A Study Evaluating Intermittent and Continuous OSI-906 and Weekly Paclitaxel in Patients With Recurrent Epithelial Ovarian Cancer (and Other Solid Tumors)

The phase 1 dose escalation portion will establish the maximum tolerated dose (MTD) in
patients with advanced solid tumors. Once the recommended phase 2 dose (RP2D) is established
for both schedules, the phase 2 study will begin. Patients with relapsed/recurrent
epithelial ovarian cancer will be randomized 1:1:1 to 3 treatment groups.

Inclusion Criteria:

- Histologically or cytologically confirmed epithelial ovarian carcinoma Patients with
fallopian or peritoneal cancer will also be eligible

- Patients with any solid tumor that may be treated with weekly paclitaxel will be
eligible for the phase 1 portion

- For the phase 2 portion, patients must have elevated CA125 levels
evaluable/assessable according to Gynecological Cancer Intergroup (GCIG) criteria
(ie, > 70 U/mL) documented by 2 measurements at least 1 week apart

- Patients must have radiologically confirmed progressive disease by RECIST v1.1
criteria within 6 months prior to randomization. (patients must have measurable
disease according to RECIST v1.1)

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

- Predicted life expectancy ≥ 12 weeks

- Patients may have had prior therapy, providing the following conditions are met:

- Chemotherapy: Prior chemotherapy must have been completed at least 3 weeks prior
to study enrollment (6 weeks for mitomycin C, nitrosoureas or high-dose
carboplatin [≥ 600 mg/m²]and 4 weeks for investigational drugs

1. Patient should have recovered from any drug-related toxicities (with the
exception of grade 1 neuropathy and or alopecia)

2. Phase 1: While there is no limit on the number of prior regimens for
patients entered into the phase 1 portion, any prior taxane therapy must
have been administered on a 3 week schedule

3. Phase 2: Patients must have received prior chemotherapy, which must have
contained a platinum and a taxanes at some point. Any prior taxanes therapy
must have been administered on a 3 week schedule. A maximum of 2 prior
chemotherapy regimens are permitted. Patients must be refractory
radiologically confirmed by computerized tomography (CT) scan progressive
disease (PD) during chemotherapy) or resistant (radiologically confirmed by
CT scan PD within six months of completing chemotherapy) to their last
platinum-containing chemotherapy regimen

- Radiation: Patients may have had prior radiation therapy provided they have
recovered from the acute, toxic effects of radiotherapy prior to
registration/randomization. Radiated lesions cannot be chosen as the target
lesions

a. A minimum of 21 days must have elapsed between the end of radiotherapy and
registration/randomization into the study unless the radiation affected less
than 25% of bone marrow

- Surgery: Previous surgery is permitted provided that adequate wound healing has
occurred prior to registration/randomization

- Fasting glucose ≤ 150 mg/dL (8.3 mmol/L)

- Adequate hematopoietic, hepatic, and renal function defined as follows:

- Neutrophil count ≥ 1.5 x 10 ^9 /L and platelet count > = 100 x 10^9/L;

- Bilirubin ≤ 1.5 x Upper Limit of Normal (ULN);

- AST and/or ALT ≤ 2.5 x ULN or < = 5 x ULN if patient has documented liver
metastases; and

- Serum creatinine ≤ 1.5 x ULN

- Female patient must be either:

- Of non childbearing potential:

1. post-menopausal (defined as at least 1 year without any menses) prior to
Screening, or

2. documented surgically sterile or status post hysterectomy (at least 1 month
prior to Screening)

- Or, if of childbearing potential:

1. must have a negative urine pregnancy test at Screening, and

2. must use two forms of birth control (one of which must be a barrier method)
starting at Screening and throughout the study period and for 28 days [or 5
half lives, whichever is longer] after final study drug administration

- Female patient must not be breastfeeding at Screening or during the study period and
for 28 days [or 5 half lives of the study drug whichever is longer] after final study
drug administration

- Female patient must not donate ova starting at Screening and throughout the study
period and for 28 days [or 5 half lives of the study drug whichever is longer] after
final study drug administration

- Patients must provide verbal and written informed consent to participate in the study

Exclusion Criteria:

- Diabetes mellitus currently requiring medication (eg, insulin or oral hypoglycemics)

- During the phase 2 portion, patients with histology of abdominal adenocarcinoma of
unknown origin or a diagnosis of a borderline ovarian tumor

- Previous or concurrent malignancies (excluding curatively treated basal or squamous
cell carcinoma of the skin or cervical carcinoma in situ) unless the patient has been
in remission for at least 3 years

- History of significant cardiovascular disease unless the disease is well-controlled.
Significant cardiac diseases includes second/third degree heart block; significant
ischemic heart disease; poorly controlled hypertension; congestive heart failure of
New York Heart Association (NYHA) Class II or worse (slight limitation of physical
activity; comfortable at rest, but ordinary physical activity results in fatigue,
palpitation, or dyspnea)

- History of cerebrovascular accident (CVA) within 6 months prior to
registration/randomization or that is not stable

- Prior therapy with an insulin-like growth factor (IGF-1R) inhibitor

- Use of drugs that have a risk of causing QT interval prolongation within 14 days
prior to Day 1 dosing

- Known or prior hypersensitivity to taxanes in spite of premedication or drugs
containing Cremophor

- Gastro-intestinal abnormalities, including bowel obstruction, inability to take oral
medication, requirement for intravenous (IV) alimentation,active peptic ulcer or
prior surgical procedures or bowel resection affecting absorption

- Active infection or serious underlying medical condition (including any type of
active seizure disorder within 12 months prior to registration/randomization) that
would impair the ability of the patient to receive protocol treatment

- History of any psychiatric condition that might impair the patient's ability to
understand or to comply with the requirements of the study or to provide informed
consent

- Pregnancy or breast-feeding

- Symptomatic brain metastases that are not stable, require steroids, are potentially
life threatening, or that have required radiation within 28 days prior to
registration/randomization

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to the study drug

- History of arrhythmia (multifocal premature ventricular contractions [PVCs],
bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation)
that is symptomatic or requires treatment (≥ grade 3), left bundle branch block
(LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients
with atrial fibrillation controlled by medication are not excluded. Patients with
mean QTcF interval ≥ 450 msec at screening are excluded

- Use of drugs that have a known risk of causing Torsade de Pointes (TdP) or that that
have a risk of causing QT interval prolongation within 14 days prior to Day 1 dosing
are prohibited

- Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent
CYP1A2 inhibitors/inducers are not excluded

- Participated in any interventional clinical study or has been treated with any
investigational drugs within 30 days or 5 half lives whichever is longer, prior to
the initiation of Screening or during the course of the study