A Study of E7386 in Combination With Other Anticancer Drug in Participants With Solid Tumor

Neoplasms Clinical Trial

Official title:

An Open-label Phase 1b Study of E7386 in Combination With Other Anticancer Drug(s) in Subjects With Solid Tumors

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04008797
• Other study ID #: E7386-J081-102
• Secondary ID: 2022-003300-3220
• Status: Recruiting
• Phase: Phase 1
• Start date: July 11, 2019
• Est. completion date: March 15, 2027

Study information

• Verified date: March 2023
• Source: Eisai Inc.
• Contact: Eisai Inquiry Service
• Email: eisai-chiken_hotline[@]hhc.eisai.co.jp
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 181
• Est. completion date: March 15, 2027
• Est. primary completion date: March 15, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. HCC part only:

Participants with confirmed diagnosis of unresectable HCC with any of the following criteria:

1. Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors

2. Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or chronic hepatitis B or C infection

ST part only (except for HCC):

Participants with histologically or cytologically confirmed diagnosis of solid tumor for which no alternative standard therapy or no effective therapy exists

2. Life expectancy of >=12 weeks

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1

4. All AEs due to previous anti-cancer therapy have either returned to Grade 0 to 1 except for alopecia or up to Grade 2 peripheral neuropathy (renal/bone marrow/liver function should meet the inclusion criteria)

5. Adequate washout period before study drug administration:

1. Chemotherapy and radiotherapy: 3 weeks or 5 times the half-life, whichever is shorter

2. Any antitumor therapy with antibody: 4 weeks or more

3. Any investigational drug or device: 4 weeks or more

4. Blood/platelet transfusion or granulocyte colony-stimulating factor (G-CSF): 2 weeks or more Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not had radiation pneumonitis

6. Adequate controlled blood pressure (BP), renal function, bone marrow function, liver function, and serum mineral level

7. At least one measurable lesion based on mRECIST (for HCC Subparts in Dose Escalation Part) or on RECIST 1.1 (for Other ST Subparts in Dose Escalation Part and all subparts in Expansion Part) meeting following criteria

• At least 1 lesion of >=1.0 centimeter (cm) in the longest diameter for a non-lymph node or >=1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 using computerized tomography (CT)/magnetic resonance imaging (MRI)

• Lesions that have had external beam radiotherapy or loco-regional therapies such as radiofrequency ablation, or transarterial chemoembolisation (TACE)/ transarterial embolization (TAE) must show evidence of progressive disease based on RECIST 1.1 to be deemed a target lesion

8. For HCC participants only: Child-Pugh score A. Note: If Child-Pugh score 7 or more was observed during Screening or Baseline, the participant is ineligible and re-assessment of the Child-Pugh score is not permitted.

9. For HCC participants only: Participants categorized to 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

10. For HCC Subpart in Expansion Part only: prior systemic therapy for locally advanced or metastatic disease is as defined below

a. Participants who have received only one prior line of immuno oncology (IO) based regimen and have progressed on or after prior treatment with IO based regimen, or IO ineligible participants who have received no prior systemic therapy. Participants who previously received lenvatinib treatment are ineligible

11. For CRC Subpart in Expansion Part only: participants must have received at least 2 prior regimens (not exceeding 4 prior regimens) or could not tolerate standard treatment and must have received the following prior therapies in the metastatic setting if approved and locally available (progressed on at least 1 prior regimen in the metastatic setting or could not tolerate standard treatment):

Note: Adjuvant chemotherapy counts as prior systemic treatment if there is documented disease progression within 6 months of treatment completion Note: If a participant is determined to be intolerant to prior standard treatment, the participant must have received at least of 2 cycles of that therapy Note: Participants who have received oral tyrosine kinase inhibitor (example, regorafenib) are ineligible

1. Fluoropyrimidine, irinotecan and oxaliplatin with or without an anti-Vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) (example, bevacizumab).

