Study of E7389 Liposomal Formulation in Participants With Solid Tumor

Study Overview
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Brief Summary
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The maximum tolerated dose (MTD) of E7389 liposomal formulation (E7389-LF) will be determined in the dose escalation part. Safety, pharmacokinetics (PK) and efficacy will be assessed using treatment regimen evaluated in dose escalation part in participants with breast cancer (up to 3 prior regimens of chemotherapy) in the expansion part 1 and in participants with adenoid cystic carcinoma (ACC), gastric cancer (GC), esophageal cancer (EGC), small cell lung cancer (SCLC) and breast cancer (with no prior regimens of chemotherapy) in the expansion part 2, 3, 4, 5 and 6 respectively.

Official Title
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An Open-label Phase 1 Study of E7389 Liposomal Formulation in Subjects With Solid Tumor

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: E7389-LF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with advanced, nonresectable, or recurrent solid tumor for which no alternative standard therapy or no effective therapy exists Expansion-part 1 only: breast cancer with confirmed diagnosis, human epidermal growth factor (HER2) negative (immunohistochemistry [IHC] 0/1+, or fluorescence in situ hybridization [FISH] negative), prior chemotherapy of anthracycline and taxane (unless contraindicated), and up to 3 prior chemotherapy regimens to advanced or metastatic disease Expansion-part 2 only: nonresectable ACC with confirmed diagnosis and one or more prior chemotherapy regimens (unless contraindicated) Expansion-part 3, 4 and 5 only: nonresectable GC, EGC and SCLC with confirmed diagnosis and 2 or more prior chemotherapy regimens (unless contraindicated) (1 or more prior chemotherapy regimens for EGC participant who received combination therapy of platinum and taxane). Ex-part 6 only: breast cancer with confirmed diagnosis, HER2 negative (IHC 0/1+, or FISH negative), no prior chemotherapy regimens to advanced or metastatic disease. As for triple-negative breast cancer, the subjects diagnosed as PD-L1 negative or subjects who were clinically judged as not eligible for Atezolizumab or other immuno-checkpoint inhibitor-containing regimen by site investigator are eligible. Life expectancy of greater than or equal to (>=) 12 weeks Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) of 0 to 1 Japanese participants aged >=20 years at the time of informed consent All adverse events (AEs) due to previous anti-cancer therapy have either returned to Grade 0 or 1 except for alopecia and Grade 2 peripheral neuropathy Adequate washout period before study drug administration: Chemotherapy, hormonal therapy and radiotherapy: 3 weeks or more Any 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 Adequate renal function defined as serum creatinine less than (<) 2.0 milligrams per deciliter (mg/dL) or creatinine clearance >=40 milliliters per minute (mL/min) per the Cockcroft and Gault formula Adequate bone marrow function: Absolute neutrophil count (ANC) >=2,000/millimeters cubed (mm^3) (>=2.0 × 10^3/microliter [µl]) Platelets >=100,000/mm^3 (>=100 × 10^9/Liter [L]) Hemoglobin >=9.0 grams (g)/dL (Expansion-part only: >=8.5 g/dL) Adequate liver function: Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to (<=) 1.5 Total bilirubin <=1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) <=3 × ULN (<=5.0 times ULN in the participants with liver metastases) Expansion-part only: At least one measurable lesion based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Willing and able to give informed consent and comply with all aspects of the protocol 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 Fridericia's corrected QT (QTcF) interval to greater than (>) 480 milliseconds (msec) History of hypersensitivity reaction by liposomal formulation agent Major surgery within 21 days prior to starting study drug Previous treatment with eribulin Previous radiation therapy encompassing an extensive region including the bone marrow (example, >30% of bone marrow) Known intolerance to the study drug or any of the excipients Known to be human immunodeficiency virus (HIV) positive Active viral hepatitis (B or C) as demonstrated by positive serology or requiring treatment Diagnosed with meningeal carcinomatosis Participants with brain or subdural metastases or invasion 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. Expansion-part only: history of active malignancy (except for primary tumor, or definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, carcinoma in-situ of the bladder or cervix, or early stage gastric/colorectal cancer) within the past 24 months prior to the first dose of study drug Evidence of clinically significant disease/status (example, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or hCG test). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. Males with impregnate potential or females of childbearing potential who or whose partner do not agree with medically effective method of contraception throughout the entire study period and for 28 days (90 days for male) after study drug discontinuation Active and acute infection of oral cavity which requires the dental procedure Ex-part 6 only: Participants who had been confirmed radiological disease progression within 12 months after completion of taxane as neo- and/or adjuvant therapy by investigator Ex-part 6 only: Child-Pugh score B or C

