Advanced Solid Tumors, Merkel Cell Carcinoma
Conditions
Brief summary
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 including Merkel Cell Carcinoma
Detailed description
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: Two additional cohorts are planned. Cohort E1: advanced ovarian 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.
Interventions
DRUGFF-10850 Topotecan Liposome Injection
FF-10850 to be diluted and infused over 60 minutes.
Sponsors
Fujifilm Pharmaceuticals U.S.A., Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None, open label
Intervention model description
Open label, dose escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all the following criteria to participate in the study: 1. Males and females ≥ 18 years of age 2. 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 3. 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 4. Adequate performance status: Eastern Cooperative Oncology Group (ECOG) ≤ 1 5. Life expectancy of ≥ 3 months 6. 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 7. 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 8. 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 9. ALT and AST ≤ 2.5 times ULN, or \< 5 × ULN for patients with liver metastases 10. 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. 11. Patient must be willing to undergo a tumor biopsy, if the patient has a biopsy-accessible tumor
Exclusion criteria
1. Patients who have not received standard/approved therapies expected to improve survival by at least 3 months 2. History of severe hypersensitivity reactions to topotecan 3. 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 4. 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 5. 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. 6. Known positive for human immunodeficiency virus (HIV), hepatitis B virus surface antigen (HBsAg) or hepatitis C virus (HCV) 7. Active infection requiring intravenous (IV) antibiotic usage within the last week prior to study treatment 8. 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 9. Pregnant or breast-feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Determine incidence of Treatment Emergent Adverse Events | 4 years | Safety and tolerability assessed by adverse events (AEs) and serious adverse events (SAEs) |
| Identify dose-limiting toxicities (DLT) of FF-10850 | 4 years | DLT is defined as any adverse event at least possibly related to FF-10850, and meeting specified DLT criteria |
| Determine maximun tolerated dose (MTD) of FF-10850 | 4 years | MTD is defined as the next lower dose of a cohort where patients experienced a DLT |
| Determine recommended Phase 2 dose (RP2D) FF-10850 | 4 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: Cmax | 4 years | Measurement of maximum plasma concentration |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: tmax | 4 years | Measurement of time to reach Cmax |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: t1/2 | 4 years | Measurement of the elimination half-life |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: AUC | 4 years | Measurement of the area under the curve of plasma concentration versus time profile |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: MRT | 4 years | Measurement of the mean residence time adjusted for duration of infusion |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: CL | 4 years | Measurement of the total plasma clearance |
| Characterize the pharmacokinetics (PK) of FF-10850 in plasma: Vss | 4 years | Measurement of the steady-state volume of distribution for total topotecan |
| Determine objective response rate (ORR) | 4 years | classified for solid tumors via RECIST v.1.1 |
| Determine the duration of response (DOR) | 4 years | Duration of Response is calculated from the date of first response to the date of progression or death. |
| Determine the time to progression (TTP) | 4 years | Time to progression is calculated from the date of first treatment to the date of first progression |
| Evaluate progression-free survival (PFS) | 4 years | Progression-free survival will be calculated from the date of first treatment to the date of progression or death |
| Evaluate overall survival (OS) (expansion cohorts only) | 4 years | 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. |
Countries
United States
Outcome results
None listed