Note: Capecitabine is acceptable as equivalent to fluoropyrimidine in prior treatment Note: Participants who have previously received fluoropyrimidine, oxaliplatin, and irinotecan as part of the same and only chemotherapy regimen, example, FOLFOXIRI or FOLFIRINOX, may be eligible after discussion with the Sponsor

2. Chemotherapy with anti- epidermal growth factor receptor (EGFR) mAb (cetuximab or panitumumab) for participants with rat sarcoma virus (RAS) (Kirsten rat sarcoma viral oncogene homolog [KRAS)/ NRAS]) wild type (WT) CRC Note: RAS (KRAS/NRAS) WT participants with right or left CRC lesions who may have not been treated with anti-EGFR mAb based on local guidelines are eligible

3. BRAF inhibitor (in combination with cetuximab ± binimetinib) for BRAF V600E mutated tumors

4. Immune checkpoint inhibitor for participants with microsatellite instability-high (MSI-H) CRC

12. For EC Subpart in Expansion Part only: Participants who have radiographic evidence of disease progression after prior systemic therapies. Participants must have received platinum-based chemotherapy regimen and IO based regimen (example, lenvatinib + pembrolizumab or pembrolizumab monotherapy) for EC. Participants may have received up to 1 additional line of platinum-based chemotherapy if given in the neoadjuvant or adjuvant treatment setting, but not exceeding 3 lines of therapies. If participants are ineligible for IO therapy, participants who have received only 1 prior systemic therapy including platinum based chemotherapy regimen are eligible Note: There is no restriction regarding prior hormonal therapy

Exclusion Criteria:

1. Any of cardiac conditions as follows:

1. Heart failure New York Heart Association (NYHA) Class II or above

2. Unstable ischaemic heart disease (myocardial infarction within 6 months prior to starting study drug, or angina requiring use of nitrates more than once weekly)

3. Prolongation of QT interval with Fridericias correction (QTcF) to greater than (>) 480 millisecond (msec)

4. Left ventricular ejection fraction (LVEF) less than 50 percent (%)

2. Major surgery within 21 days or minor surgery (that is, simple excision) within 7 days prior to starting study drug. Participant must have recovered from the surgery related toxicities to less than Grade 2.

Note: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility

3. Known to be human immunodeficiency virus (HIV) positive Note: the sponsor has evaluated whether to include participant with HIV. Given that this is the first combination study of E7386 with lenvatinib and that the main mechanism of action of E7386 is immunomodulation of the tumor microenvironment along with the fact that several anti-retroviral therapies have drug-drug interaction with cytochrome P450 3A (CYP3A) substrates, the sponsor has decided not to include these participants at the current time. However, further considerations will be made moving forward based on new emerging data Note: HIV testing is required at screening only when mandated by local health authority

4. Participants with proteinuria >1 positive on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein >=1 gram per 24 hour will be ineligible

5. Active infection requiring systemic treatment (Except for Hepatitis B and/or C [HBV/HCV] infection in HCC participants)

In case of HBsAg (+) participants in HCC participants:

• Antiviral therapy for HBV is not ongoing

• HBV viral load is 2000 international unit per milliliter (IU/mL) or more at the Screening Period although antiviral therapy for HBV is ongoing

• Has dual active HBV infection (HBsAg (+) and/or detectable HBV deoxyribonucleic acid [DNA]) and HCV infection (anti-HCV Ab (+) and detectable HCV ribonucleic acid [RNA]) at study entry

6. Diagnosed with meningeal carcinomatosis

7. Participants with central nervous system metastases are only eligible if they have been previously treated and are radiologically stable, (that is, without evidence of progression for at least 4 weeks prior to first dose of study treatment by repeat imaging), clinically stable, and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.

8. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen

9. Any of bone disease/conditions as follows:

• Osteoporosis with T-score of < minus (-) 3.0 at the left or right total hip, left or right femoral neck or lumbar spine (L1-L4) as determined by dual energy x-ray absorptiometry (DXA) scan. Participants with T-score <-2.5 to -3.0 and no prior medical therapy for osteoporosis can only be included if treatment with a bisphosphonate (example, zoledronic acid) or denosumab has been started at least 14 days prior to the first dose of study drug

• 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

• Bone metastasis requiring orthopedic intervention

• Bone metastasis not being treated by bisphosphonate or denosumab. Participants may be included if treatment with bisphosphonate or denosumab has been started at least 14 days prior to the first dose of study drug. Participants with previous solitary bone lesions controlled with radiotherapy are eligible.

• History of symptomatic vertebral fragility fracture or any fragility fracture of the hip, pelvis, wrist or other location (defined as any fracture without a history of trauma or because of a fall from standing height or less)

• Moderate (25% to 40% decrease in the height of any vertebrae) or severe (>40% decrease in the height of any vertebrae) morphometric vertebral fracture at baseline

10. History of malignancy (except for original disease, or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, carcinoma in-situ [example, bladder or cervix]) within the past 24 months prior to the first dose of study drug

11. For HCC Subpart in Dose Escalation Part only: Participants who experienced discontinuation of lenvatinib, 2 or more multiple dose reductions of lenvatinib required from initial dose level of this study due to its toxicity, or participants who experienced single dose reduction or consecutive >=8 days dose interruption of lenvatinib within 60 days from the first dose, due to its toxicity. EC Subpart in Expansion Part only: Participants previously treated with lenvatinib who experienced discontinuation of lenvatinib due to toxicity, or dose reduction to less than 14 mg of lenvatinib due to toxicity

12. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic International Normalized Ratio (INR) monitoring for HCC participants only (example, warfarin or similar agents). Treatment with low molecular weight heparin and factor X inhibitors is permitted. Treatment with antiplatelet agents is prohibited for HCC participants in Dose Escalation Part only

13. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug

14. For HCC participants only: History of hepatic encephalopathy within 6 months prior to starting study drug

15. For EC Subpart in Expansion Part only: carcinosarcoma (malignant mixed Mullerian tumor), endometrial leiomyosarcoma, and endometrial stromal sarcomas

16. Has preexisting >=Grade 3 gastrointestinal or non-gastrointestinal fistula

17. Evidence of current COVID-19 infection or ongoing unrecovered active sequelae of COVID-19 infection

18. Males who have not had a successful vasectomy (confirmed azoospermia) if their female partners meet the exclusion criteria above (that is, the female partners are of childbearing potential and are not willing to use a highly effective contraceptive method throughout the study period and for 90 days after study drug discontinuation). No sperm donation is allowed during the study period and for 90 days after study drug discontinuation

19. Has a known psychiatric or substance abuse disorder that would interfere with the participant ability to cooperate with the requirements of the study

20. Evidence of clinically significant disease (example, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator could affect the participant safety or interfere with the study assessments

21. Scheduled for major surgery during the study

Related Conditions & MeSH terms

• Carcinoma, Hepatocellular
• Colorectal Neoplasms
• Endometrial Neoplasms
• Liver Neoplasms
• Neoplasms

Intervention

Drug:
• E7386
E7386, tablets, orally.
• Lenvatinib
Lenvatinib, capsules, orally.

