as hyperparathyroidism, Paget’s disease, or osteomalacia – Symptomatic hypercalcemia requiring bisphosphonate therapy – History of any fracture within 6 months prior to starting study drug – Bone metastasis requiring orthopedic intervention – Bone metastasis not being treated by bisphosphonate or denosumab. Subject may be included if treatment with bisphosphonate or denosumab have been started at least 14 days prior to the first dose of study drug. Subjects with previous solitary bone lesions controlled with radiotherapy are eligible – History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less) – Moderate (25% to 40% decrease in the height of any vertebrae) or severe (>40% decrease in the height of any vertebrae) morphometric vertebral fracture at Baseline"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-History of malignancy (except for original disease, or definitively treated melanoma in situ, basal or squamous cell carcinoma of the skin, carcinoma in situ [eg, bladder or cervix]) within the past 24 months prior to the first dose of study drug"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-For HCC Subpart in Dose Escalation Part only: Subjects who experienced discontinuation of lenvatinib, 2 or more dose reductions of lenvatinib required from initial dose level of this study due to its toxicity, or subjects who experienced single dose reduction or consecutive ≥8 days dose interruption of lenvatinib within 60 days from the first dose, due to its toxicity. HCC Subpart in Expansion Part only: Subjects who previously received lenvatinib treatment are ineligible. EC Subpart in Expansion Part only: Subjects previously treated with lenvatinib who experienced discontinuation of lenvatinib due to toxicity, or dose reduction to less than 10 mg of lenvatinib due to toxicity within 60 days from the first dose . EC Dose Optimization Part only: Subjects who previously received lenvatinib treatment are ineligible."}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-For HCC subjects only: History of hepatic encephalopathy within 6 months prior to starting study drug"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-For EC Subpart in Expansion and Dose Optimization Parts only: carcinosarcoma (malignant mixed Müllerian tumor), endometrial leiomyosarcoma, and endometrial stromal sarcomas."}
• {"criterion_text":"-Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-For HCC subjects only: Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring for HCC subjects only (eg, warfarin or similar agents). Treatment with low molecular weight heparin and factor X inhibitors is permitted. Treatment with antiplatelet agents is prohibited for HCC subjects in Dose Escalation Part only"}
• {"criterion_text":"-Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug."}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-see protocol"}
• {"criterion_text":"-Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners meet the exclusion criteria above (ie, the female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the study period and for 90 days (30 days for subjects whose partner is randomized in the lenvatinib monotherapy arm) after study drug discontinuation). No sperm donation is allowed during the study period and for 90 days (30 days for subjects whose partner is randomized in the lenvatinib monotherapy arm) after study drug discontinuation."}
• {"criterion_text":"-Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the study"}
• {"criterion_text":"-Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments"}
• {"criterion_text":"-Scheduled for major surgery during the study"}
• {"criterion_text":"-Known to be human immunodeficiency virus (HIV) positive. Note: The sponsor has evaluated whether to include subject with HIV. Given that this is the first combination study of E7386 with lenvatinib and that the main mechanism of action of E7386 is immunomodulation of the tumor microenvironment along with the fact that several anti-retroviral therapies have drug-drug interaction with cytochrome P450 3A (CYP3A) substrates, the sponsor has decided not to include these subjects at the current time. However, further considerations will be made moving forward based on new emerging data. Note: HIV testing is required at screening only when mandated by local health authority."}
• {"criterion_text":"-Subjects with proteinuria on urine dipstick testing (urinalysis) will undergo 24-h urine collection for quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 hour will be ineligible."}
• {"criterion_text":"-Active infection requiring systemic treatment (except for Hepatitis B and/or C [HBV/HCV] infection in HCC subjects) In case of HBsAg (+) subjects in HCC subjects: - Antiviral therapy for HBV is not ongoing - HBV viral load is 2000 IU/mL or more at the Screening Period although antiviral therapy for HBV is ongoing - Has dual active HBV infection (HBsAg (+) and/or detectable HBV DNA) and HCV infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry"}
• {"criterion_text":"-Diagnosed with meningeal carcinomatosis."}
• {"criterion_text":"-Subjects with central nervous system metastases are only eligible if they have been previously treated and are radiologically stable (ie, without evidence of progression for at least 4 weeks prior to first dose of study treatment by repeat imaging), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment."}
• {"criterion_text":"-Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen."}

Primary endpoints

• {"endpoint_text":"-Safety related endpoints including DLT and/or defining the RP2D ORR defined as the proportion of subjects who have BOR of confirmed CR or PR per RECIST 1.1 by investigator assessment (Dose Optimization Parts only)","definition_or_measurement_approach":"Safety endpoints: DLTs and determination of RP2D (dose-limiting toxicities and recommended Phase 2 dose). ORR: defined as the proportion of subjects who have BOR of confirmed CR or PR per RECIST 1.1 by investigator assessment (Dose Optimization Parts only)."}

