A Study of FF-10850 Topotecan Liposome Injection in Advanced Solid Tumors

Study Overview
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Brief Summary
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To determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and recommended Phase 2 dose (RP2D) of FF-10850 (topotecan liposome injection) in patients with advanced solid tumors.

Detailed Description
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Dose-escalation Phase: Approximately 48 patients are planned for the dose-escalation phase, with at least 6 patients treated at the RP2D. Cohort Expansion Phase: Four additional cohorts of 12 patients each are planned. Cohort E1: advanced ovarian cancer; Cohort E2: advanced cervical cancer, Cohort E3: advanced sarcomas, Cohort E4: advanced neuroendocrine tumors including small cell lung cancer; and Cohort E5 Merkel cell carcinoma. Each cohort will be treated at the RP2D. In each cohort, FF-10850 will be administered intravenously (IV) until progression of disease, observation of unacceptable AEs, or, after discussion between the Investigator and the Medical Monitor, changes in the patient's condition that prevent further study participation. A sufficient number of cohorts will be enrolled to identify the RP2D. There will be 3 initial dose levels in this study. FF-10850 will be diluted and infused over 60 minutes. Approximately 96 patients are planned for the entire trial. It is anticipated that approximately 4 centers will participate in the dose-escalation phase, with an expansion to approximately 10 centers in the cohort expansion phase. Accrual for the dose-escalation and expansion phases is expected to be approximately 3 years, with patients followed every 3 months from the last dose of study treatment to assess survival.

Official Title
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A Phase 1 Study of FF-10850 Topotecan Liposome Injection in Advanced Solid Tumors Including Ovarian and Cervical Carcinoma, Sarcomas, and Neuroendocrine Tumors Including Small Cell Lung Cancer and Merkel Cell Carcinoma

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: FF-10850 Topotecan Liposome Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all the following criteria to participate in the study: Males and females ≥ 18 years of age Dose-escalation phase: Histologically or cytologically confirmed metastatic and/or unresectable solid tumor, relapsed or refractory to standard therapy, or for which no standard therapy is available that is expected to improve survival by at least 3 months At least 3 weeks beyond the last chemotherapy (or 3 half-lives, whichever is shorter), radiotherapy, major surgery, or experimental treatment, and recovered from all acute toxicities (≤ Grade 1), prior to the first dose of FF-10850 Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 1 Life expectancy of ≥ 3 months Adequate hematologic parameters without ongoing transfusion support: Hemoglobin (Hb) ≥ 9 g/dL Absolute neutrophil count (ANC) ≥ 1.0 × 109 cells/L Platelets ≥ 100 × 109 cells/L Creatinine ≤ 1.5 × ULN, or calculated creatinine clearance ≥ 50 mL/minute by either the Cockcroft-Gault formula or as measured by a 24-hour urine collection Total bilirubin ≤ 2 × ULN unless due to Gilbert's disease; patients with Gilbert's disease who have a total bilirubin > 6 mg/dL are to be excluded ALT and AST ≤ 2.5 times ULN, or < 5 × ULN for patients with liver metastases QT interval corrected for rate (QT interval corrected for rate using Fridericia's Correction Formula, QTcF) ≤ 470 msec for women and ≤ 450 msec for men on the ECG obtained at Screening and confirmed pre-treatment on Cycle 1 Day 1. Patient must be willing to undergo a tumor biopsy, if the patient has a biopsy-accessible tumor Exclusion Criteria: Patients who have not received standard/approved therapies expected to improve survival by at least 3 months History of severe hypersensitivity reactions to topotecan Serious cardiac condition within the last 6 months, such as uncontrolled arrhythmia, myocardial infarction, unstable angina or heart disease defined by the New York Heart Association (NYHA) Class III or Class IV or hereditary long QT syndrome Concomitant medication(s) that may cause QTc prolongation or induce Torsades de Pointes, except for antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered by the Investigator to be essential for patient care Active central nervous system (CNS) malignant disease in patients with a history of CNS malignancy. Patients with previously treated stable brain metastases are allowed if they have been stable off steroid therapy for at least 4 weeks. Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV) Active infection requiring intravenous (IV) antibiotic usage within the last week prior to study treatment Any other medical intervention or other condition which, in the opinion of the Principal Investigator, could compromise adherence to study requirements or confound the interpretation of study results Pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 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: Sequential Assignment
Interventional Model Description: Open label, dose escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Treatment at Dose Level 1<br>FF-10850 Topotecan Liposome Injection, Dose Level 1 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle | Drug: FF-10850 Topotecan Liposome Injection<br>* FF-10850 to be diluted and infused over 60 minutes.<br>* Other names: FF-10850;|
| Experimental: Cohort 2: Treatment at Dose Level 2<br>FF-10850 Topotecan Liposome Injection, Dose Level 2 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle | Drug: FF-10850 Topotecan Liposome Injection<br>* FF-10850 to be diluted and infused over 60 minutes.<br>* Other names: FF-10850;|
| Experimental: Cohort 3: Treatment at Dose Level 3<br>FF-10850 Topotecan Liposome Injection, Dose Level 3 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle | Drug: FF-10850 Topotecan Liposome Injection<br>* FF-10850 to be diluted and infused over 60 minutes.<br>* Other names: FF-10850;|
| Experimental: Cohort E1: Treatment at Recommended Phase 2 Dose (RP2D)<br>For patients with advanced ovarian cancer: FF-10850 Topotecan Liposome Injection, RP2D administered intravenously (IV) on Days 1 and 15 of each 28-day cycle | Drug: FF-10850 Topotecan Liposome Injection<br>* FF-10850 to be diluted and infused over 60 minutes.<br>* Other names: FF-10850;|
| Experimental: Cohort E5: Treatment at Recommended Phase 2 Dose (RP2D)<br>For patients with advanced Merkel cell carcinoma: FF-10850 Topotecan Liposome Injection, RP2D administered intravenously (IV) on Days 1 and 15 of each 28-day cycle | Drug: FF-10850 Topotecan Liposome Injection<br>* FF-10850 to be diluted and infused over 60 minutes.<br>* Other names: FF-10850;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine incidence of Treatment Emergent Adverse Events | Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs) | 4 years | 
| Identify dose-limiting toxicities (DLT) of FF-10850 | DLT is defined as any adverse event at least possibly related to FF-10850, and meeting specified DLT criteria | 4 years | 
| Determine maximun tolerated dose (MTD) of FF-10850 | MTD is defined as the next lower dose of a cohort where patients experienced a DLT | 4 years | 
| Determine recommended Phase 2 dose (RP2D) FF-10850 | The highest dose level below the dose level eliciting DLT in ≥ 2 patients will be declared the MTD. The RP2D will be chosen based on the MTD or on PK and biological activity if an MTD has not been determined. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: Cmax | Measurement of maximum plasma concentration | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: tmax | Measurement of time to reach Cmax | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: t1/2 | Measurement of the elimination half-life | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: AUC | Measurement of the area under the curve of plasma concentration versus time profile | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: MRT | Measurement of the mean residence time adjusted for duration of infusion | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: CL | Measurement of the total plasma clearance | 4 years | 
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: Vss | Measurement of the steady-state volume of distribution for total topotecan | 4 years | 
| Determine objective response rate (ORR) | classified for solid tumors via RECIST v.1.1 | 4 years | 
| Determine the duration of response (DOR) | Duration of Response is calculated from the date of first response to the date of progression or death. | 4 years | 
| Determine the time to progression (TTP) | Time to progression is calculated from the date of first treatment to the date of first progression | 4 years | 
| Evaluate progression-free survival (PFS) | Progression-free survival will be calculated from the date of first treatment to the date of progression or death | 4 years | 
| Evaluate overall survival (OS) (expansion cohorts only) | Overall survival will be calculated from the date of first treatment to the date of death from any cause; patients who do not experience death will be censored at the last follow-up time. | 4 years |