Topotecan Liposomes Injection for Small Cell Lung Cancer (SCLC), Ovarian Cancer and Other Advanced Solid Tumors

The study will utilize an accelerated design with small initial cohort sizes that allow fewer
subjects to be enrolled at sub-therapeutic doses such as the very low starting doses in both
arms of the study. Initial cohorts will include only one subject and dose escalations will be
in 100% increments until a single Grade 2 toxicity related to study drug or DLT occurs in
Cycle 1. Dose escalation will proceed until the MTD is exceeded. MTD is defined as average of
the highest dose level for which 2 out of 6 subjects experience a DLT and the previous dose
level, provided no additional DLTs occur. Subjects who discontinue TLI treatment before
completion of Cycle 1 for reasons other than toxicity will not be evaluable for the
determination of MTD and will be replaced.

The study will consist of a screening period, treatment period, and a post-treatment period.
Subjects will be followed for 30 days after their last TLI dose. Safety and tolerability
parameters include clinical laboratory assessments, vital signs, physical examinations, and
adverse events (AEs).

Inclusion Criteria:

1. Age ≥ 18 years

2. Histologically or cytologically confirmed advanced solid tumor that has relapsed, is
refractory to standard treatment, or for whom there is no standard therapy available.

3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

4. Normal organ and marrow function as defined below within 14 days of study entry

1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

2. Platelet count ≥100 x 109/L

3. Hemoglobin ≥ 9 g/dL

4. Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper
limit of normal (ULN), or 5 x ULN for subjects with liver metastases

6. Serum creatinine ≤ 1.5 x ULN or calculated estimated creatinine clearance ≥ 50
mL/min/1.73m2 for subjects with creatinine levels above institutional normal
based on the Cockcroft and Gault formula.

5. Never received prior TLI or topotecan HCl (Hycamtin®)

6. At least 4 weeks must have elapsed from the last dose of chemotherapy.

7. Life expectancy ≥ 3 months

8. Women of childbearing potential must have a negative urine or blood pregnancy test
within 7 days prior to initiation of treatment.

9. If female, subject is post-menopausal, surgically sterilized, or willing to use
acceptable methods of birth control (e.g., hormonal contraceptive, intra-uterine
device (IUD), diaphragm with spermicide, condom with spermicide or abstinence) from
the screening visit through the duration of study participation.

10. If male, subject agrees to use an acceptable barrier method for contraception from the
screening visit though the duration of study participation.

11. Before enrollment, the subject is capable of understanding and complying with
parameters as outlined in the protocol and able to sign a written informed consent
according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

1. Use of any investigational drugs, biologics, or devices within 28 days prior to study
treatment or planned use during the course of the study.

2. Primary tumors of central nervous system (CNS). Symptomatic brain metastases (unless
subject is stable without requirement of steroids and/or antiseizure medications for
at least three months) or leptomeningeal tumor involvement. Imaging studies are not
required to rule this out unless there is a clinical suspicion of CNS disease.

3. Prior chemotherapy or radiotherapy within 4 weeks of Day 1 of study (6 weeks for
nitrosureas or mitomycin C).

4. Planned concurrent systemic therapy (cytotoxic and/or cytostatic) and/or radiotherapy
during study treatment.

5. Less than 4 weeks have elapsed from the time of major surgery.

6. Subjects with a history of allergic reactions or sensitivity attributed to compounds
of similar chemical or biologic composition to TLI, including known allergies to the
ingredients comprising the liposome (e.g., cholesterol and/or sphingomyelin), which in
the Investigator's opinion may put the subject at risk for significant reaction to the
study drug.

7. Subjects who are pregnant or lactating.

8. Subjects known to be positive for human immunodeficiency virus (HIV), hepatitis C
antibody, or hepatitis B surface antigen.

9. Prophylactic hematologic growth factors administered ≤ 2 weeks prior to start of
treatment with TLI (excluding darbepoetin alfa and epoetin alfa).

10. Active infection or any serious underlying medical condition, which would impair the
ability of the subject to receive protocol treatment.