Study of Temsirolimus, Erlotinib and Cisplatin in Solid Tumors

The stratification of breast cancer patients for treatment targeting either the estrogen
receptor (ER) or human epidermal growth factor receptor 2 (HER2) receptor based upon the
measurement of ER/progesterone receptor (PR) and HER2 in tumor tissue has changed the
treatment of breast cancer. However, the success of this stratification has resulted in the
recognition that no effective rational treatment exists for patients that lack these
receptors. The term "triple negative breast cancer" (TNBC) has been used to define a class of
unresponsive patients, which is based upon their lack of the hormone receptors for estrogen
and progesterone and the HER2 oncogene. TNBC represents a form of breast cancer for which no
targeted therapy is known.

Thus, identifying and understanding the signaling pathways and receptors that contribute to
triple negative tumor growth is of high priority in order to develop therapies analogous to
the ones that have already been developed for HER2 and ER.

Available data from Phase I trials have demonstrated that mTOR inhibitors and EGFR inhibitors
have been safely given together at doses shown to inhibit their respective targets and Phase
II studies are ongoing in advanced renal cell, pancreatic, glioma, and breast (not
specifically TNBC) cancers.

The rationale for adding cisplatin to erlotinib and an mTOR inhibitor are many. Cisplatin is
a known active cytotoxic against breast cancer. It has non overlapping toxicity with
erlotinib and TORC1 mTOR inhibitors and patients are unlikely to have been previously treated
with cisplatin. Therefore, as a cytotoxic DNA damaging agent, cisplatin could trigger cell
death in a cell whose survival pathways are effectively inhibited by mTOR inhibition and
erlotinib.

Inclusion Criteria:

- Confirmed pathologic diagnosis of a solid tumor that is not curable with available
therapies for which the combination of cisplatin, temsirolimus, and erlotinib is a
reasonable treatment.

- Patients with measurable or non-measurable disease are eligible for entry to this
study. Tumor markers may be considered non-measurable disease.

- Patients must have recovered from the acute toxic effects of all prior chemotherapy,
immunotherapy, or radiotherapy prior to entering this study. No chemotherapy or
radiotherapy may be given within 3 weeks prior to the start of protocol treatment.

- Patients must be ≥18 years old.

- Performance Status: Eastern Cooperative Oncology Group (ECOG) 0-1

- Life expectancy of greater than 12 weeks.

- Patients must have recovered from uncontrolled intercurrent illness including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris or cardiac arrhythmia.

- Required Laboratory Values: absolute neutrophil count (ANC) ≥1,500/mm3, platelets
≥100,000/mm3, hemoglobin ≥9.0 g/dL, total bilirubin ≤1.5 x upper limit of normal
(ULN), aspartate transaminase (AST)/alanine transaminase (ALT) ≤3.0 x ULN, alkaline
phosphatase ≤2.5 x ULN, creatinine ≤2.0 x ULN OR Patients must have either a normal
serum creatinine (<= IULN) OR estimated creatinine clearance 60 ml/min
(Cockcroft-Gault formula) within 28 days prior to registration. Prothrombin time
(PT)/INR ≤1.5, unless the patient is on full dose warfarin or stable dose of
low-molecular-weight (LMW) heparin with a therapeutic INR of >1.5 - ≤3. Patients with
triglyceride levels >400 mg/dL can be started on lipid lowering agents and reevaluated
within 1 week. If levels go to ≤400 mg/dL, they can be considered for the trial and
continue the lipid lowering agents.

- Concomitant Medications: Temsirolimus and Erlotinib are primarily metabolized by
CYP3A4. Patients CANNOT be receiving enzyme-inducing or enzyme inhibiting agents
listed here: Inhibitors: Amiodarone, Amprenavir, Atazanavir, Chloramphenicol,
Clarithromycin, Conivaptan, Cyclosporine, Darunavir, Dasatinib, Delavirdine,
Diltiazem, Erythromycin, Fluconazole, Fluoxetine, Fluvoxamine, Fosamprenavir,
Imatinib, Indinavir, Isoniazid, Itraconazole, Ketoconazole, Lapatinib, Miconazole,
Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Quinupristin, Saquinavir, Tamoxifen,
Telithromycin, Troleandomycin, Verapamil, Voriconazole. Inducers: Aminoglutethimide,
Bexarotene, Bosentan, Carbamazepine, Efavirenz, Fosphenytoin, Griseofulvin, Modafinil,
Nafcillin, Nevirapine, Oxcarbazepine, Phenobarbital, Phenytoin, Primidone, Rifabutin,
Rifampin, Rifapentine, St. John's wort, Sulfadimidine, Sulfinpyrazone, Troglitazone,
Troleandomycin. All concomitant medications must be recorded. Patients also must agree
to refrain from drinking grapefruit juice while on study.

- Sexually Active Patients: For all sexually active patients, the use of adequate
contraception (hormonal or barrier method of birth control) will be required prior to
study entry and for the duration of study participation. Non-pregnant status will be
determined in all women of childbearing potential.

- Patients must have signed an approved informed consent.

Exclusion Criteria:

- More than 3 prior chemotherapy treatments for metastatic disease.

- Patients receiving anti-retroviral therapy (HAART) for HIV infection because of
possible pharmacokinetic interactions.

- Active central nervous system (CNS) disease

- Any serious medical or psychiatric illness that would prevent either the giving of
informed consent or the receipt of treatment.

- Patients pregnant or nursing.

- Patients who have used tobacco or nicotine products containing medications within the
last three months given their significant effect on erlotinib drug levels.