Secondary endpoints

• {"endpoint_text":"-PK profile of study drug(s)","definition_or_measurement_approach":"Pharmacokinetic profiling of study drug(s) (measurement of PK parameters)."}
• {"endpoint_text":"-BOR","definition_or_measurement_approach":"Best overall response as assessed by investigator per RECIST 1.1 (BOR)."}
• {"endpoint_text":"-ORR (Dose Escalation and Dose Expansion Parts)","definition_or_measurement_approach":"Objective response rate per RECIST 1.1 in Dose Escalation and Dose Expansion Parts."}
• {"endpoint_text":"-DCR: defined as the proportion of subjects who have a BOR of CR or PR, or SD","definition_or_measurement_approach":"DCR is the proportion of subjects with BOR of CR or PR, or stable disease."}
• {"endpoint_text":"-CBR: defined as the proportion of subjects who have a BOR of CR or PR, or durable SD","definition_or_measurement_approach":"CBR is the proportion of subjects with BOR of CR or PR, or durable stable disease."}
• {"endpoint_text":"-PFS: defined as the time from the first dose of study drug to the first documentation of PD or death due to any cause (whichever occurs first)","definition_or_measurement_approach":"Progression-free survival measured from first dose to first documentation of progression or death (any cause)."}
• {"endpoint_text":"-OS (all subparts in Expansion and Dose Optimization Part and HCC Subparts in Dose Escalation Part): defined as the time from the first dose of study drug to death due to any cause","definition_or_measurement_approach":"Overall survival measured from first dose to death from any cause."}
• {"endpoint_text":"-DOR: among subjects with PR or CR, defined as the time from the first documentation of PR or CR to the first documentation of PD or death due to any cause (whichever occurs first)","definition_or_measurement_approach":"Duration of response measured from first documentation of PR/CR to progression or death."}

France

Earliest CTIS Part Ii Submission Date

13-12-2023

Latest Decision Or Authorization Date

05-11-2025

Processing Time Days

693

Number Of Sites

21

Number Of Participants

38

Denmark

Earliest CTIS Part Ii Submission Date

28-03-2025

Latest Decision Or Authorization Date

06-11-2025

Processing Time Days

223

Number Of Sites

2

Number Of Participants

15

Spain

Earliest CTIS Part Ii Submission Date

03-03-2025

Latest Decision Or Authorization Date

30-04-2026

Processing Time Days

423

Number Of Sites

3

Number Of Participants

15

Italy

Earliest CTIS Part Ii Submission Date

10-01-2025

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

466

Number Of Sites

3

Number Of Participants

15

Primary sponsor

Full Name

Eisai Limited

Organisation Type

Pharmaceutical company

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Bioclinica Inc.

Responsibilities

Centralized medical imaging assessment services, Medical image analysis, primary surrogate endpoint analysis

Name

PPD Global Central Labs

Responsibilities

Central lab services (Beta-CTX, P1NP and Autotaxin, knitting services)

Name

Suvoda LLC

Responsibilities

IVRS – treatment randomisation

Name

Fortrea Inc.

Responsibilities

Clinical services (roles with codes 1,12,9 listed)

Name

QPS LLC

Responsibilities

Laboratory/clinical support (duty code 4 listed)

Name

Rules Based Medicine Inc.

Responsibilities

Laboratory services (duty code 4 listed)

Name

CellCarta

Responsibilities

Histopathology / PD services

Third parties

• {"country":"United States","full_name":"Bioclinica Inc.","duties_or_roles":"Centralized medical imaging assessment services, Medical image analysis, primary surrogate endpoint analysis","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Belgium","full_name":"PPD Global Central Labs","duties_or_roles":"Beta-CTX, P1NP and Autotaxin, Knitting services; additional duty code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"Japan","full_name":"Sekisui Medical Co. Ltd.","duties_or_roles":"Pharmacodynamic testing","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"CellCarta","duties_or_roles":"histopathology","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Personal Genome Diagnostics Inc.","duties_or_roles":"Analytical Chemistry","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"IVRS30 – treatment randomisation","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"QPS LLC","duties_or_roles":"duty code: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"roles with codes 1, 12, 9 (responsibilities not further detailed in provided source)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Rules Based Medicine Inc.","duties_or_roles":"duty code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Oracle America Inc.","duties_or_roles":"duty code: 7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Personalis Inc.","duties_or_roles":"duty code: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Scisafe Inc.","duties_or_roles":"Longterm sample storage","organisation_type":"Pharmaceutical company"}