Locations

Country	Name	City	State
France	CHU Amiens-Picardie (Hopital Sud)	Amiens
France	Hôpital Beaujon	Clichy
France	Centre Georges-François Leclerc	Dijon
France	Grenoble University Hospital (Centre Hospitalier Universitaire Grenoble Alpes)	La Tronche
France	CHU de LILLE - Hôpital HURIEZ	Lille
France	Hepatology, Hopital de la Croix-Rousse - 103 grande rue de la Croix-Rousse	Lyon
France	APHP Hospital Saint-Antoine	Paris
France	Centre Hospitalier Universitaire de Bordeaux (CHU Bordeaux)(Hopitaux de Bordeaux) - Groupe hospitalier Sud - Hopital Haut-Levequ	Pessac
France	Gustave Roussy Institute (IGR)	Villejuif
Japan	Eisai Trial Site #4	Chiba
Japan	Eisai Trial Site #1	Chuo-Ku	Tokyo
Japan	Eisai Trial Site #9	Hidaka	Saitama
Japan	Eisai Trial Site #12	Kamigyo-ku	Kyoto
Japan	Eisai Trial Site #2	Kashiwa	Chiba
Japan	Eisai Trial Site #10	Kawasaki	Kanagawa
Japan	Eisai Trial Site #6	Koto-ku	Tokyo
Japan	Eisai Trial Site #7	Kurume	Fukuoka
Japan	Eisai Trial Site #8	Matsuyama	Ehime
Japan	Eisai Trial Site #5	Nagoya	Aichi
Japan	Eisai Trial Site #3	Osakasayama	Osaka
Japan	Eisai Trial Site #11	Toyoake	Aichi
Korea, Republic of	Eisai Trial Site #5	Jongno-gu	Seoul
Korea, Republic of	Eisai Trial Site #2	Seodaemun	Seoul
Korea, Republic of	Eisai Trial Site #1	Seongnamsi Bundang	Gyeonggi-Do
Korea, Republic of	Eisai Trial Site #3	Seoul
Korea, Republic of	Eisai Trial Site #4	Songpa-gu	Seoul
Taiwan	Chang Gung Medical Foundation - Kaohsiung Branch	Kao-Hsiung
Taiwan	Taichung Veterans General Hospital	Taichung
Taiwan	National Cheng Kung University Hospital	Tainan
Taiwan	National Taiwan University Hospital	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Medical Foundation - Linkou Branch	Taoyuan
United States	University of Colorado Cancer Center - Anschutz Medical Campus	Aurora	Colorado
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Mary Crowley Cancer Research	Dallas	Texas
United States	University of Texas Southwestern Medical	Dallas	Texas
United States	MD Anderson Cancer Center	Houston	Texas
United States	Kansas City Research Institute	Kansas City	Missouri
United States	University of California San Diego (UCSD) - Moores Cancer Center(All)	La Jolla	California
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	Vanderbilt University Medical Center (VUMC) - Vanderbilt-Ingram Cancer Center (VICC) - Nashville	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Perlmutter Cancer Center- NYU Langone Health	New York	New York
United States	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma
United States	Pasadena Liver Center	Pasadena	California
United States	UCLA University of California - Los Angeles	Santa Monica	California
United States	Florida Cancer Specialists - South	Sarasota	Florida
United States	Florida Cancer Specialists - East	West Palm Beach	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Eisai Inc.

