E7386 + Lenvatinib for Solid Cancer

Recruiting in Palo Alto (17 mi)

+73 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Eisai Inc.

Must not be taking: Antiretrovirals, Antiplatelets

Disqualifiers: HIV, Cardiac conditions, Active infection, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The primary objective of this study is to assess the safety and tolerability and to determine the recommended Phase 2 dose (RP2D) of E7386 in combination with other anticancer drug(s), and to determine the optimal dose of E7386 in combination with lenvatinib in endometrial carcinoma (EC) (for EC Dose Optimization Part only).

Will I have to stop taking my current medications?

The trial requires an adequate washout period (time without taking certain medications) before starting the study drugs. This includes stopping chemotherapy and radiotherapy for 3 weeks or more, and any antitumor therapy with antibodies for 4 weeks or more. You should discuss your specific medications with the study team to see if they need to be stopped.

What data supports the effectiveness of the drug Lenvatinib for solid cancer?

Lenvatinib has shown effectiveness in treating aggressive thyroid cancer and advanced liver cancer by inhibiting proteins that help tumors grow and spread. It has also been studied in combination with other drugs for lung cancer, suggesting its potential in treating various solid tumors. ^{1 2 3 4 5}

What is the safety profile of Lenvatinib in humans?

Lenvatinib, used for various cancers, often causes side effects like high blood pressure, diarrhea, tiredness, loss of appetite, and weight loss. These side effects are common with this type of cancer treatment and may require careful management by doctors to ensure patients can continue their treatment safely. ^{1 4 6 7 8}

What makes the drug E7386 + Lenvatinib unique for treating solid cancer?

The combination of E7386 and Lenvatinib is unique because Lenvatinib is a multitargeted drug that blocks several pathways involved in tumor growth and blood vessel formation, which may enhance the effectiveness of E7386 in treating solid cancers. ^{2 3 4 5 9}

Research Team

Eligibility Criteria

This trial is for adults with certain solid tumors like liver cancer, colorectal cancer, or endometrial cancer. They should have a specific stage of disease and no effective standard treatments left to try. Participants need to be relatively healthy otherwise, with good organ function and performance status. Those who've had recent major surgeries or active infections (except hepatitis B/C in liver cancer patients) can't join.

Inclusion Criteria

For HCC participants only: Child-Pugh score A

I haven't had blood transfusions or G-CSF treatments in the last 2 weeks and have recovered from any radiation side effects without needing steroids.

My blood pressure, kidney, liver, bone marrow functions, and mineral levels are all within normal ranges.

Exclusion Criteria

I am currently infected with COVID-19 or still recovering from its effects.

I do not have an active infection needing treatment, except for HBV/HCV if I have liver cancer.

My urine protein levels are below 1 gram per 24 hours.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive E7386 in combination with lenvatinib in 28-day treatment cycles to determine the recommended Phase 2 dose

28 days per cycle

Cycle 0: 6 or 7 days, followed by Cycle 1: 28 days

Dose Expansion

Participants receive E7386 in combination with lenvatinib or lenvatinib monotherapy in 28-day treatment cycles to assess safety and tolerability

28 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• E7386 (Microtubule Inhibitor)
• Lenvatinib (Tyrosine Kinase Inhibitor)

Trial Overview The study is testing the safety and best dose of E7386 when combined with another anticancer drug called Lenvatinib in people with various solid tumors. The goal is to find out what amount of E7386 can be given safely without causing too many side effects.

Participant Groups

Group I: Dose Optimization Part: EC Participants Experimental Treatment 4 Interventions

Participants with EC will be randomized to receive 2 different doses of E7386 in combination with lenvatinib capsule or lenvatinib capsule monotherapy in 28-days cycles, or treatment of physician's choice (TPC; doxorubicin in 21-day cycles or paclitaxel in 28-day cycles \[3 weeks on/1 week off\]), until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group II: Dose Expansion Part: HCC Subpart: Lenvatinib Only Experimental Treatment 1 Intervention

Participants with HCC will receive lenvatinib 8 mg (participants with body weight of \<60 kg) or 12 mg (participants with body weight \>=60 kg), capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program

