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

Sponsor

Eisai Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04008797

Collaborator

(none)

181

Enrollment

Locations

Arms

59.7

Anticipated Duration (Months)

45.3

Patients Per Site

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief 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).

Condition or Disease	Intervention/Treatment	Phase
Neoplasms Carcinoma, Hepatocellular Liver Neoplasms Colorectal Neoplasms Endometrial Neoplasms	Drug: E7386 Drug: Lenvatinib	Phase 1

Study Design

Study Type:

Interventional

Anticipated Enrollment :

181 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label Phase 1b Study of E7386 in Combination With Other Anticancer Drug in Subjects With Solid Tumor

Actual Study Start Date :

Jul 11, 2019

Anticipated Primary Completion Date :

Jun 30, 2024

Anticipated Study Completion Date :

Jun 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation Part: HCC: E7386 QD Subpart + Lenvatinib Participants with hepatocellular carcinoma (HCC) will receive E7386 tablets, orally, QD for 5 or 6 consecutive days followed by 48 hours of without treatment in Cycle 0 (6 or 7 days). Participants with HCC will receive E7386 tablets, orally, QD in combination with lenvatinib 8 mg (participants with body weight of less than [<] 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. Dose escalation of E7386 will be based on the available safety data from the previous cohorts.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Escalation Part: HCC: E7386 BID Subpart + Lenvatinib Participants with HCC will receive E7386 tablets, orally, BID for 5 or 6 consecutive days in Cycle 0 (6 or 7 days). Participants with HCC will receive E7386 tablets, orally, 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. Dose escalation of E7386 will be based on the available safety data from the previous cohorts.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Escalation Part: Other ST: E7386 QD Subpart + Lenvatinib Participants with solid tumor (ST) (except for HCC) will receive E7386 tablets, alone orally, QD for 5 or 6 consecutive days followed by 48 hours of without treatment in Cycle 0 (6 or 7 days). Participants with ST (except for HCC) will receive E7386 tablets, orally, 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. Dose escalation of E7386 will be based on the available safety data from the previous cohorts.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Escalation Part: Other ST: E7386 BID Subpart + Lenvatinib Participants with ST (except for HCC) will receive E7386 tablets, alone orally, BID for 5 or 6 consecutive days in Cycle 0 (6 or 7 days). Participants with ST (except for HCC) will receive E7386 tablets, orally, 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. Dose escalation of E7386 will be based on the available safety data from the previous cohorts.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Expansion Part: HCC Subpart: Lenvatinib Only 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.	Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Expansion Part: HCC Subpart: E7386 + Lenvatinib 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 tablets, orally, 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. E7386 dose will be determined from recommended dose level of the HCC BID Subpart in Dose Escalation Part.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Expansion Part: CRC Subpart: E7386 + Lenvatinib Participants with colorectal cancer (CRC) will receive E7386 tablets, orally, 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. E7386 dose will be determined from recommended dose level of the ST BID Subpart in Dose Escalation Part.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima
Experimental: Dose Expansion Part: EC Subpart: E7386 + Lenvatinib Participants with endometrial cancer (EC) will receive E7386 tablets, orally, 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. E7386 dose will be determined from recommended dose level of the ST BID Subpart in Dose Escalation Part.	Drug: E7386 E7386, tablets, orally. Drug: Lenvatinib Lenvatinib, capsules, orally. Other Names: Lenvima

Outcome Measures

Primary Outcome Measures

Dose Escalation Part: Number of Participants with Dose-limiting Toxicities (DLTs) [Cycle 0 (Cycle 0 length=6 or 7 days) up to Cycle 1 (Cycle 1 length=28 days)]
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).
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 Outcome Measures

