A Randomized Phase II Study of Cisplatin and Etoposide in Combination With Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients With Extensive Stage

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of patients with extensive stage small
cell lung cancer (SCLC-ED) treated with cisplatin and etoposide (CE), CE with hedgehog (HH)
inhibitor GDC-0449 (vismodegib), and CE with insulin-like growth factor-1 receptor (IGF-1R)
monoclonal antibody (IMC-A12) (cixutumumab).

SECONDARY OBJECTIVES:

I. To evaluate response rate, overall survival, and toxicity for each arm. II. To explore
putative correlates of clinical benefit from combination therapy in tumor and circulating
tumor cells in patients treated on this protocol.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A (CE): Patients receive cisplatin (75 mg/m^2) intravenously (IV) over 1-2 hours on day 1
and etoposide (100 mg/m^2) IV over 1-2 hours on days 1-3. Treatment repeats every 21 days for
4 courses in the absence of disease progression or unacceptable toxicity.

ARM B (CE +GDC-0449): Patients receive cisplatin and etoposide as in Arm A and vismodegib
(GDC-0449; 150 mg tablet) orally (PO) once daily (QD) on days 1-21. Treatment repeats every
21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Patients then receive vismodegib alone QD in the absence of disease progression or
unacceptable toxicity.

ARM C (CE + IMC-A12): Patients receive cisplatin and etoposide as in Arm A and cixutumumab
(IMC-A12; 6 mg/kg) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 4
courses in the absence of disease progression or unacceptable toxicity. Patients then receive
cixutumumab alone once weekly in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 1 year.

Inclusion Criteria:

- Histologically or cytologically confirmed small cell lung cancer (SCLC)

- Extensive stage SCLC

- Extensive stage disease: the extensive disease classification for this protocol
includes all patients with disease sites not defined as limited stage; limited
stage disease category includes patients with disease restricted to one
hemithorax with regional lymph node metastases, including hilar, ipsilateral and
contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive
disease patients are defined as those patients with extrathoracic metastatic
disease, malignant pleural effusion, bilateral or contralateral supraclavicular
adenopathy

- Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST);
baseline measurements and evaluations of all sites of disease must be obtained =< 4
weeks prior to randomization

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelets >= 100,000/mm^3

- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine
aminotransferase (ALT) (serum glutamate pyruvate transaminase) =< 3 x institutional
ULN (=< 5 x ULN if liver function test [LFT] elevations are due to liver metastases)

- Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2
for patients with creatinine levels > 1.5 x institutional ULN

- Leukocytes >= 3,000/mm^3

- Hemoglobin >= 9 g/dL

- Fasting serum glucose < 120 mg/dL or below institutional ULN =< 7 days prior to
protocol randomization

- Patients with central nervous system (CNS) metastases will be eligible if they have
completed a course of CNS radiotherapy and have stable neurologic function for a
minimum of 28 days prior to study randomization; radiotherapy must have been completed
a minimum of 28 days prior to randomization, and patients must have recovered from any
adverse events related to the radiotherapy (except alopecia and grade 1 neuropathy)
and have stable neurologic function for a minimum of 28 days prior to study
randomization

- NOTE: the use of prophylactic cranial irradiation (recommended dose 25 Gy) in
those who completed protocol chemotherapy and have a response (in the absence of
progressive disease [PD]) is allowed; for patients on Arms B and C, GDC-0449 and
IMC-A12 will be held while patient is receiving prophylactic cranial irradiation
(PCI); these agents can be reinstituted after PCI is completed

- Women of child-bearing potential (WCBP) 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

- WCBP must agree to use two reliable forms of contraception simultaneously or to
practice complete abstinence from heterosexual intercourse; the two methods of
reliable contraception must include one highly effective method (i.e.,
intrauterine device [IUD], hormonal [birth control pills, injections, or
implants], tubal ligation, partner?s vasectomy) and one additional effective
(barrier) method (i.e., latex condom, diaphragm, cervical cap); WCBP must be
referred to a qualified provider of contraceptive methods if needed

- NOTE: the WCBP randomized to Arm B must agree to use two reliable forms of
contraception simultaneously or to practice complete abstinence from
heterosexual intercourse during the following two additional time periods
related to this study: 1) while participating in the study; and 2) for at
least 12 months after discontinuation from the study

- Before starting the study drugs, all WCBP must have a negative pregnancy test
(sensitivity of at least 50 mIU/mL); the pregnancy test must be performed within
10-14 days prior to randomization

- NOTE: the WCBP randomized to Arm B must have a second pregnancy test
performed within the 24 hours prior to the start of the GDC-0449; the
subject may not receive GDC-0449 until the investigator has verified that
the results of these pregnancy tests are negative

- The WCBP randomized to Arm B will be warned that sharing the study drug is
prohibited and will be counseled about pregnancy precautions and potential risks
or fetal exposure; she must also agree to abstain from donating blood during
study participation and at least 12 months after discontinuation from the study
drug

- NOTE: male subjects randomized to Arm B must agree to use a latex condom
during sexual contact with WCBP while participating in the study and for at
least 12 months following discontinuation from the study even if he has
undergone a successful vasectomy

- Male subjects randomized to Arm B will be warned that sharing study drug is
prohibited and will be counseled about pregnancy precautions and potential risks
of fetal exposure; male subjects must agree to abstain from donating blood,
semen, or sperm during study participation and for at least 3 months after
discontinuation from the study drug

Exclusion Criteria:

- Pregnant or breastfeeding; all WCBP must have a blood test within 10-14 days prior to
randomization to rule out pregnancy

- Prior chemotherapy or biologic therapy for SCLC; patients with prior radiation may be
eligible or after palliative radiotherapy for other sites of disease; patients
receiving prior radiation cannot start therapy within 14 days after completion of
radiation, and must have recovered from adverse events attributed to radiation; no
previous irradiation to the only site of measurable or evaluable disease, unless that
site had subsequent evidence of progression

- Receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or
biological composition to GDC-0449 and IMC-A12 or other agents used in the study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy

- Poorly controlled diabetes mellitus; patients with a history of diabetes mellitus are
allowed to participate, provided that their blood glucose is within normal range
(fasting < 120 mg/dL or below institutional upper limit of normal) and that they are
on a stable dietary or therapeutic regimen for this condition

- Patients with major surgery, hormonal therapy (other than replacement), within 4 weeks
prior to entering the study or those who have not recovered from adverse events

- Prior treatment with other agents targeting the IGFR or the Hedgehog signaling pathway