Phase II Etirinotecan Pegol in Refractory Brain Metastases & Advanced Lung Cancer / Metastatic Breast Cancer

Primary Objective:

For cohort A and Cohort C, to determine the CNS disease control rate (number of patients with
stable disease or partial response or complete response / total number of treated patients)
at 12 weeks following treatment with etirinotecan pegol in patients with advanced NSCLC or
with MBC with refractory brain metastases

Secondary Objectives:

Cohorts A and C:

- To measure the overall disease control rate and response rate for patients receiving
study therapy

- To measure the systemic (non CNS) disease control rate and response rate for patients
receiving study therapy

- To observe the progression free survival of the study population

- To observe the overall survival of the study population

Cohort B:

- To observe CNS and systemic disease control in SCLC

Cohorts A, B and C:

- To determine the safety profile of etirinotecan pegol (NKTR 102)

Inclusion Criteria:

- At least 18 years of age.

- Life expectancy of 3 months or longer.

- ECOG performance status of 0, 1, or 2.

Advanced or refractory cancer, consisting of

- Metastatic breast cancer (mBC) for which single-agent cytotoxic chemotherapy is
indicated. OR

- Histologically-proven metastatic lung cancer:

- Non-small cell lung cancer (NSCLC) as Stage IV disease or recurrent metastatic
disease (per lung cancer TNM classification system, 7th ed) (Cohort A) OR

- Small cell lung cancer (SCLC) as extensive stage or recurrent metastatic disease
(cohort B), including tumors with mixed small cell and non-small cell elements.

Prior chemotherapy (at least one of the following):

- At least one line of prior systemic chemotherapy

- At least one line of prior targeted treatment for metastatic disease Adjuvant systemic
chemotherapy within prior 6 months Prior treatment for mBC must have included
taxane-based regimen

Prior chemotherapy, including other investigational therapy, has been completed prior to
initiation of study treatment, according to the following:

- ≥ 2 weeks if immediately preceding treatment was chemotherapy/targeted therapy
administered on a daily or weekly schedule

- ≥ 3 weeks if immediately preceding treatment was chemotherapy/targeted therapy
administered every 2 weeks

- ≥ 4 weeks if immediately preceding treatment was chemotherapy/targeted therapy
administered every 3 weeks Previously received at least one CNS directed treatment
(such as surgery or radiation) OR not be eligible for CNS stereotactic radiosurgery
Measurable CNS disease, either previously untreated (not counting systemic therapy),
or progressed following previous radiation treatment. Lesions that have progressed
after prior radiosurgery should not be selected as measurable disease if they are
suspected of being radionecrosis.

The following measurement criteria are required, as visualized by contrast-enhanced MRI
with slice thickness of ≤ 1.5 mm, unless absence of contrast or thicker slices is
specifically authorized by Protocol Director. Measurements do not include tumor edema.

- At least one CNS tumor measuring ≥ 10 mm in longest diameter, OR

- At least one CNS tumor measuring 5-9 mm in longest diameter, plus one or two
additional CNS tumors measuring ≥ 3 mm in longest diameter, for which the sum of the
longest diameters is ≥ 10 mm. Additional tumors are not exclusionary.

Adequate organ function as evidenced by:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10e9/L without G-CSF (filgrastim,
pegfilgrastim, or equivalent) support within 7 days

- Hemoglobin (Hgb) ≥ 9.0 g/dL (90 g/L) without blood transfusion within 7 days

- Platelet count ≥ 100 x 10e9/L without platelet transfusion within 7 days

- Bilirubin ≤ 1.5 X upper limit of normal (ULN), except for patients with documented
history of Gilbert's disease who may have DIRECT bilirubin ≤ 1.5 X ULN

- Alanine aminotransferase (ALT) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver
metastases

- Aspartate aminotransferase (AST) ≤ 2.5 X ULN, except ≤ 5 X ULN for patients with liver
metastases

- Serum creatinine ≤ 1.5 X ULN; or calculated creatinine clearance ≥ 50 mL/min (using
Cockcroft-Gault formula), or measured creatinine clearance ≥ 50 mL/min.

Exclusion Criteria:

- Previous treatment with a camptothecin derivative (eg., irinotecan, topotecan, and
investigational agents including but not limited to exatecan, rubitecan, gimatecan,
karenitecan, SN38 investigational agents, EZN 2208, SN 2310, and AR 67) is not allowed

- Patients may not have a known history of leptomeningeal disease, as diagnosed by
positive CSF cytology, unless prospective permission for enrollment is granted from
the sponsor and the PI

- Patients may not have had major surgery or radiotherapy (therapeutic and/or
palliative) within 14 days prior to initiation of study treatment, including
CNS-directed radiation therapy. Minor procedures, such as tumor biopsy, thoracentesis,
or intravenous catheter placement are allowed with no waiting period

- Patients may not have the following co morbid disease or concurrent illness:

- Chronic or acute gastrointestinal (GI) disorders resulting in diarrhea of any
severity grade; patients may not use chronic anti-diarrheal supportive care (more
than 3 days/week) to control diarrhea in the 28 days prior to first dose of
investigational drug. (exception: anti-diarrheal medications used to control
symptoms from a medication that will be discontinued prior to study are allowed
with a 7 day washout before study therapy, for example loperamide for
erlotinib-associated diarrhea)

- Known cirrhosis, defined as Child Pugh class A or higher liver disease

- Other active malignancy, except for non melanoma skin cancer and carcinoma in
situ (of the cervix or bladder)

- Any other severe/uncontrolled inter current illness or significant co morbid
conditions that in the opinion of the investigator would impair study
participation or cooperation

- Patients may not have a known allergy or hypersensitivity to any of the components of
the investigational therapy, including polyethylene glycol (PEG) or topoisomerase
inhibitors

- Patients may not be receiving the following medications at the time of first dose of
investigational drug:

- Pharmacotherapy for known hepatitis B or C, tuberculosis, or human
immunodeficiency virus (HIV)

- Any of the following enzyme inducing anti epileptic medications (EIAEDs):
phenytoin, carbamazepine, oxcarbazepine, phenobarbital

- Other chemotherapy, hormonal therapy, immunotherapy, other investigational
agents, or biologic agents for the treatment of cancer except for bisphosphonates
or denosumab

- Pregnant or nursing patients will be excluded from the study