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

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: 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.

Objective
Primary:
-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

Secondary:
-Characterize the pharmacokinetics (PK) of topotecan in plasma and urine following FF-10850 administration
-Determine objective response rate (ORR)
-Determine the duration of response (DOR) and time to progression (TTP)
-Evaluate progression-free survival (PFS)
-Evaluate overall survival (OS) (expansion cohorts only)
-Evaluate the effect of FF-10850 on peripheral blood CA19-9, CA-125, PSA, any other clinically relevant tumor marker as markers for clinical activity

Treatment Experimental: Cohort 1: Treatment at Dose Level 1
FF-10850 Topotecan Liposome Injection, Dose Level 1 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle
Experimental: Cohort 2: Treatment at Dose Level 2
FF-10850 Topotecan Liposome Injection, Dose Level 2 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle
Experimental: Cohort 3: Treatment at Dose Level 3
FF-10850 Topotecan Liposome Injection, Dose Level 3 administered intravenously (IV) on Days 1 and 15 of each 28-day cycle
Experimental: Cohort E1: Treatment at Recommended Phase 2 Dose (RP2D)
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
Experimental: Cohort E5: Treatment at Recommended Phase 2 Dose (RP2D)
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

Key Eligibility 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 (
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 /= 50 mL/minute by either the Cockcroft-Gault formula or as measured by a 24-hour urine collection

Total bilirubin 6 mg/dL are to be excluded

ALT and AST
QT interval corrected for rate (QT interval corrected for rate using Fridericia's Correction Formula, QTcF)
Patient must be willing to undergo a tumor biopsy, if the patient has a biopsy-accessible tumor

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

Applicable Disease Sites
Melanoma/Skin cancer

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital