The primary objective of this study is to assess the safety and tolerability and to determine the recommended Phase 2 dose (RP2D) of E7386 in combination with other anticancer drug(s), and to determine the optimal dose of E7386 in combination with lenvatinib in endometrial carcinoma (EC) (for EC Dose Optimization Part only).

The Dose Escalation and Dose Expansion parts of the study have completed enrollment. The Dose Optimization part of the study is enrolling participants with endometrial carcinoma (EC) only.

Inclusion Criteria:

1. HCC part only:

   Participants with confirmed diagnosis of unresectable HCC with any of the following criteria:

   1. Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors
   2. 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

   ST part only (except for HCC):

   Participants with histologically or cytologically confirmed diagnosis of solid tumor for which no alternative standard therapy or no effective therapy exists

2. Life expectancy of >=12 weeks

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1

4. All AEs due to previous anti-cancer therapy have either returned to Grade 0 to 1 except for alopecia or up to Grade 2 peripheral neuropathy (renal/bone marrow/liver function should meet the inclusion criteria)

5. Adequate washout period before study drug administration:

   1. Chemotherapy and radiotherapy: 3 weeks or 5 times the half-life, whichever is shorter
   2. Any antitumor therapy with antibody: 4 weeks or more
   3. Any investigational drug or device: 4 weeks or more
   4. Blood/platelet transfusion or granulocyte colony-stimulating factor (G-CSF): 2 weeks or more Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not had radiation pneumonitis

6. Adequate controlled blood pressure (BP), renal function, bone marrow function, liver function, and serum mineral level

7. At least one measurable lesion based on mRECIST (for HCC Subparts in Dose Escalation Part) or on RECIST 1.1 (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 centimeter (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 chemoembolisation (TACE)/ transarterial embolization (TAE) must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion

8. For HCC participants only: Child-Pugh score A. Note: If Child-Pugh score 7 or more was observed during Screening or Baseline, the participant is ineligible and re-assessment of the Child-Pugh score is not permitted

9. For HCC participants only: Participants 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

10. For HCC Subpart in Expansion Part only: prior systemic therapy for locally advanced or metastatic disease is as defined below

    a. Participants who have received only one prior line of immuno oncology (IO) based regimen and have progressed on or after prior treatment with IO based regimen, or IO ineligible participants who have received no prior systemic therapy. Participants who previously received lenvatinib treatment are ineligible

11. For CRC Subpart in Expansion Part only: participants 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 participant is determined to be intolerant to prior standard treatment, the participant must have received at least of 2 cycles of that therapy Note: Participants who have received oral tyrosine kinase inhibitor (example, regorafenib) are ineligible

    1. Fluoropyrimidine, irinotecan and oxaliplatin with or without an anti-Vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) (example, bevacizumab) Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior treatment Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and irinotecan as part of the same and only chemotherapy regimen, example, FOLFOXIRI or FOLFIRINOX, may be eligible after discussion with the Sponsor
    2. Chemotherapy with anti- epidermal growth factor receptor (EGFR) mAb (cetuximab or panitumumab) for participants with rat sarcoma virus (RAS) (Kirsten rat sarcoma viral oncogene homolog [KRAS)/ NRAS]) wild type (WT) CRC Note: RAS (KRAS/NRAS) WT participants with right or left CRC lesions who may have not been treated with anti-EGFR mAb based on local guidelines are eligible
    3. BRAF inhibitor (in combination with cetuximab ± binimetinib) for BRAF V600E mutated tumors
    4. Immune checkpoint inhibitor for participants with microsatellite instability-high (MSI-H) CRC

12. For EC Subpart in Expansion Part only: Participants 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 (participants 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: Participants 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. Participants 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. Note: Prior hormonal therapy and radiation are allowed and do not count as prior lines of therapy.

Exclusion Criteria:

1. Any of cardiac conditions as follows:

   • Heart failure New York Heart Association (NYHA) Class II or above
   • Prolongation of QT interval with Fridericias correction (QTcF) to greater than (>) 480 millisecond (msec)
   • Left ventricular ejection fraction (LVEF) less than (<) 50 percent (%)

2. Major surgery within 21 days or minor surgery (that is, simple excision) within 7 days prior to starting study drug. Participant must have recovered from the surgery related toxicities to less than Grade 2 Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility

3. Known to be human immunodeficiency virus (HIV) positive Note: the sponsor has evaluated whether to include participant 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 participants 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

4. Participants with proteinuria on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 gram per 24 hour will be ineligible

5. Active infection requiring systemic treatment (Except for Hepatitis B and/or C [HBV/HCV] infection in HCC participants)

   In case of HBsAg (+) participants in HCC participants:

   • Antiviral therapy for HBV is not ongoing
   • HBV viral load is 2000 international unit per milliliter (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 deoxyribonucleic acid [DNA]) and HCV infection (anti-HCV Ab (+) and detectable HCV ribonucleic acid [RNA]) at study entry

6. Diagnosed with meningeal carcinomatosis

7. Participants with central nervous system metastases are only eligible if they have been previously treated and are radiologically stable, (that is, 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

8. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen

9. Any of bone disease/conditions as follows:

   • T-score of < minus (-) 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. Participants with T-score <-2.5 to -3.0 can only be included if treatment with a bisphosphonate (example, 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. Participants may be included if treatment with bisphosphonate or denosumab has been started at least 14 days prior to the first dose of study drug. Participants 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

10. History of malignancy (except for original disease, or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, carcinoma in-situ [example, bladder or cervix]) within the past 24 months prior to the first dose of study drug

11. For HCC Subpart in Dose Escalation Part only: Participants 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 participants 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: Participants who previously received lenvatinib treatment are ineligible.

    EC Subpart in Expansion Part only: Participants 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: Participants who previously received lenvatinib treatment are ineligible.

12. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic International Normalized Ratio (INR) monitoring for HCC participants only (example, warfarin or similar agents). Treatment with low molecular weight heparin and factor X inhibitors is permitted. Treatment with antiplatelet agents is prohibited for HCC participants in Dose Escalation Part only

13. 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

14. For HCC participants only: History of hepatic encephalopathy within 6 months prior to starting study drug

15. For EC Subpart in Expansion and Dose Optimization Parts only: carcinosarcoma (malignant mixed Mullerian tumor), endometrial leiomyosarcoma, and endometrial stromal sarcomas

16. Has preexisting >=Grade 3 gastrointestinal or non-gastrointestinal fistula

17. Evidence of current Coronavirus disease 2019 (COVID-19) infection or ongoing unrecovered active sequelae of COVID-19 infection

18. Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners meet the exclusion criteria above (that is, the female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the study period and after study drug discontinuation). No sperm donation is allowed during the study period and after study drug discontinuation

19. Has a known psychiatric or substance abuse disorder that would interfere with the participant ability to cooperate with the requirements of the study

20. Evidence of clinically significant disease (example, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator could affect the participant safety or interfere with the study assessments

21. Scheduled for major surgery during the study

Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.