Carboplatin/Taxol/Ridaforolimus in Endometrial, Ovarian and Solids

This is a phase 1A/1B study. Phase 1A is designed to determine the maximal tolerated dose
(MTD) and toxicity of ridaforolimus in combination with paclitaxel and carboplatin in
patients with advanced or recurrent solid tumors. The MTD determined in this study will be
the recommended dose to study in the phase 1B or in future phase 2 trials.

Inclusion Criteria:

- Must have measurable disease or evaluable disease. Measurable disease is defined as at
least one lesion that can be accurately measured in at least one dimension (longest
dimension to be recorded). Each lesion must be a minimum size of 10 mm by CT scan (CT
scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam
or 20 mm by chest X-ray. Lymph node must be ≥ 15 mm in short axis when assessed by CT
scan. Evaluable disease is disease evident on imaging that does not meet Response
Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, however, meets tumor marker
evaluation, e.g., Gynecologic Cancer Intergroup (GCIG) criteria. Notes: i) If the
patient's only disease is confined to a solitary lesion, its neoplastic nature must be
confirmed by histology or cytology unless it is accompanied by GCIG criteria or can be
clearly be shown as new disease when compared to prior imaging. ii) Disease in a
previously irradiated field is acceptable as the only site of measurable disease only
if there has been clear progression since completion of radiotherapy.

- Age > 18 years and competent to give informed consent.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2 and a life
expectancy of at least 60 days.

- Patients must have adequate: Bone marrow function: Absolute neutrophil count (ANC)
greater than or equal to 1,500/ul, equivalent to Common Toxicity Criteria (CTCAE v4.0)
grade 1. Platelets greater than or equal to 100,000/ul.; Renal function: creatinine
less than or equal to 1.5 x institutional upper limit normal (ULN), CTCAE v4.0 grade
1.; Hepatic function: Bilirubin less than or equal to 1.5 x ULN (CTCAE v4.0 grade 1).
serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase less than or
equal to 2.5 x ULN (CTCAE v4.0 grade 1).; Neurologic function: Neuropathy (sensory and
motor) less than or equal to CTCAE v4.0 grade 1.; No chemotherapy, radiotherapy,
biologic, hormonal, or investigational drug therapy within 28 days prior to start of
treatment on study.

- Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
prior to the study entry and be practicing an effective method of birth control during
the course of the study, in a manner such that risk of failure is minimized. Prior to
study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during
trial participation and the potential risk factors for an intentional pregnancy.

- Phase 1A - Additional criteria applicable to phase 1A

- Must have pathologically confirmed solid cancer that is locally advanced or
metastatic cancer.

- Patient's physician believes that the cancer is advanced, recurrent or metastatic
and not curable by local measures (i.e., surgery, radiation, other drugs).

- Patient's physician believes the patient may potentially benefit from this
combination of therapy.

- Patients may have had up to three (3) prior cytotoxic chemotherapeutic regimens
including prior treatment with carboplatin and paclitaxel. Chemotherapy drug
changes and modifications made for reasons other than progression are not
considered a separate regimen. Examples would be drug changes for toxicity or
consolidation chemotherapy after adjuvant treatment. Patients may have received
any number of prior non-cytotoxic regimens such as monoclonal antibodies,
cytokines, signal transduction inhibitors, or hormonal therapy. Previous
radiation therapy is allowed.

- Phase 1B - Endometrial: Additional Inclusion Criteria

- Epithelial endometrial cancer. (i.e. carcinosarcoma, leiomyosarcoma, and
endometrial stromal sarcoma are excluded).

- May have had up to one prior chemotherapy for endometrial cancer. Prior taxane or
platinum therapy is allowed as long as it was received either as adjuvant therapy
or if there were a response to prior therapy and at least 6 months have elapsed
since platinum treatment. Radiation sensitizing chemotherapy will not count as a
prior regimen.

- Must have measurable disease

- Phase 1B - Ovarian: Additional Inclusion Criteria

- Recurrent epithelial ovarian cancer (no stromal or germ cell ovarian cancers)

- Platinum-sensitive defined as a recurrence at least 6 months (180 days) after the
last day of primary adjuvant chemotherapy. Patients may have been retreated with
a salvage line of chemotherapy but there must be a platinum-free interval of 6 or
more months.

- Two (2) or less prior therapies including adjuvant chemotherapy

- Measurable or evaluable disease

Exclusion Criteria:

- An upper gastrointestinal or other condition that would impair swallowing or
absorption of oral medication

- Any serious illness or medical condition that would not permit the patient to be
managed according to the protocol, including, but not limited to, any the following:

- History of significant neurologic or psychiatric disorder (e.g., uncontrolled
psychiatric disorders) that would impair the ability to obtain consent or limit
compliance with study requirement

- Active uncontrolled or serious infection

- Active peptic ulcer disease

- Patients who have the following cardiac conditions: Uncontrolled angina or
myocardial infarction with the past six months; Diagnosed or suspected congenital
long QT syndrome; Any history of clinically significant ventricular arrhythmias
(such as ventricular tachycardia, ventricular fibrillation, or Torsades de
pointes); Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on
both the Fridericia and Bazett's correction

- Uncontrolled hypertension defined as systolic greater than 180 and diastolic greater
than 100.

- History of other invasive malignancies in the last 3 years, with the exception of
non-melanoma skin cancer, unless they have had no evidence of recurrence from that
cancer for last two years.

- Serum creatinine >1.5 times the institutional upper limits of normal

- Patients taking certain concomitant medications (see below). Patients can enroll on
protocol if they stop these medications and a wash-out period of ≥14 days, unless
otherwise noted, is done prior to starting ridaforolimus.

- There must be at least 14 days since prior (and no current expectations to receive)
CYP3A4 inhibitors including, but not limited to, any of the following: Azole
antifungals ( i.e., ketoconazole, itraconazole, miconazole, fluconazole); HIV protease
inhibitors (i.e., indinavir, saquinavir, ritonavir, atazanavir, nelfinavir);
Clarithromycin; Verapamil; Erythromycin; Delavirdine; Diltiazem; Nefazodone;
Telithromycin

- There must be at least 14 days since prior (and no current expectations to receive)
CYP3A4 inducers including, but not limited to, any of the following

- Rifampin

- Phenytoin

- Rifabutin

- St.John's wort

- Carbamazepine

- Efavirenz

- Phenobarbital

- Tipranavir

- Full dose anticoagulation with warfarin (coumadin) or other vitamin K dependent
anticoagulant. Low-dose prophylactic warfarin (i.e. 1mg per day port prophylaxis) is
allowable. Low molecular heparin (e.g., danaparoid, dalteparin, tinzaparin,
enoxaparin) is allowable if patient has been established on therapy.

- Have received an estimated dose of radiation therapy to >35% of the bone marrow.

- Patients previously exposed to mTOR inhibitors are permitted in phase 1A but not
allowed in phase 1B.

- History of grade 3 hypersensitivity to paclitaxel. However, if after prior
hypersensitivity the patient was subsequently successfully rechallenged without
incident, the patient may be eligible at investigator's discretion.

- Known hypersensitivity to the study drug ridaforolimus or its components.
Ridaforolimus should be administered with caution to patients known to be
hypersensitive to macrolide antibiotics, Tween80 (polysorbate 80), or any other
excipient in the product formulation.

- Significant lipid abnormalities: Serum cholesterol > 350mg/dL; Triglycerides >
400mg/dL