Group III: Dose Expansion Part: HCC Subpart: E7386 + Lenvatinib Experimental Treatment 2 Interventions

Participants with HCC will receive lenvatinib 8 mg (participants with body weight of \<60 kg) or 12 mg (participants with body weight \>=60 kg), capsule, orally QD in combination with E7386 y, BID in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group IV: Dose Expansion Part: EC Subpart: E7386 + Lenvatinib Experimental Treatment 2 Interventions

Participants with endometrial cancer (EC) will receive E7386, BID in combination with lenvatinib 14 mg, capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group V: Dose Expansion Part: CRC Subpart: E7386 + Lenvatinib Experimental Treatment 2 Interventions

Participants with colorectal cancer (CRC) will receive E7386, BID in combination with lenvatinib 20 mg, capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group VI: Dose Escalation Part: Other ST: E7386 QD Subpart + Lenvatinib Experimental Treatment 2 Interventions

Participants with solid tumor (ST) (except for HCC) will receive E7386, QD for 5 or 6 consecutive days followed by a period of time without treatment in Cycle 0 (6 or 7 days). Participants with ST (except for HCC) will receive E7386, QD in combination with lenvatinib 20 mg, capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group VII: Dose Escalation Part: Other ST: E7386 BID Subpart + Lenvatinib Experimental Treatment 2 Interventions

Participants with ST (except for HCC) will receive E7386, BID for 5 or 6 consecutive days in Cycle 0 (6 or 7 days). Participants with ST (except for HCC) will receive E7386, BID in combination with lenvatinib 20 mg, capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group VIII: Dose Escalation Part: HCC: E7386 QD Subpart + Lenvatinib Experimental Treatment 2 Interventions

Participants with hepatocellular carcinoma (HCC) will receive E7386, once daily (QD) for 5 or 6 consecutive days followed by a period of time without treatment in Cycle 0 (6 or 7 days). Participants with HCC will receive E7386, QD in combination with lenvatinib 8 milligram (mg) (participants with body weight of less than \[\<\] 60 kilograms \[kg\]) or 12 mg (participants with body weight \>=60 kg), capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Group IX: Dose Escalation Part: HCC: E7386 BID Subpart + Lenvatinib Experimental Treatment 2 Interventions

Participants with HCC will receive E7386, twice daily (BID) for 5 or 6 consecutive days in Cycle 0 (6 or 7 days). Participants with HCC will receive E7386, BID in combination with lenvatinib 8 mg (participants with body weight of \< 60 kg) or 12 mg (participants with body weight \>=60 kg) capsules, orally, QD in 28-day treatment cycles until PD, development of unacceptable toxicity, participant request to discontinue, withdrawal of consent, or termination of the study program.

Who Is Running the Clinical Trial?

Eisai Inc.

Lead Sponsor

Trials

524

Recruited

161,000+

Founded

Eisai Inc. was established in 1995 as the U.S. subsidiary of Eisai Co., Ltd.

Headquarters

Woodcliff Lake, NJ, USA

Known For

Neurology and Oncology

Top Products

Aricept (donepezil), Lenvima (lenvatinib), Leqembi (lecanemab), Halaven (eribulin)

Lynn Kramer

Eisai Inc.

Chief Medical Officer since 2019

MD

Tatsuyuki Yasuno

Eisai Inc.

Chief Executive Officer since 2023

MBA from Kellogg School of Management, Northwestern University; Bachelor of Political Science from Waseda University

Findings from Research

The maximum tolerated dose (MTD) of lenvatinib when combined with carboplatin and paclitaxel for treating advanced non-small-cell lung cancer (NSCLC) is established at 4 mg taken twice daily, showing manageable side effects.

The treatment regimen resulted in a response rate of 68% and a median progression-free survival of 9.0 months, indicating promising antitumor activity in chemotherapy-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. Nishio, M., Horai, T., Horiike, A., et al.[2021]

In a phase 1 study involving 27 patients, lenvatinib treatment led to significant tumor shrinkage, which correlated with changes in plasma angiogenic biomarkers such as increased VEGF and SDF1α levels and decreased sVEGFR2 levels.

Adverse events like hypertension and proteinuria were also linked to changes in these biomarkers, suggesting that monitoring plasma angiogenic proteins could help predict lenvatinib's efficacy and side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. Koyama, N., Saito, K., Nishioka, Y., et al.[2021]

In a phase 2 study involving 46 patients with advanced hepatocellular carcinoma, lenvatinib demonstrated significant clinical activity with a median time to progression of 7.4 months and a median overall survival of 18.7 months.

The treatment was associated with manageable side effects, although 74% of patients required dose reductions due to adverse events, particularly in those with lower body weight, suggesting that body weight should be considered for dose adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. Ikeda, K., Kudo, M., Kawazoe, S., et al.[2018]

Lenvatinib, a multitargeted Tyrosine Kinase Inhibitor, has shown significant improvement in Progression-Free Survival (PFS) for patients with aggressive Differentiated Thyroid Cancer (DTC) not responsive to radioiodine, with a median PFS of 18.2 months compared to 3.6 months for placebo.

While lenvatinib is effective, it is associated with a high rate of adverse effects (over 40%), including hypertension and fatigue, and about 14% of patients may need to discontinue treatment due to these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib in the Therapy of Aggressive Thyroid Cancer: State of the Art and New Perspectives with Patents Recently Applied. Ferrari, SM., Ruffilli, I., Centanni, M., et al.[2018]

Lenvatinib effectively inhibits the growth of liver cancer cells in vitro and in vivo, with its efficacy varying based on the expression levels of specific receptors (FGFR1-4, RET) in the cancer cells.

In animal models, lenvatinib reduced tumor growth by significantly decreasing blood vessel formation (angiogenesis) and increasing tumor necrosis, although it did not induce apoptosis in the cancer cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo. Ogasawara, S., Mihara, Y., Kondo, R., et al.[2020]

Lenvatinib is an effective multikinase inhibitor approved for treating radioiodine-refractory differentiated thyroid cancer and advanced renal cell carcinoma, showing favorable efficacy in various malignancies.

While lenvatinib has beneficial effects, it is associated with common adverse events like hypertension and fatigue, necessitating careful monitoring and management to enhance patient quality of life and treatment adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. Cabanillas, ME., Takahashi, S.[2019]

Lenvatinib (LEN) is an effective multikinase inhibitor used for treating certain types of cancer, but it often causes significant adverse events (AEs) like hypertension and diarrhea, which can lead to dose modifications or discontinuation of treatment.

A multidisciplinary approach to managing these AEs is crucial for maintaining treatment efficacy and patient safety, as it helps address the side effects that frequently arise during LEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature. Denaro, N., Latina, A., Cesario, F., et al.[2019]

In a phase three study involving 392 patients with differentiated thyroid cancer, lenvatinib (24 mg/day) was associated with common adverse events such as diarrhea (67%), fatigue (67%), and proteinuria (32%), which typically occurred early and were manageable through dose modifications.

Overall survival was significantly linked to the occurrence of diarrhea, with patients experiencing diarrhea having a median overall survival that was not reached, compared to 17.1 months for those without diarrhea.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. Haddad, RI., Schlumberger, M., Wirth, LJ., et al.[2019]

Lenvatinib is an effective oral treatment for various cancers, including thyroid, liver, kidney, and endometrial cancers, and can be used alone or in combination with other therapies, based on extensive clinical trial data.

The dosing strategies for lenvatinib have been carefully established to maximize patient benefits while managing side effects, which are similar to those of other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies. Motzer, RJ., Taylor, MH., Evans, TRJ., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Phase 1 study of lenvatinib combined with carboplatin and paclitaxel in patients with non-small-cell lung cancer. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Pharmacodynamic change in plasma angiogenic proteins: a dose-escalation phase 1 study of the multi-kinase inhibitor lenvatinib. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

Phase 2 study of lenvatinib in patients with advanced hepatocellular carcinoma. [2018]

4. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Lenvatinib in the Therapy of Aggressive Thyroid Cancer: State of the Art and New Perspectives with Patents Recently Applied. [2018]

5. Greece pubmed.ncbi.nlm.nih.gov

Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Managing the adverse events associated with lenvatinib therapy in radioiodine-refractory differentiated thyroid cancer. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies. [2023]