Clinical trial NCT05091346: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Melanoma
Carcinoma, Hepatocellular
Colorectal Neoplasms
Keywords: metastatic or unresectable melanoma
metastatic or unresectable hepatocellular carcinoma
metastatic or unresectable colorectal cancer
Solid tumors
E7386
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2021-10-25
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Cycle length is equal to [=] 21 days)
measure: Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: 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)
measure: Phase 2 Part: Objective Response Rate (ORR)
timeFrame: 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)
Secondary outcomes:
measure: Phase 1b Part: Best of Response (BOR)
timeFrame: 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)
measure: Duration of Response (DOR)
timeFrame: 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)
measure: Disease Control Rate (DCR)
timeFrame: 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)
measure: Clinical Benefit Rate (CBR)
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Phase 2 Part: Number of Participants With DLTs for E7386 in Combination With Pembrolizumab Plus Lenvatinib
timeFrame: Cycle 1 (Cycle length = 21 days)
measure: Phase 1b Part, Cmax: Maximum Observed Plasma Concentration for E7386 When Co-administered With Pembrolizumab
timeFrame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle length = 21 days)
measure: Phase 1b Part, Tmax: Time to Reach the Maximum Plasma Concentration for E7386 When Co-administered With Pembrolizumab
timeFrame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle length = 21 days)
measure: 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
timeFrame: Cycle 1 Days 1 and 8: 0-12 hours post-dose (Cycle length = 21 days)
measure: Phase 2 Part: Apparent Clearance for E7386 When Co-administered With Lenvatinib and Pembrolizumab
timeFrame: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length = 21 days)
measure: Phase 2 Part: Apparent Clearance for Lenvatinib When Co-administered With E7386 and Pembrolizumab
timeFrame: Cycle 1 Day 1: 0.5-8 hours post-dose; Cycle 1 Day 8: 0-8 hours post-dose (Cycle length = 21 days)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Orange
country: United States
facility: University of California, Irvine Health
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: West Palm Beach
country: United States
facility: SCRI Florida Cancer Specialists East
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Center
state: Michigan
city: New Brunswick
country: United States
facility: Rutgers cancer Institute of NJ
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Portland
country: United States
facility: Providence Medical Center
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Cancer Care in Nashville
state: Tennessee
city: Chiba-shi
country: Japan
facility: Chiba University Hospital
city: Chuo-ku
country: Japan
facility: National Cancer Center Hospital
city: Fukuoka
country: Japan
facility: Kurume University Hospital
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Osaka
country: Japan
facility: Kindai University Hospital
city: Osaka
country: Japan
facility: Osaka Metropolitan University Hospital
city: Sapporo shi
country: Japan
facility: Sapporo-Kosei General Hospital
city: Shizouka
country: Japan
facility: Shizuoka Cancer Center Hospital
city: Tokyo
country: Japan
facility: Toranomon Hospital
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Malaga
state: Avenida Carolos Haya S/n
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
state: Calle Profesor Martín Lagos
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Badajoz
country: Spain
facility: Hospital Universitario de Badajoz
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: Hospital Universitario de la Paz
city: Valencia
country: Spain
facility: Consorcio Hospital General Universitario de Valencia
city: Sutton
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust - The Royal Marsden Hospital
state: Surrey
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Imperial College London
city: London
country: United Kingdom
facility: Royal Free Hospital NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References: