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

• ClinicalTrials.gov Identifier: NCT05091346
• Recruitment Status: Recruiting
• First Posted: October 25, 2021
• Last Update Posted: March 13, 2023
• Sponsor: Eisai Inc.
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Eisai Inc.

Tracking Information

• First Submitted Date: October 14, 2021
• First Posted Date: October 25, 2021
• Last Update Posted Date: March 13, 2023
• Actual Study Start Date: October 27, 2021
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 10, 2023)

• 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.
• Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From date of first dose of study drug up to 30 days after last administration of study drug (approximately up to 3 years 11 months) ]
• 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 3 years 11 months) ]
  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.

Original Primary Outcome Measures (submitted: October 14, 2021)

• 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.
• 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) ]
• 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.

Current Secondary Outcome Measures (submitted: March 10, 2023)

• 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 3 years 11 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.
• 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 due to any causes (up to approximately 3 years 11 months) ]
  DOR is defined as the time from the first documentation of CR or PR to the first documentation of disease progression or death due to any causes, whichever occurs first in participants with confirmed CR or PR as per RECIST version 1.1.
• 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 3 years 11 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.
• 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 3 years 11 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.
• Phase 2 Part: Number of Participants With TEAEs and Treatment-related Adverse Events for E7386 in Combination With Pembrolizumab and E7386 in Combination With Pembrolizumab Plus Lenvatinib [ Time Frame: From date of first dose of study drug up to 30 days after last administration of study drug (approximately up to 3 years 11 months) ]
• Phase 2 Part: Number of Participants With DLTs for E7386 in Combination With Pembrolizumab Plus Lenvatinib [ Time Frame: Cycle 1 (Cycle length = 21 days) ]
  DLTs are any pre-specified toxicities occurring during Cycle 1, based on investigator assessment as related to study drug. All AEs of the specified grades should count as DLTs except those that are clearly and incontrovertibly due to disease progression or extraneous causes. All toxicity will be graded using NCI CTCAE version 5.0.
• Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab [ Time Frame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle length = 21 days) ]
• Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab [ Time Frame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle 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 [ Time Frame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle length = 21 days) ]
• Phase 2 Part: Apparent Clearance for E7386 When Co-administered With Lenvatinib and Pembrolizumab [ Time Frame: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length = 21 days) ]
• Phase 2 Part: Apparent Clearance for Lenvatinib When Co-administered With E7386 and Pembrolizumab [ Time Frame: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length = 21 days) ]

Original Secondary Outcome Measures (submitted: October 14, 2021)

• 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.
• 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.
• 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.
• 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.
• 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) ]
• 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) ]
• 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) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of E7386 in Combination With Pembrolizumab in Previously Treated Participants With Selected Solid Tumors
• Official Title: An Open-Label, Multicenter, Phase 1b/2 Study of E7386 in Combination With Pembrolizumab in Previously Treated Subjects With Selected Solid Tumors

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 (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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Melanoma
• Carcinoma, Hepatocellular
• Colorectal Neoplasms

Intervention

• Drug: E7386
  E7386 tablet.
• Drug: Pembrolizumab
  Pembrolizumab IV infusion.
• Drug: Lenvatinib
  Lenvatinib capsule.
  Other Name: E7080

Study Arms

• 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.
  Interventions:

  • Drug: E7386
  • Drug: Pembrolizumab
• 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.
  Interventions:

  • Drug: E7386
  • Drug: Pembrolizumab
  • Drug: Lenvatinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 10, 2023): 156
• Original Estimated Enrollment (submitted: October 14, 2021): 108
• Estimated Study Completion Date: September 30, 2025
• Estimated Primary Completion Date: September 30, 2025 (Final data collection date for primary outcome measure)

Eligibility 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 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Japan, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT05091346
• Other Study ID Numbers: E7386-G000-201; 2021-001568-10 ( EudraCT Number ); KEYNOTE-C83 ( Other Identifier: Merck Sharp & Dohme )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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/.

• Current Responsible Party: Eisai Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Eisai Inc.
• Original Study Sponsor: Same as current
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Not Provided
• PRS Account: Eisai Inc.
• Verification Date: March 2023