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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05091346
Recruitment Status : Recruiting
First Posted : October 25, 2021
Last Update Posted : May 5, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Eisai Inc.

Brief Summary:

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 in participants with previously treated selected solid tumors (melanoma, colorectal cancer [CRC], hepatocellular carcinoma [HCC]) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.


Condition or disease Intervention/treatment Phase
Melanoma Carcinoma, Hepatocellular Colorectal Neoplasms Drug: E7386 Drug: Pembrolizumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Phase 1b/2 Study of E7386 in Combination With Pembrolizumab in Previously Treated Subjects With Selected Solid Tumors
Actual Study Start Date : October 27, 2021
Estimated Primary Completion Date : November 24, 2023
Estimated Study Completion Date : May 24, 2024

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma

Arm Intervention/treatment
Experimental: E7386
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: E7386
E7386 tablet.

Drug: Pembrolizumab
Pembrolizumab IV infusion.




Primary Outcome Measures :
  1. Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (Cycle length is equal to [=] 21 days) ]
    DLTs are any pre-specified toxicities occurring during Cycle 1, based on investigator assessment as related to study drug. All adverse events (AEs) of the specified grades should count as DLTs except those that are clearly and incontrovertibly due to disease progression or extraneous causes. DLTs will be assessed to determine the RP2D of E7386 in combination with pembrolizumab. All toxicity will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

  2. Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From date of first dose of study drug up to 30 days after last administration of study drug (approximately up to 2 years 1 month) ]
  3. Phase 2 Part: Objective Response Rate (ORR) [ Time Frame: From first dose of study drug until progressive disease (PD) or death, development of unacceptable toxicity, withdrawal of consent, or study termination (up to approximately 2 years) ]
    ORR is defined as the percentage of participants with a best overall response (BOR) of confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. CR is defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to less than (<) 10 millimeters (mm). PR is defined as at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.


Secondary Outcome Measures :
  1. Phase 1b Part: Best of Response (BOR) [ Time Frame: From first dose of study drug until PD or death, development of unacceptable toxicity, withdrawal of consent, or study termination (up to approximately 2 years 7 months) ]
    BOR is defined as CR, PR, stable disease (SD), PD, and not evaluable (NE), where SD has to be achieved at greater than equal to (>=) 5 weeks after the first dose per RECIST version 1.1. CR is defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD is defined as >=20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD.

  2. Duration of Response (DOR) [ Time Frame: From the date of first documented CR or PR until first documentation of recurrent or progressive disease or death (up to approximately 2 years 7 months) ]
    DOR is defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death, whichever occurs first in participants with confirmed CR or PR as per RECIST version 1.1. CR is defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD is defined as >=20% increase in sum of diameters of target lesions, reference-smallest sum recorded in study (sum at baseline if that was smallest). Sum of diameters must have absolute increase of >=5 mm. Appearance of >=1 new lesions also considered PD.

  3. Disease Control Rate (DCR) [ Time Frame: From first dose of study drug until PD or death, development of unacceptable toxicity, withdrawal of consent, or study termination (up to approximately 2 years 7 months) ]
    DCR is defined as the percentage of participants with BOR of confirmed CR, PR, or SD after >=5 weeks from first dose per RECIST version 1.1. CR is defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  4. Clinical Benefit Rate (CBR) [ Time Frame: From first dose of study drug until PD or death, development of unacceptable toxicity, withdrawal of consent, or study termination (up to approximately 2 years 7 months) ]
    CBR is defined as the percentage of participants who have a BOR of confirmed CR, PR, or durable SD (duration of SD >=23 weeks) per RECIST 1.1. CR is defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  5. Cmax: Maximum Observed Plasma Concentration for E7386 [ Time Frame: Phase 1b: Cycle 1 Days 1 and 8: 0-12 hours post-dose; Phase 2: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length is 21 days) ]
  6. Tmax: Time to Reach the Maximum Plasma Concentration for E7386 [ Time Frame: Phase 1b: Cycle 1 Days 1 and 8: 0-12 hours post-dose; Phase 2: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length is 21 days) ]
  7. AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero (Pre-dose) to Time of Last Quantifiable Concentration for E7386 [ Time Frame: Phase 1b: Cycle 1 Days 1 and 8: 0-12 hours post-dose; Phase 2: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length is 21 days) ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  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 known BRAF mut +ve, 2 lines of therapies prior to study enrollment and must have progressed on 1 prior BRAF inhibitor
  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. HCC cohort (phase 2), participants must have:

    • Barcelona Clinic Liver Cancer (BCLC) Stage B (not amenable for transarterial chemoembolization [TACE]) or Stage C and Child Pugh class A
    • Has 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

Exclusion Criteria

  1. 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
  2. Participants with brain or subdural metastases, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study
  3. Any active infection requiring systemic treatment
  4. Has severe hypersensitivity to study drugs and/or any of its excipients
  5. Has 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.
  6. Has an active autoimmune disease that has required systemic treatment in the past 2 years
  7. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
  8. 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
  9. 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
  10. Known to be human immunodeficiency virus (HIV) positive
  11. Received blood/platelet transfusion or G-CSF within 4 weeks before study entry
  12. For Melanoma only, participants with ocular melanoma are excluded
  13. For CRC only, participants are excluded if:

    • has a tumor that is microsatellite instability high (MSI H)/ DNA mismatch repair-deficient (dMMR) positive
    • has received prior treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  14. For HCC only, participants are excluded if:

    • clear invasion to bile duct or portal vein invasion of Vp4
    • symptomatic gastric or esophageal varices per Investigator's clinical judgement
    • history of hepatic encephalopathy within 6 months prior to starting study drug

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05091346


Contacts
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Contact: Eisai Medical Information 1-888-274-2378 esi_oncmedinfo@eisai.com

Locations
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United States, California
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90024
Japan
Eisai Trial Site 4 Recruiting
Chiba-shi, Japan
Eisai Trial Site 1 Recruiting
Kashiwa, Japan
Eisai Trial Site 3 Recruiting
Osaka, Japan
Eisai Trial Site 2 Recruiting
Tokyo, Japan
Sponsors and Collaborators
Eisai Inc.
Merck Sharp & Dohme LLC
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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT05091346    
Other Study ID Numbers: E7386-G000-201
2021-001568-10 ( EudraCT Number )
KEYNOTE-C83 ( Other Identifier: Merck Sharp & Dohme )
First Posted: October 25, 2021    Key Record Dates
Last Update Posted: May 5, 2022
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Eisai's data sharing commitment and further information on how to request data can be found on our website http://eisaiclinicaltrials.com/.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc.:
metastatic or unresectable melanoma
metastatic or unresectable hepatocellular carcinoma
metastatic or unresectable colorectal cancer
Solid tumors
E7386
Additional relevant MeSH terms:
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Melanoma
Colorectal Neoplasms
Carcinoma, Hepatocellular
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Adenocarcinoma
Liver Neoplasms
Liver Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents