A Study of E7090 as Monotherapy and in Combination With Other Anticancer Agents in Participants With Estrogen Receptor Positive (ER+) and Human Epidermal Growth Receptor 2 Negative (HER2-) Recurrent/Metastatic Breast Cancer

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the tolerability and safety of E7090 as monotherapy and in combination with other anticancer agents in participants with ER+, HER2- recurrent/metastatic breast cancer and to determine the recommended dose (RD) of E7090 in combination with other anticancer agents for subsequent phase studies.

Official Title
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An Open-label Phase 1b Study of E7090 Monotherapy and in Combination With Other Anticancer Agents in Subjects With ER+, HER2- Recurrent/Metastatic Breast Cancer

Conditions
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Breast Neoplasms

Intervention / Treatment
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* Drug: E7090
* Drug: Fulvestrant
* Drug: Exemestane


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent. Female participants who are age >=18 years at the time of informed consent. Post-menopausal or pre/peri-menopausal concurrently given a luteinizing hormone-releasing hormone (LHRH) agonist before the start of trial therapy and is planned to continue LHRH agonist during the study. Participants with pathologically confirmed diagnosis of recurrent/metastatic, ER+, HER2 negative breast cancer. Participants who received prior CDK4/6 inhibitor treatment. Participants with Performance Status (PS) score of 0-1 established by Eastern Cooperative Oncology Group (ECOG). Part 1 and Part 2: Participants with at least one accessible lesion prior to study treatment (if archived tissues collected after CDK4/6 inhibitor treatment is not available) and on Cycle 3 Day 1. Part 3 participants must agree to undergo a biopsy at screening if no archival tissue is available (tissue collection must be after CDK4/6 inhibitor treatment and prior to study treatment). Collection of fresh tumor tissue on Cycle 3 Day 1 is not mandatory. Participants who agree to provide archival or fresh tumor tissue collected after CDK4/6 inhibitor treatment. Part 2 only: Participants with fibroblast growth factor receptor (FGFR) positive tumor collected after CDK4/6 inhibitor treatment at the central laboratory. Exclusion criteria: Participants with brain or subdural metastases, 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. Participant who have received more than 1 regimen of chemotherapy in the metastatic setting. For Part 3, participant who have received chemotherapy or antibody-drug conjugate therapy in the metastatic setting. Participant with inflammatory breast cancer. Participant with bilateral breast cancer of different histologic types. Participants who have bilateral breast cancers that are both ER+ and HER2- may be enrolled in the study. Participant who have history of active malignancy within the past 24 months prior to the first dose of study drugs. Participants with clinically significant cardiovascular impairment. Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors. Concomitant active infection requiring systemic treatment. Participants who test positive for human immunodeficiency virus (HIV antibody), or positive for hepatitis B surface (HBs antigen) or hepatitis C (HCV antibody and RNA). Participants with following ocular disorders: a. Current evidence of Grade 2 or higher corneal disorder. Current evidence of active retinopathy (example. age-related macular degeneration, central serous chorioretinal disease, retinal tear) Participants who received prior treatment with an FGFR inhibitor. Females who are pregnant or breastfeeding. Part 1 only: Participants with T-score less than (<) -2.5 by dual-energy X-ray absorptiometry (DXA) scan. Part 3 only: Participants who received more than 2 prior lines of endocrine therapy in advanced/metastatic setting.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Part 1 Dose Escalation: E7090 + Fulvestrant or Exemestane<br>Participants will receive E7090 tablets, orally, once daily along with fulvestrant 500 milligram (mg), intramuscular injection on Days 1 and 15 of Cycle 1 and each Day 1 of cycle 2 or later, or along with exemestane 25 mg tablet, orally, once daily in 28 days cycle. Each cycle length equals to (=) 28 days. | Drug: E7090<br>* E7090 oral tablet.<br>Drug: Fulvestrant<br>* Fulvestrant intramuscular injection.<br>Drug: Exemestane<br>* Exemestane oral tablet.<br>|
| Experimental: Part 2 Monotherapy: E7090<br>Participants will receive E7090 tablets, orally, once daily in 28 days cycle. Each cycle length =28 days. | Drug: E7090<br>* E7090 oral tablet.<br>|
| Experimental: Part 3 Dose Expansion: E7090 + Fulvestrant<br>Participants will receive E7090 tablets, orally, once daily along with fulvestrant 500 mg, intramuscular injection on Days 1 and 15 of Cycle 1 and each Day 1 of cycle 2 or later. Each cycle length =28 days. The dose of E7090 for Part 3 in combination with fulvestrant will be determined based on the safety, tolerability, pharmacokinetic (PK), and biomarker data obtained from Part 1. | Drug: E7090<br>* E7090 oral tablet.<br>Drug: Fulvestrant<br>* Fulvestrant intramuscular injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Recommended Dose (RD) of E7090 in Combination With Other Anticancer Agents |  | Up to Cycle 1 (each cycle length = 28 days) | 
| Part 1: Number of Participants With Dose-limiting Toxicities (DLTs) | DLTs will be assessed based on combination regimen-related adverse events (AEs) occurred during Cycle 1 of Part 1 and the severity of AEs will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0. | Up to Cycle 1 (each cycle length = 28 days) | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Safety assessments will consist of monitoring and recording all AEs and SAEs; regular measurement of vital signs and ECG; and regular monitoring of clinical laboratory parameters, body weight and bone density. | Up to 30 days after last administration of study drug (approximately up to 41 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration of E7090, its Metabolite (M2) and Exemestane |  | For E7090 and its metabolite (M2)- Parts 1 and 2 Cycle 1 Day 1: 0-24 hours post-dose; For exemestane- Part 1 Cycle 1 Day 1: 0-24 hours post-dose (each cycle length = 28 days) | 
| AUC: Area Under the Plasma Concentration-time Curve of E7090, its Metabolite (M2) and Exemestane |  | For E7090 and its metabolite (M2)- Parts 1 and 2 Cycle 1 Day 1: 0-24 hours post-dose; For exemestane- Part 1 Cycle 1 Day 1: 0-24 hours post-dose (each cycle length = 28 days) | 
| Part 1: Plasma Concentration of Fulvestrant |  | Cycles 2 and 3 Day 1: pre-dose (each cycle length = 28 days) | 
| Objective Response Rate (ORR) | The ORR will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR is defined as a percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR). CR: disappearance of all lesions. PR: For PR, longest diameter will be used for non-lymph target lesions but short axis is measured for lymph lesions. PR: greater than or equal to (>=) 30 percent (%) decrease in sum of diameters of target lesions taking as reference baseline, associated to non-progressive disease (non-PD) response for non-target (NT) lesions. | Baseline up to 51 months | 
| Disease Control Rate (DCR) | DCR will be assessed according to RECIST version 1.1. DCR is defined as a percentage of participants with BOR of CR, PR or stable disease (SD). The BOR of SD has to be observed >=7 weeks from the date of first study dose. CR: disappearance of all lesions. PR: For PR, longest diameter will be used for non-lymph target lesions but short axis is measured for lymph lesions. PR: >=30% decrease in sum of diameters of target lesions taking as reference baseline, associated to non-PD response for NT lesions. | Baseline up to 51 months | 
| Clinical Benefit Response (CBR) | CBR will be assessed according to RECIST version 1.1. CBR is defined as a percentage of participants with BOR of CR, PR or durable SD (dSD) (duration of SD >=23 weeks). CR: disappearance of all lesions. PR: For PR, longest diameter will be used for non-lymph target lesions but short axis is measured for lymph lesions. PR: >=30% decrease in sum of diameters of target lesions taking as reference baseline, associated to non-PD response for NT lesions. | Baseline up to 51 months | 
| Progression-free Survival (PFS) | PFS will be assessed according to RECIST version 1.1. PFS is defined as the time from the date of first dose to the date of first documentation of disease progression or date of death from any cause, whichever occurs first. | Baseline up to 51 months | 
| Overall Survival (OS) | OS is defined as the time from the date of first dose to the date of death from any cause. | Baseline up to 51 months | 
| Time to Response (TTR) | TTR will be assessed according to RECIST version 1.1. TTR is defined as the time from the date of first study dose to the date of first documentation of CR or PR. CR: disappearance of all lesions. PR: For PR, longest diameter will be used for non-lymph target lesions but short axis is measured for lymph lesions. PR: >=30% decrease in sum of diameters of target lesions taking as reference baseline, associated to non-PD response for NT lesions. | Baseline up to 51 months | 
| Duration of Response (DOR) | DOR will be assessed according to RECIST version 1.1. DOR is defined as the time from the date of first documentation of CR or PR to the date of first documentation of disease progression or date of death from any cause, whichever occurs first. CR: disappearance of all lesions. PR: For PR, longest diameter will be used for non-lymph target lesions but short axis is measured for lymph lesions. PR: >=30% decrease in sum of diameters of target lesions taking as reference baseline, associated to non-PD response for NT lesions. | Baseline up to 51 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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E7090, Fulvestrant, Exemestane, Receptors, Fibroblast Growth Factor