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Schedule 1: E7389-LF<br>Participants will receive E7389-liposomal formulation (LF) at a starting dose of 1.0 to 2.5 milligrams per meters squared (mg/m^2), administered as an intravenous (IV) infusion on Day 1 of a 21-day cycle (tri-weekly). | Drug: E7389-LF<br>* intravenous infusion<br>|
| Experimental: Schedule 2: E7389-LF<br>Participants will receive E7389-LF at a starting dose of 1.0 to 1.5 mg/m^2, administered as an IV infusion on Day 1 and Day 15 of a 28-day cycle (bi-weekly). | Drug: E7389-LF<br>* intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of E7389 liposomal formulation (E7389-LF) | The MTD is defined as the maximum dose with 0 or 1 dose-limiting toxicity (DLT) in 6 participants. DLTs are defined as study drug-related adverse events (AEs) and graded using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 4.03 occurring during Cycle 1 (Schedule 1: 3 weeks; Schedule 2: 4 weeks) of the Dose Escalation part of the study (DE-part). | Cycle 1 (21 days): Schedule 1; Cycle 1 (28 days): Schedule 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with any serious adverse event (SAE) | The number of participants with any SAE will be assessed as a measure of the safety and tolerability of E7389- liposomal formulation (LF). | From date of first dose of study drug up to 30 days after last administration of study drug (approximately up to 6 years) | 
| Number of participants with any adverse event (AE) | The number of participants with any AE will be assessed as a measure of the safety and tolerability of E7389-LF. | From date of first dose of study drug up to 30 days after last administration of study drug (approximately up to 6 years) | 
| Maximum observed concentration (Cmax) of E7389-LF | Blood samples will be collected for pharmacokinetic (PK) analyses. Cmax is the highest concentration of drug in the blood that is measured after a dose. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after start of infusion (inf); 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Time from dosing to the maximum observed concentration (Tmax) of E7389-LF | Blood samples will be collected for PK analyses. Tmax is the time to the highest concentration of drug in the blood that is measured after a dose. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after start of infusion (inf); 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Area under the plasma concentration time course profile (AUC) | Blood samples will be collected for PK analyses. AUC represents the overall amount of drug in the bloodstream after dosing. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after infusion (inf) start; 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; and C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Half-life (t1/2) of E7389-LF | Blood samples will be collected for PK analyses. t1/2 is the time required for the concentration of the drug to reach half of its original value. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after start of infusion (inf); 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Clearance (CL) of E7389-LF | Blood samples will be collected for PK analyses. Clearance is the volume of plasma cleared of the drug per unit time. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after infusion (inf) start; 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; and C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Volume of distribution (Vd) of E7389-LF | Blood samples will be collected for PK analyses. Vd is the volume in which a drug is distributed. DE = Dose Escalation. Exp = Expansion. | DE part: predose; 15 minutes (min) after infusion (inf) start; 5 min after end of inf on Cycle 1 Day 1 (C1D1); 0.5, 1, 2, 4, 6, 8, and 24 hours (hr) postdose (from end of inf on C1D1); C1D4; C1D8; and C1D10. Exp part: predose and end of inf on C1D1; C1D8 | 
| Objective response rate (ORR) | ORR is defined as the percentage of participants who have a best overall response of complete response (CR) or partial response (PR), per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. For target lesions, CR is defined as the disappearance of all target lesions. For non-target lesions, CR is defined as the disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (less than [<] 10 millimeter [mm] short axis). Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to <10 mm. For target lesions, PR is defined as at least a 30 percent (%) decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | From date of first dose of study drug until first documentation of CR or PR (up to approximately 6 years) | 
| Progression free survival (PFS) | PFS is defined as the time from the date of first dose of study drug to the date of the first documentation of disease progression or date of death, whichever occurs first. For target lesions PD is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. For non-target lesions, progressive disease is defined as the unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression. | From the date of first dose of study drug until progressive disease (PD), death, whichever occurs first (up to approximately 6 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E7389 liposomal formulation, dose escalation, maximum tolerated dose, pharmacokinetics