What is the mechanism of action of this treatment?

Pembrolizumab is an anti-PD-1 monoclonal antibody that enhances the immune system's ability to attack melanoma cells by blocking the PD-1 receptor on T-cells. Lenvatinib is a multi-kinase inhibitor that targets multiple pathways involved in tumor growth and angiogenesis, inhibiting cancer cell proliferation and blood vessel formation. E7386, a novel therapeutic agent, is being studied for its potential to disrupt specific signaling pathways critical for tumor growth. This multi-faceted approach of combining immune checkpoint inhibitors with agents that target tumor growth and survival pathways is crucial for melanoma patients, as it may lead to more effective and durable responses.

What side effects are associated with this type of intervention?

Common treatments for melanoma, particularly those involving pembrolizumab and lenvatinib, have well-documented side effects. Pembrolizumab often causes hypothyroidism, decreased appetite, and fatigue, with some patients experiencing severe grade 3 to 4 adverse events. Lenvatinib is associated with hypertension, diarrhea, and nausea, and has a high incidence of severe adverse events. When combined, these treatments can result in a range of side effects, including significant immune-related and systemic toxicities.

What prior FDA approvals exist?

Pembrolizumab, an anti-PD-1 monoclonal antibody, has been FDA-approved for the treatment of melanoma, particularly for patients with unresectable or metastatic melanoma. It works by blocking the PD-1 pathway, thereby enhancing the immune system's ability to fight cancer cells. Lenvatinib, a multi-kinase inhibitor, is not specifically approved for melanoma but has shown efficacy in combination with pembrolizumab in other cancers. Similar agents include nivolumab, another anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody, both of which have been approved for melanoma treatment. These immunotherapies have significantly improved outcomes for patients with advanced melanoma.

What other types of research exist?

Promising alternatives for melanoma treatment in 2024 include: 1) Nivolumab (Anti-PD-1) combined with Ipilimumab (Anti-CTLA-4), which has shown durable long-term responses. 2) Pembrolizumab combined with Axitinib (VEGFR Inhibitor), which has demonstrated efficacy in various solid tumors. 3) Atezolizumab (Anti-PD-L1) combined with Bevacizumab (Anti-VEGF), which has shown promise in other cancers and may be applicable to melanoma. These combinations leverage different mechanisms of action to enhance anti-tumor activity.

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Microtubule Inhibitor

E7386 + Pembrolizumab for Solid Cancers

Phase 1 & 2

Recruiting

Research Sponsored by Eisai Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Must have disease progression on current or since the last anticancer treatment

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. 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). 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.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 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)

Awards & highlights

Study Summary

This trial is studying a combination of E7386 and pembrolizumab to see how well it works in treating patients with solid tumors that have been previously treated.

Who is the study for?

This trial is for adults with certain advanced solid tumors (melanoma, colorectal cancer, or hepatocellular carcinoma) that have progressed despite previous treatments. Participants must be in good physical condition and have at least one measurable tumor. Specific criteria apply to each type of cancer regarding prior therapies and disease stage.Check my eligibility

What is being tested?

The study tests E7386 combined with pembrolizumab for safety, tolerability, and the optimal dose in Phase 1b. In Phase 2, it evaluates how well this combination works on melanoma, colorectal cancer, and hepatocellular carcinoma; plus lenvatinib is added for some liver cancer patients.See study design

What are the potential side effects?

Potential side effects include reactions related to immune system activation such as inflammation in various organs, fatigue, digestive issues like nausea or diarrhea. Blood pressure may need monitoring especially when lenvatinib is included.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My cancer has worsened despite treatment.

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Participants with liver cancer must be in stage B or C and have only received one prior treatment for their advanced cancer. They must have progressed on treatment with a specific type of immunotherapy and meet certain blood pressure and vitamin D levels.

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My advanced cancer (melanoma, colorectal, or liver) has not responded to standard treatments.

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I am fully active or restricted in physically strenuous activity but can do light work.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 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)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~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)

This trial's timeline: 3 weeks for screening, Varies for treatment, and 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) for reporting.

Treatment Details

Study Objectives

Outcome measures can provide a clearer picture of what you can expect from a treatment.

Primary outcome measures

Phase 1b Part: Number of Participants With Dose-limiting Toxicities (DLTs)

Phase 1b Part: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Phase 2 Part: Objective Response Rate (ORR)

Secondary outcome measures

Clinical Benefit Rate (CBR)

Disease Control Rate (DCR)

Duration of Response (DOR)

+8 more

Side effects data

From 2024 Phase 2 trial • 57 Patients • NCT03004183

21%

Fatigue

13%

Nausea

11%

Back pain

Shortness of Breath

Anemia

Abdominal pain

Diarrhea

Pneumonia

Kidney Injury and/or Infection

Dyspnea

Weight Loss

Pneumothorax

Malnutrition, Hypercalcemia and Weakness

Intractable pain, back pain, hip pain

Activated partial thromboplastin time prolonged

Pleural effusion

Atrial fibrillation with rapid ventricular response

Thrombocytopenia

Respiratory failure

Skin rash

colitis

100%

80%

60%

40%

20%

Study treatment Arm

Single Arm

Trial Design

2Treatment groups

Experimental Treatment

Group I: Phase 2: E7386 + Pembrolizumab + LenvatinibExperimental Treatment3 Interventions

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.

Group II: Phase 1b and 2: E7386 + PembrolizumabExperimental Treatment2 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Lenvatinib

2005

Completed Phase 4

~2690

E7386

2019

Completed Phase 1

~20

Pembrolizumab

2017

Completed Phase 2

~2010

0 / 4Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Pembrolizumab is an anti-PD-1 monoclonal antibody that enhances the immune system's ability to attack melanoma cells by blocking the PD-1 receptor on T-cells. Lenvatinib is a multi-kinase inhibitor that targets multiple pathways involved in tumor growth and angiogenesis, inhibiting cancer cell proliferation and blood vessel formation. E7386, a novel therapeutic agent, is being studied for its potential to disrupt specific signaling pathways critical for tumor growth. This multi-faceted approach of combining immune checkpoint inhibitors with agents that target tumor growth and survival pathways is crucial for melanoma patients, as it may lead to more effective and durable responses.

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors.