A Study of E7386 in Combination With Pembrolizumab in Previously Treated Participants With Selected Solid Tumors

An Open-Label, Multicenter, Phase 1b/2 Study of E7386 in Combination With Pembrolizumab in Previously Treated Subjects With Selected Solid Tumors

The Phase 1b part of this study is conducted to assess the safety and tolerability of E7386 in combination with pembrolizumab in participants with previously treated selected solid tumors, and to determine the recommended Phase 2 dose (RP2D) of E7386 in combination with pembrolizumab.

The Phase 2 part of this study is conducted to assess the objective response rate (ORR) of E7386 in combination with pembrolizumab (melanoma, colorectal cancer [CRC], hepatocellular carcinoma [HCC]) or of E7386 in combination with pembrolizumab plus lenvatinib (HCC) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Study Overview

• Status: Completed
• Conditions: Melanoma; Carcinoma, Hepatocellular; Colorectal Neoplasms
• Intervention / Treatment: Drug: Lenvatinib; Drug: Pembrolizumab; Drug: E7386

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chiba, Japan
    • Chiba University Hospital
  • Chūōku, Japan
    • National Cancer Center Hospital
  • Fukuoka, Japan
    • Kurume University Hospital
  • Kashiwa, Japan
    • National Cancer Center Hospital East
  • Osaka, Japan
    • Osaka Metropolitan University Hospital
  • Sapporo, Japan
    • Sapporo-Kosei General Hospital
  • Shizouka, Japan
    • Shizuoka Cancer Center Hospital
  • Tokyo, Japan
    • Toranomon Hospital
  • Ōsaka-sayama, Japan
    • Kindai University Hospital
• Spain
  • Badajoz, Spain
    • Hospital Universitario de Badajoz
  • Barcelona, Spain
    • Hospital Clínic de Barcelona
  • Barcelona, Spain
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain
    • Hospital Universitario de La Paz
  • Valencia, Spain
    • Consorcio Hospital General Universitario de Valencia
  • Avenida Carolos Haya S/n
    • Málaga, Avenida Carolos Haya S/n, Spain
      • Hospital Regional Universitario de Malaga
  • Calle Profesor Martín Lagos
    • Madrid, Calle Profesor Martín Lagos, Spain
      • Hospital Clinico San Carlos
  • Navarre
    • Pamplona, Navarre, Spain
      • Clinica Universidad de Navarra
• United Kingdom
  • Glasgow, United Kingdom
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom
    • Royal Free Hospital NHS Foundation Trust
  • London, United Kingdom
    • Imperial College London - Hammersmith Hospital
  • Manchester, United Kingdom
    • The Christie NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
    • Orange, California, United States, 92868
      • University of California, Irvine Health
  • Florida
    • Fort Myers, Florida, United States, 33916
      • Florida Cancer Specialists
    • West Palm Beach, Florida, United States, 33401
      • SCRI Florida Cancer Specialists East
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmanos Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute of NJ
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • Oregon
    • Portland, Oregon, United States, 97213
      • Providence Medical Center Institute Franz Clinic
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology PPLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. Male or female, age >=18 years at the time of informed consent
2. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) selected solid tumor for which prior standard systemic therapy has failed. Selected tumor types: melanoma (excluding uveal melanoma), CRC, HCC
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
4. Must have disease progression on current or since the last anticancer treatment
5. At least one measurable lesion by computer tomography (CT) or magnetic imaging resonance (MRI) based on RECIST 1.1

6. Adequate organ function and serum mineral level per blood work as confirmed by the investigator

   1. Calcium (albumin-corrected) within normal range
   2. Potassium within normal reference range
   3. Magnesium less than or equal to (>=) 1.2 milligram per deciliter (mg/dL) or 0.5 millimoles per litre (mmol/L).

7. Melanoma cohort (Phase 2), participants must have:

   • Unresectable Stage III or Stage IV melanoma, not amenable to local therapy.
   • Received only 1 or, if BRAF mut +ve, 2 lines of therapies locally advanced or metastatic setting prior to study enrolment. Note: Adjuvant anti-PD-1/PD-L1 mAb/ BRAF inhibitor treatment will be counted as prior line of treatment if relapse occurred during active treatment or within 12 weeks of treatment discontinuation.
8. CRC cohort (Phase 2), participants must have received at least 2 prior systemic therapies in adjuvant and/or metastatic setting (not exceeding 4 lines of therapies in the metastatic setting, progressed on at least 1 prior regimen in the metastatic setting or could not tolerate standard treatment)

9. Participants with HCC cohort (Phase 2) must have:

   • 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 and Child-Pugh class A only.
   • Have received only 1 prior line of systemic therapy in the locally advanced or metastatic setting, and must have progressed on treatment with an anti-PD-1/L1 monoclonal antibodies (mAb) administered either as monotherapy, or in combination
10. Must agree to take Vitamin D continuous supplementation as per local institutional guideline/ investigator's clinical discretion if their 25-hydroxyvitamin D levels are less than 10 nanogram per milliliter (ng/mL).
11. Triplet treatment cohorts only: Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as BP <=150/90 millimeter of mercury (mmHg) at Screening/Baseline and no change in antihypertensive medications within 1 week before starting treatment in this study.

Exclusion Criteria

1. Have present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 2 weeks prior to study drug administration. The participant can receive diuretic drugs as needed per the treating physician. Consult with the sponsor if the participant has more than trivial/trace fluid accumulation.
2. Prior treatment with E7386 or prior therapy with anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (example, CTLA-4, OX 40, CD137) that was discontinued due to a Grade 3 or higher immune-related (ir)AE
3. Participants with central nervous system (CNS) metastases are not eligible unless they are previously treated are radiologically stable, that is, without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), and are clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment
4. Any active infection requiring systemic treatment
5. Have severe hypersensitivity to study drugs and/or any of its excipients
6. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
7. Have an active autoimmune disease that has required systemic treatment in the past 2 years
8. Have a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis

9. Any bone disease/conditions as follows:

   • Osteoporosis with T-score <-2.5 by DXA scan
   • 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
   • History of symptomatic vertebral fragility fracture or any fragility fracture
   • Moderate or severe morphometric vertebral fracture at baseline.
   • Any condition requiring orthopedic intervention.
   • Bone metastases not being treated with a bisphosphonate or denosumab
10. Active viral hepatitis (B or C) as demonstrated by positive serology for participants with melanoma and CRC. Dual active hepatitis B virus (HBV) infection and hepatitis C virus (HCV) infection at study entry for participants with HCC
11. Known to be human immunodeficiency virus (HIV) positive
12. Received blood/platelet transfusion or G-CSF within 4 weeks before study entry
13. For Melanoma only, participants with ocular melanoma are excluded. Note: Participants with mucosal melanoma will not exceed 20% of the enrolled participants in melanoma cohort in Phase 2.

14. For CRC only, participants are excluded if:

    - have a tumor that is microsatellite instability high (MSI H)/ DNA mismatch repair-deficient (dMMR) positive

15. For HCC only, participants are excluded if:

    • Clear invasion to bile duct
    • Have had esophageal or gastric variceal bleeding within the last 6 months. Participants in triplet treatment cohorts will be screened for esophageal or gastric varices unless such screening has been performed in the past 3 months before first dose of treatment. If varices are present, they should be treated according to institutional standards before starting study intervention; esophageal or gastric varices that require interventional treatment within 28 days prior to first dose of study drug are excluded
    • History of hepatic encephalopathy within 6 months prior to starting study drug unresponsive to therapy within 3 days. Participants on rifaximin or lactulose during screening to control their hepatic encephalopathy are not allowed

16. For participants in the triplet treatment cohorts only:

    • Proteinuria greater than (>) 1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 gram per 24 hours (g/24 hours) will be ineligible
    • Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR monitoring (example, warfarin or similar agents). Treatment with low molecular weight heparin and factor X inhibitors is permitted
    • Clinically significant hemoptysis from any source or tumor bleeding within 3 weeks prior to the first dose of study drug
    • Pre-existing >=Grade 3 gastrointestinal or non-gastrointestinal fistula

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1b and 2: E7386 + Pembrolizumab; Participants will receive E7386 twice daily (BID) along with pembrolizumab 200 mg intravenous (IV) infusion once every 3 weeks (Q3W) in 21-day treatment cycle until RP2D is determined in Phase 1b. The recommended dose for Phase 2 part of the study will be based on Phase 1b result. Participants will continue to receive study treatment in Phase 2 part until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the study.	Drug: Pembrolizumab; Pembrolizumab IV infusion.; Other Names: KEYTRUDA®; Drug: E7386; E7386 tablet.
Experimental: Phase 2: E7386 + Pembrolizumab + Lenvatinib; Participants will be randomized to receive E7386 Dose 1 (Cohort 1) or Dose 2 (Cohort 2) tablet, BID, orally in combination with pembrolizumab 200 mg Q3W IV infusion plus lenvatinib 8 mg capsule, orally, once daily (QD) continuously in 21-days treatment cycles until disease progression, development of unacceptable toxicity, withdrawal of consent, or termination of the study. The dose of treatment depends on tolerability data of both Cohorts.	Drug: Lenvatinib; Lenvatinib capsule.; Other Names: E7080; Drug: Pembrolizumab; Pembrolizumab IV infusion.; Other Names: KEYTRUDA®; Drug: E7386; E7386 tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs)	DLT was graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 based on investigator assessment. DLT was defined as any of the hematological or non-hematological toxicities events that: - Failure to administer greater than or equal to (>=) 75 percentage (%) of the planned dosage of E7386 as a result of treatment-related toxicity; - Any treatment-related toxicity that causes the participant to discontinue treatment, even if the toxicity does not meet DLT criteria; - Prolonged delay (greater than [>] 2 weeks) in initiating Cycle 2 due to treatment-related toxicities; - Any Grade 5 event or any death not clearly due to the underlying disease or extraneous causes.	Cycle 1 (Cycle length=21 days)
Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs)	A TEAE was defined as an adverse event (AE) that emerged during treatment, having been absent at pretreatment (Baseline) or reemerged during treatment, or up to 30 days following last dose of study drug, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment or up to 30 days following last dose of study drug, relative to the pretreatment state, when the AE was continuous.	Up to 30 days after last dose of study drug (up to 12.73 months)
Phase 1b Part: Number of Participants With Serious TEAEs	An SAE was any untoward medical occurrence that at any dose: Resulted in death; Was life-threatening (i.e., the participant was at immediate risk of death from the AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death); Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent or significant disability/incapacity; Was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug). An SAE was also counted as a TEAE if it emerged up to 90 days after the participant's last dose of study drug, or up to 30 days following cessation of study drug if the participant initiated new anticancer therapy, whichever was earlier.	Up to 90 days after last dose of study drug (up to 14.73 months)
Phase 2 Part: Objective Response Rate (ORR)	ORR was defined as the percentage of participants achieving a best overall response of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to less than [<] 10 millimeters [mm]). PR: At least a 30 percent (%) decrease in sum of the diameters (SOD) of target lesions, taking as reference the screening SOD. Additionally, progression of target lesions must not be present.	Up to 20.40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b Part: Percentage of Participants With Best Overall Response (BOR)	BOR was defined as CR, PR, stable disease (SD), progressive disease (PD), and not applicable (NA)/not evaluable (NE) as per RECIST version 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to <10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of >=5 mm. NA: No target lesions were identified at Screening.	Up to 11.73 months
Phase 1b and Phase 2 Parts: Duration of Response (DOR)	DOR was defined as the time from the first documentation of CR or PR to the first documentation of PD or death due to any cause (whichever occurs first), in participants with confirmed CR or PR per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to <10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of >=5 mm.	Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 1b and Phase 2 Parts: Disease Control Rate (DCR)	DCR was defined as the percentage of participants who had a best overall response of confirmed CR or PR, or SD (after >=5 weeks from the first dose) as per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to <10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD. PD: At least a 20% increase in the SOD of target lesions, taking as reference nadir SOD (or the screening, if screening is nadir value). In addition to relative increase of 20% in SOD, the SOD must also demonstrate an absolute increase of >=5 mm.	Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 1b and Phase 2 Parts: Clinical Benefit Rate (CBR)	CBR was defined as the percentage of participants who had a best overall response of confirmed CR or PR, or durable SD (duration of SD >=23 weeks) per RECIST 1.1. CR: Disappearance of all non-nodal target lesions and any pathological lymph nodes must have become normal (i.e., decrease in short axis to <10 mm). PR: At least a 30% decrease in SOD of target lesions, taking as reference screening SOD. Additionally, progression of target lesions must not be present. SD: Neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD.	Phase 1b Part: Up to 11.73 months; Phase 2 Part: Up to 20.40 months
Phase 2 Part: Number of Participants With TEAEs and Treatment-related TEAEs	A TEAE was defined as an AE that emerged during treatment, having been absent at pretreatment (Baseline) or reemerged during treatment, or up to 30 days following last dose of study drug, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment or up to 30 days following last dose of study drug, relative to the pretreatment state, when the AE was continuous. Related TEAEs was defined as AE for which a causal relationship between the study drug and the AE was a reasonable possibility.	Up to 30 days after last dose of study drug (up to 21.40 months)
Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab	Cmax was defined as the maximum plasma concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.	Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab	Tmax was defined as the time to reach maximum observed plasma concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.	Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for E7386 When Co-administered With Pembrolizumab	AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 (pre-dose) to time of last quantifiable concentration for E7386 when co-administered with Pembrolizumab. PK parameters were derived by noncompartmental analysis.	Cycle 1 Days 1 and 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)
Phase 1b Part, CLss/F: Apparent Clearance From Plasma at Steady State for E7386 When Co-administered With Pembrolizumab	CLss/F for E7386 when co-administered with Pembrolizumab was reported. PK parameters were derived by noncompartmental analysis.	Cycle 1 Day 8: Pre-dose up to 12 hours post-dose (Cycle 1 length=21 days)

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Collaborators: Merck Sharp & Dohme LLC

Study record dates

Study Major Dates

• Study Start (Actual): October 27, 2021
• Primary Completion (Actual): October 15, 2024
• Study Completion (Actual): October 15, 2024

Study Registration Dates

• First Submitted: October 14, 2021
• First Submitted That Met QC Criteria: October 14, 2021
• First Posted (Actual): October 25, 2021

Study Record Updates

• Last Update Posted (Estimated): October 24, 2025
• Last Update Submitted That Met QC Criteria: October 10, 2025
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Solid tumors; E7386; metastatic or unresectable melanoma; metastatic or unresectable hepatocellular carcinoma; metastatic or unresectable colorectal cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Colonic Diseases; Neoplastic Processes; Skin Diseases; Carcinoma; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Pathological Conditions, Signs and Symptoms; Skin and Connective Tissue Diseases; Carcinoma, Hepatocellular; Colorectal Neoplasms; Neoplasm Metastasis; Melanoma; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; pembrolizumab; E-7386; lenvatinib
• Other Study ID Numbers: E7386-G000-201; 2021-001568-10 (EudraCT Number); 2023-505425-14 (Registry Identifier: CTIS); MK-3475-C83 (Other Identifier: Merck Sharp & Dohme)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No