Dose Escalation Part: Cmax: Maximum Observed Plasma Concentration 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)]
Here BID is twice daily and QD is once daily.
Dose Escalation Part: Cmax: Maximum Observed Plasma Concentration for Lenvatinib [QD and BID Subparts: Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)]
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)]
Dose Escalation Part: Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Lenvatinib [QD and BID Subparts: Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)]
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)]
Dose Escalation Part: AUC: Area Under the Plasma Concentration Versus Time Curve for Lenvatinib [QD and BID Subparts: Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)]
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)]
Dose Escalation Part: CL/F: Apparent Total Body Clearance for Lenvatinib [QD and BID Subparts: Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)]
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)]
Dose Escalation Part: Vz/F: Apparent Volume of Distribution for Lenvatinib [QD and BID Subparts: Cycle 1 Day 8: 0-24 hours post-dose (Cycle 1 length=28 days)]
Percentage of Participants with Best Overall Response (BOR) [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)]
BOR is defined as complete response (CR), 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.
Objective Response Rate (ORR) [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)]
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.
Disease Control Rate (DCR) [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)]
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.
Clinical Benefit Rate (CBR) [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)]
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.
Progression-free Survival (PFS) [From first dose of study drug until PD, or death from any cause, whichever occurs first (up to approximately 60 months)]
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.
Overall Survival (OS) [From first dose of study drug until death from any cause (up to approximately 60 months)]
OS is defined as the time from the first dose of study drug to death due to any cause.
Duration of Response (DOR) [From first dose of study drug until PD, or death from any cause, whichever occurs first (up to approximately 60 months)]
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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HCC part only:

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

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

Life expectancy of >=12 weeks
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1
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)
Adequate washout period before study drug administration:
Chemotherapy and radiotherapy: 3 weeks or 5 times the half-life, whichever is shorter
Any antitumor therapy with antibody: 4 weeks or more
Any investigational drug or device: 4 weeks or more
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
Adequate controlled blood pressure (BP), renal function, bone marrow function, liver function, and serum mineral level
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

For HCC participants only: Child-Pugh score A
For HCC participants only: Participants categorized to stage B (not applicable for trans arterial chemoembolization), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system
For HCC Subpart in Expansion Part only: prior systemic therapy for locally advanced or metastatic disease is as defined below

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

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 adjuvant and/or 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

Fluoropyrimidine, irinotecan and oxaliplatin 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
Chemotherapy with or without an anti-vascular endothelial growth factor receptor (VEGF) monoclonal antibodies (mAb) (example, bevacizumab)
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
BRAF inhibitor (in combination with cetuximab ± binimetinib) for BRAF V600E mutated tumors
Immune checkpoint inhibitor for participants with microsatellite instability-high (MSI-H) CRC
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/or 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:

Any of cardiac conditions as follows:
Heart failure New York Heart Association (NYHA) Class II or above
Unstable ischaemic heart disease (myocardial infarction within 6 months prior to starting study drug, or angina requiring use of nitrates more than once weekly)
Prolongation of QT interval with Fridericias correction (QTcF) to greater than (>) 480 millisecond (msec)
Left ventricular ejection fraction (LVEF) less than 50 percent (%)
Major surgery within 21 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

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
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
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

Diagnosed with meningeal carcinomatosis
Participants with brain or subdural metastases are not eligible, unless they have completed local therapy and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (example, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment
Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen
Any of bone disease/conditions as follows:

Osteoporosis with T-score of < minus (-) 2.5 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
Fasting beta-CTX (serum) >1000 picogram per milliliter (pg/mL) (that is, 1000 nanogram per liter [ng/L])
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 treated by bisphosphonate or denosumab (except for lesion treated by radiation)
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

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 only
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
For EC Subpart in Expansion Part only: carcinosarcoma (malignant mixed Mullerian tumor), endometrial leiomyosarcoma, and endometrial stromal sarcomas
Has preexisting >=Grade 3 gastrointestinal or non-gastrointestinal fistula
Evidence of current COVID-19 infection or ongoing unrecovered active sequelae of COVID-19 infection
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 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation
Has a known psychiatric or substance abuse disorder that would interfere with the participant ability to cooperate with the requirements of the study
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
Scheduled for major surgery during the study