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

Waitlist Available

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.

Must not have

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, 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, Known to be human immunodeficiency virus (HIV) positive, Received blood/platelet transfusion or G-CSF within 4 weeks before study entry, 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., For CRC only, participants are excluded if: have a tumor that is microsatellite instability high (MSI H)/ DNA mismatch repair-deficient (dMMR) positive, 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, 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

Any active infection requiring systemic treatment

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

No Placebo-Only Group

Summary

This trial tests a new drug (E7386) combined with pembrolizumab and sometimes lenvatinib in patients with certain cancers who have already tried other treatments. The goal is to see if these drugs can stop cancer growth and help the immune system destroy cancer cells.

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.

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.

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.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I am currently being treated for an infection.

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I stopped a cancer treatment due to severe side effects.

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I have been treated for an autoimmune disease in the last 2 years.

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I have an immune system disorder or have been on steroids or other immune-weakening drugs in the last week.

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I have had pneumonitis treated with steroids or have it now.

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

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

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

Phase 2 Part: Objective Response Rate (ORR)

Secondary study objectives

Clinical Benefit Rate (CBR)

Disease Control Rate (DCR)

Duration of Response (DOR)

+2 more

Side effects data

From 2024 Phase 3 trial • 804 Patients • NCT03040999

64%

Radiation skin injury

63%

Stomatitis

58%

Anaemia

56%

Nausea

48%

Dry mouth

45%

Constipation

45%

Weight decreased

44%

Dysphagia

42%

Neutrophil count decreased

33%

Dysgeusia

33%

Vomiting

32%

Fatigue

31%

White blood cell count decreased

28%

Hypomagnesaemia

26%

Decreased appetite

25%

Hypothyroidism

25%

Hypokalaemia

24%

Lymphocyte count decreased

24%

Platelet count decreased

23%

Oropharyngeal pain

23%

Blood creatinine increased

22%

Diarrhoea

22%

Odynophagia

20%

Hypoacusis

20%

Alanine aminotransferase increased

20%

Hyponatraemia

19%

Tinnitus

19%

Oral candidiasis

19%

Asthenia

16%

Pyrexia

16%

Cough

15%

Aspartate aminotransferase increased

15%

Rash

14%

Insomnia

13%

Acute kidney injury

13%

Pharyngeal inflammation

13%

Pruritus

12%

Dysphonia

12%

Gamma-glutamyltransferase increased

11%

Pneumonia

11%

Dehydration

10%

Hyperthyroidism

10%

Hypoalbuminaemia

10%

Hypocalcaemia

10%

Headache

10%

Productive cough

Neck pain

Peripheral sensory neuropathy

Gastrooesophageal reflux disease

Hiccups

Hyperglycaemia

Hyperuricaemia

Dizziness

Hypophosphataemia

Urinary tract infection

Ear pain

Localised oedema

Hyperkalaemia

Erythema

Oral pain

Abdominal pain upper

Arthralgia

Anxiety

Febrile neutropenia

Dyspepsia

Saliva altered

Back pain

Oedema peripheral

Hypertension

Dyspnoea

Nasopharyngitis

Alopecia

Dry skin

Sepsis

Pneumonia aspiration

Trismus

Pneumonitis

Laryngeal oedema

Malnutrition

Pharyngeal haemorrhage

Cellulitis

Septic shock

Clostridium difficile colitis

Systemic infection

Cardiac arrest

Death

Bronchitis

Hepatitis

Immune-mediated hepatitis

Oesophagitis

General physical health deterioration

Hypophagia

Tumour haemorrhage

Cerebrovascular accident

Syncope

Acute respiratory failure

Aspiration

Colitis

Mouth haemorrhage

Hypersensitivity

Acute myocardial infarction

Abscess neck

Device related infection

Stoma site infection

Vascular device infection

Wound infection

Hypercalcaemia

Pulmonary embolism

Respiratory failure

100%

80%

60%

40%

20%

Study treatment Arm

Placebo + CRT Followed by Placebo

Pembrolizumab + CRT Followed by Pembrolizumab

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

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

E7386

2019

Completed Phase 2

~110

Pembrolizumab

2017

Completed Phase 3

~2810

Lenvatinib

2017

Completed Phase 4

~2040

0 / 10Eligibility 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.