Randomized Phase II Study of Single Agent OSI-906 Versus Topotecan for Relapsed Small Cell Lung Cancer (SCLC)

Coordinating Center: Southeast Phase 2 Consortium (SEP2C) Moffitt Cancer Center 12902
Magnolia Drive Tampa, FL 33612

Once patients have been appropriately consented and registered on trial, they will be
randomized in a 2:1 ratio, either to the experimental OSI-906 arm or the standard topotecan
arm. Randomization will be performed at the Moffitt Cancer Center (MCC) by the Consortium
Coordinator. Randomization will be accomplished through MCC's Automated Patient Registration
and Treatment Randomization System (APRTRS). APRTRS is a web-based database system that
provides centralized subject registration and treatment randomization for research studies.
This system provides an automated method for single or multi-center clinical trials to
centrally register and randomize subjects.

Inclusion Criteria:

- Histologically or cytologically confirmed SCLC

- Patients must have measurable disease as defined in the protocol document. At least
one lesion that can be accurately measured is required.

- Must have progression of disease after receiving ONLY 1 previous platinum-containing
regimen. Prior treatment with biological response modifiers or targeted agents will
NOT count towards this requirement. Previous topotecan or any type of pharmacologic
IGF-1R inhibition are NOT allowed.

- Life expectancy > 6 weeks

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2; Karnofsky ≥60%

- Adequate hematologic (bone marrow), hepatic and renal function as defined below
(within 4 weeks prior to enrollment): leukocytes (WBC) ≥3,000/mcL OR absolute
neutrophil count (ANC) ≥1,500/mcL AND platelets ≥100,000/mcL; total bilirubin within
normal institutional limits (NIL); aspartate aminotransferase (AST)[serum
glutamic-oxaloacetic transaminase (SGOT)] / alanine aminotransferase (ALT)[serum
glutamic pyruvic transaminase (SGPT)] ≤2.0 times institutional upper limit of normal
(ULN) without demonstrable liver metastases OR < 5.0 times ULN within liver
metastases present; Serum creatinine within NIL OR measured/calculated creatinine
clearance (CrCl) ≥60 mL/min/1.73 m^2 for patients with creatinine levels above NIL;
Fasting blood glucose <160 mg/dL at baseline

- Patients on oral antihyperglycemic therapies may be enrolled provided they have been
taking a stable dose of these medications for ≥2 weeks at the time of randomization.

- Prior radiation is permitted IF the site(s) of measurable disease has progressed
since prior irradiation and radiation is completed at least 2 weeks before initiation
of drug treatment (stereotactic radiotherapy excluded).

- Patients with central nervous system (CNS) metastases are ELIGIBLE, provided that
prior to drug treatment, the metastases have been treated, remain clinically or
radiographically stable and the patient has no significant neurologic symptoms.

- Patients must NOT have prior malignancy EXCEPT for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
Stage I or II cancer from which the patient is currently in complete remission, or
any other cancer from which the patient has been disease-free for ≥ 3 years.

- Women of child-bearing potential (WOCBP) and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, she should inform her treating physician immediately. WOCBP must provide a
negative pregnancy test (serum or urine) within 14 days prior to registration.

- Available archival tumor tissue is NOT mandatory for enrollment (will be requested).

- Patients must have the ability to understand and the willingness to sign a written
informed consent document.

Exclusion Criteria:

- Have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C) or
radiotherapy within 2 weeks prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Receiving any other investigational agents

- Patients with CNS metastases are NOT EXCLUDED, provided that prior to drug treatment,
the metastases have been treated, remain radiographically stable and the patient has
no significant neurologic symptoms.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to OSI-906 or other agents used in the study (topotecan)

- The primary route of metabolism of OSI-906 involves CYP1A2. While CYP1A2
inhibitors/inducers are not specifically excluded, investigators should be aware that
the metabolism and consequently overall pKs of OSI-906 (OSI-906 exposure) could be
altered by concomitant use of these drugs (inhibitors, inducers and/or other
substrates of CYP1A2). Exception: Potent CYP1A2 inhibitors ciprofloxacin and
fluvoxamine are prohibited. OSI-906 is a moderate inhibitor of CYP2C9. While CYP2C9
substrates are not specifically excluded, investigators should be aware that levels
of drugs metabolized by CYP2C9 may be increased by the concomitant administration of
OSI-906. Caution should be used when administering CYP2C9 substrates to study
patients. Lists including medications and substances known or with the potential to
interact with CYP1A2 and CYP2C9.

- P-glycoprotein inhibitors (e.g., cyclosporine A, elacridar, ketoconazole, ritonavir,
and saquinavir) can cause significant increases in topotecan exposure. The
concomitant use of p-glycoprotein inhibitors with topotecan capsules is not allowed.
Enzyme inhibition by Topotecan has not been evaluated in vivo but in vitro inhibition
studies indicate that the activities of these enzymes were not altered by topotecan.
Hence there are no specific exclusions for such medications that are metabolized
through this pathway.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, significant cardiac disease (i.e: symptomatic congestive heart failure,
unstable angina pectoris, symptomatic or lifethreatening cardiac arrhythmia), or
psychiatric illness/social situations that would limit compliance with study
requirements.

- Pregnant or breast-feeding women are excluded from this study. Prior negative
pregnancy test is required.

- Human immunodeficiency virus (HIV) positive patients on combination antiretroviral
therapy are ineligible because of the potential for Pharmacokinetic (pK) interactions
with OSI-906. In addition, these patients are at increased risk of lethal infections
when treated with marrow-suppressive therapy.

- Patients in the following scenarios are also excluded: corrected QT interval (QTc
interval) >450 msec at baseline; concomitant drugs that prolong the QTc interval; Use
of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited
within 14 days prior to randomization; Fasting blood glucose ≥160 mg/dl at baseline,
these patients can initiate oral antihyperglycemic therapies and be retested or
rescreened 2 weeks later to meet baseline fasting blood glucose criteria; Concomitant
use of insulin or insulinotropic medications.

- Patients with cirrhosis of the liver are excluded from this study.

- Archival tumor tissue is NOT mandatory for enrollment, but will be requested.