Countries where clinical trial is conducted

United States,  France,  Japan,  Korea, Republic of,  Taiwan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Escalation Part: Number of Participants with Dose-limiting Toxicities (DLTs)	DLT will be defined as any of the events that are considered by the investigator to be at least possibly related to therapy with the study medication. Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE 5.0).	Cycle 0 (Cycle 0 length=6 or 7 days) up to Cycle 1 (Cycle 1 length=28 days)
Primary	Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)		Up to 30 days after the last dose of study drug or before initiating post anti-cancer treatment (up to approximately 60 months)
Secondary	Dose Escalation Part: Cmax: Maximum Observed Plasma Concentration for E7386	Here BID is twice daily and QD is once daily.	QD Subpart-Cycle 0 Day 1: 0-24 hours post-dose; Cycle 0 Day 5: 0-48 hours post-dose; Cycle 1 Day 8: 0-24 hours post-dose; BID Subpart-Cycle 0 Day 1 Day 5: 0-12 hours post-dose; Cycle 1 Day 8: 0-12 hours post-dose (Cycle 0=6 or 7 days, Cycle 1=28 days)
Secondary	Dose Escalation Part: Cmax: Maximum Observed Plasma Concentration for Lenvatinib		Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)
Secondary	Dose Escalation Part: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for E7386		QD Subpart-Cycle 0 Day 1: 0-24 hours post-dose; Cycle 0 Day 5: 0-48 hours post-dose; Cycle 1 Day 8: 0-24 hours post-dose; BID Subpart-Cycle 0 Day 1 Day 5: 0-12 hours post-dose; Cycle 1 Day 8: 0-12 hours post-dose (Cycle 0=6 or 7 days, Cycle 1=28 days)
Secondary	Dose Escalation Part: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib		Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)
Secondary	Dose Escalation Part: AUC: Area Under the Plasma Concentration Versus Time Curve for E7386		QD Subpart-Cycle 0 Day 1: 0-24 hours post-dose; Cycle 0 Day 5: 0-48 hours post-dose; Cycle 1 Day 8: 0-24 hours post-dose; BID Subpart-Cycle 0 Day 1 Day 5: 0-12 hours post-dose; Cycle 1 Day 8: 0-12 hours post-dose (Cycle 0=6 or 7 days, Cycle 1=28 days)
Secondary	Dose Escalation Part: AUC: Area Under the Plasma Concentration Versus Time Curve for Lenvatinib		Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)
Secondary	Dose Escalation Part: CL/F: Apparent Total Body Clearance for E7386		QD Subpart-Cycle 0 Day 1: 0-24 hours post-dose; Cycle 0 Day 5: 0-48 hours post-dose; Cycle 1 Day 8: 0-24 hours post-dose; BID Subpart-Cycle 0 Day 1 Day 5: 0-12 hours post-dose; Cycle 1 Day 8: 0-12 hours post-dose (Cycle 0=6 or 7 days, Cycle 1=28 days)
Secondary	Dose Escalation Part: CL/F: Apparent Total Body Clearance for Lenvatinib		Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)
Secondary	Dose Escalation Part: Vz/F: Apparent Volume of Distribution for E7386		QD Subpart-Cycle 0 Day 1: 0-24 hours post-dose; Cycle 0 Day 5: 0-48 hours post-dose; Cycle 1 Day 8: 0-24 hours post-dose; BID Subpart-Cycle 0 Day 1 Day 5: 0-12 hours post-dose; Cycle 1 Day 8: 0-12 hours post-dose (Cycle 0=6 or 7 days, Cycle 1=28 days)
Secondary	Dose Escalation Part: Vz/F: Apparent Volume of Distribution for Lenvatinib		Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)
Secondary	Percentage of Participants with Best Overall Response (BOR)	BOR is defined as confirmed complete response (CR), confirmed partial response (PR), stable disease (SD), PD, and not evaluable (NE), where SD has to be achieved at greater than or equal to (>=) 7 weeks after the first dose. The BOR will be assessed by investigator based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC subparts in dose escalation part and based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for ST subparts in dose escalation part, and for HCC subpart, CRC subpart, EC subpart in dose expansion part.	From first dose of study drug until progression of disease (PD), development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 60 months)
Secondary	Objective Response Rate (ORR)	The ORR is defined as the percentage of participants with a BOR of CR or PR. The ORR will be assessed by investigator based on mRECIST for HCC subparts in dose escalation part and based on RECIST version 1.1 for ST-subparts in dose escalation part, and for HCC subpart, CRC subpart, EC subpart in dose expansion part.	From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 60 months)
Secondary	Disease Control Rate (DCR)	DCR is defined as the percentage of participants with a BOR of CR, PR, or SD after >=7 weeks from the first dose. The DCR will be assessed by investigator based on mRECIST for HCC subparts in dose escalation part and based on RECIST version 1.1 for ST-subparts in dose escalation part, and for HCC subpart, CRC subpart, EC subpart in dose expansion part.	From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 60 months)
Secondary	Clinical Benefit Rate (CBR)	The CBR is defined as the percentage of participants with a BOR of CR, PR, or durable SD (duration of SD >=23 weeks). The CBR will be assessed by investigator based on mRECIST for HCC subparts in dose escalation part and based on RECIST version 1.1 for ST-subparts in dose escalation part, and for HCC subpart, CRC subpart, EC subpart in dose expansion part.	From first dose of study drug until PD, development of unacceptable toxicity, participant requests to discontinue, withdrawal of consent or study termination (up to approximately 60 months)
Secondary	Progression-free Survival (PFS)	PFS is defined as the time from the date of the first dose to the date of the first documentation of confirmed PD or death, whichever occurs first.	From first dose of study drug until PD, or death from any cause, whichever occurs first (up to approximately 60 months)
Secondary	Overall Survival (OS)	OS is defined as the time from the first dose of study drug to death due to any cause. OS will be calculated for all subparts in dose expansion part and HCC subparts in dose escalation part only.	From first dose of study drug until death from any cause (up to approximately 60 months)
Secondary	Duration of Response (DOR)	DOR is defined as the time from the first documentation of PR or CR to the first documentation of disease progression or death due to any cause (whichever occurs first).	From first dose of study drug until PD, or death from any cause, whichever occurs first (up to approximately 60 months)