Temsirolimus, Carboplatin, and Paclitaxel as First-Line Therapy in Treating Patients With Newly Diagnosed Stage III-IV Clear Cell Ovarian Cancer

PRIMARY OBJECTIVES:

I. To assess the activity of the study regimen as measured by the proportion of patients who
are alive and progression-free for at least 12 months after study entry in patients with
newly diagnosed stage III or IV clear cell ovarian cancer in the following populations:
patients in the United States (U.S.) and worldwide (outside of Japan) and patients in Japan.

II. To compare progression-free survival in newly diagnosed stage III or IV clear cell
ovarian cancer patients in patients in the U.S. and worldwide (outside of Japan) versus
patients in Japan.

SECONDARY OBJECTIVES:

I. To characterize the duration of overall survival and progression-free survival in each
population.

II. To examine the frequency and severity of adverse events as assessed by Common
Terminology Criteria for Adverse Events (CTCAE) version 4 in each population.

III. To estimate the rate of objective tumor response in patients with measurable disease.

TERTIARY OBJECTIVES:

I. To explore whether immunohistochemical (IHC) expression of components of the mammalian
target of rapamycin (mTOR) signaling pathway (phosphatase and tensin homolog [PTEN], total
and phosphorylated protein kinase B [Akt], as well as, ATP-binding cassette, sub-family C
[CFTR/MRP], member 3 [ABCC3] [MRP3], ATPase, H+ transporting, lysosomal accessory protein 1
[AB CF2], cyclin E, and vascular endothelial growth factor [VEGF]) are associated with
outcome, nationality or clinical characteristics.

II. To explore whether there is any differences in differential gene expression profiles
between U.S. and worldwide (outside of Japan) versus Japanese patients.

OUTLINE:

Patients receive paclitaxel* intravenously (IV) over 3 hours and carboplatin IV over 30
minutes on day 1 and temsirolimus IV on days 1 and 8. Treatment repeats every 3 weeks for 6
courses. Patients then receive consolidation therapy comprising temsirolimus IV on days 1,
8, and 15. Treatment repeats every 3 weeks for 11 courses in the absence of disease
progression or unacceptable toxicity.

NOTE: * For circumstances in which docetaxel should be substituted for paclitaxel, docetaxel
is given IV over 1 hour.

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

Inclusion Criteria:

- Patients must have stage III or IV clear cell ovarian cancer; primary tumors must be
at least 50% clear cell histomorphology in order to be eligible; in addition, the
tumors should be negative for expression of Wilms tumor 1 (WT-1) antigen and estrogen
receptor (ER) antigen by immunohistochemistry; appropriate tissue sections to confirm
stage and histologic classification of cell type must be sent to Gynecologic Oncology
Group (GOG) for central pathology review; immunohistochemical stained slides for ER
and WT-1 antigen must be also be submitted to GOG for pathology review

- Patients who have met the pre-entry requirements

- Patients must have signed an approved informed consent and authorization permitting
release of personal health information

- Patients with a GOG performance status of 0, 1, or 2

- Patients must be entered between 2 and 12 weeks after initial surgery; performed for
the combined purpose of diagnosis, staging and cytoreduction

- Patients should be free of active infection requiring antibiotics (with the exception
of uncomplicated urinary tract infection [UTI])

- Absolute neutrophil count >= 1,500/mcl

- Platelets >= 100,000/mcl

- Total bilirubin within normal institutional limits

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =<
2.5 times institutional upper limit of normal (< 5 times upper limit of normal [ULN]
for subjects with liver metastases)

- Alkaline phosphatase =< 2.5 times institutional upper limit of normal (< 5 times ULN
for subjects with liver metastases)

- Creatinine =< 1.5 x institutional upper limit of normal, grade 1 per CTCAE v. 4.0

- Cholesterol =< 350 mg/dL (fasting)

- Triglycerides =< 400 mg/dL (fasting)

- Albumin >= 3.0 g/dL

- Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 (or an
in-range INR, usually between 2 and 3, if a patient is on a stable dose of
therapeutic warfarin for management of venous thrombosis including pulmonary
thrombo-embolus)

- Partial thromboplastin time (PTT) < 1.2 times the upper limit of normal

- Neurologic function (sensory and motor) =< CTCAE grade 1

Exclusion Criteria:

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer, are excluded if there is any evidence of other malignancy
being present within the last five years; patients are also excluded if their
previous cancer treatment contraindicates this protocol therapy

- Patients who have received prior radiotherapy to any portion of the abdominal cavity
or pelvis are excluded; prior radiation for localized cancer of the breast, head and
neck, or skin is permitted, provided that it was completed more than five years prior
to registration, and the patient remains free of recurrent or metastatic disease

- Patients who have received prior chemotherapy for any abdominal or pelvic tumor
including neo-adjuvant chemotherapy for their clear cell ovarian cancer

- Patients with primary peritoneal and fallopian tube carcinoma are not eligible

- Previous treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus),
paclitaxel, or carboplatin

- Patients cannot be receiving enzyme-inducing antiepileptic drugs (enzyme-inducing
antiepileptic drugs [EIAEDs]; e.g., phenytoin, carbamazepine, phenobarbital) nor any
other cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) inducer such as
rifampin or St. John's Wort; use of agents that potently inhibit CYP3A4 (and hence
may raise temsirolimus levels), such as ketoconazole, is discouraged, but not
specifically prohibited; the appropriateness of use of such agents is left to
physician discretion; strong CYP3A4 inhibitors are prohibited

- Patients receiving any investigational agents

- Patients with severely impaired lung function defined as a diffusion lung capacity
for carbon monoxide (DLCO) =< 50% of the normal predicted value and/or oxygen (O2)
saturation =< 88% at rest on room air

- Patients with symptomatic congestive heart failure of New York Heart Association
class III or IV, unstable angina pectoris, symptomatic congestive heart failure,
myocardial infarction =< 6 months of start of study drug, serious uncontrolled
cardiac arrhythmia or any other clinically significant disease

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major
vessels

- Patients on maintenance corticosteroids are ineligible with the exception of short
term use (fewer than 5 days)

- Patients with baseline requirement for oxygen

- Patients with serious concomitant illness which, in the opinion of the treating
physician, will place patient at unreasonable risk from therapy on this protocol

- Patients who are pregnant or nursing; patients of childbearing potential must agree
to use contraceptive measures during study therapy and for at least six months after
completion of study therapies

- Patients with poorly controlled diabetes