Erlotinib and Temsirolimus for Solid Tumors

Inclusion Criteria:

- Histologic Diagnosis: Patients must have a histologically or cytologically proven
solid malignancy which is resistant to conventional therapy or for which no effective
therapy is known.

- Dose Expansion Phase ONLY: Patients must have archived tumor tissue available
(paraffin blocks, unstained tissue sections, tissue cores).

- Tumor Mutational Status (Dose Expansion Phase ONLY): Patients must have tumor
harboring PTEN loss, PIK3CA mutation, , and/or EGFR mutation. Patients cannot have
KRAS or BRAF mutations. Patients must have mutational status determined by Genomic
and Pathology Services at Washington University (GPS@WU) or other CLIA-certified
laboratories.

- Dose Expansion Phase ONLY: Patients with squamous carcinoma histology, papillary
thyroid carcinoma, and adenoid cystic carcinoma are eligible for the expansion cohort
regardless of genetic alterations..

- Measurable or Non-Measurable Disease: Patients with measurable or non-measurable
disease are eligible for entry to this study. In addition, patients without
measurable or non-measurable disease are also eligible.

- Measurable lesions are defined as those that can be accurately measured in at least
one dimension (longest diameter to be recorded) as ≥20 mm with conventional
techniques (PET, CT, MRI, x-ray) or as ≥10 mm with spiral CT scan. All tumor
measurements must be recorded in millimeters (or decimal fractions of centimeters).

- Tumor markers may be considered non-measurable disease.

- A positive bone scan, osteoblastic metastases, and pleural or peritoneal effusions
are not considered measurable or non-measurable. Patients with only these lesions
are eligible for entry to the study.

- Dose Expansion Phase ONLY: Patients must have a tumor that is easily accessible for
biopsy determined by the treating physician or the study PI. Patients must agree to
a mandatory biopsy at the end of cycle 1 treatment.

- Recovery from Prior Therapy: 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. No prior therapy with erlotinib or temsirolimus allowed.

- Age: Patients must be ≥18 years old. Because no dosing or toxicity data are
currently available on the use of temsirolimus in combination with erlotinib in
patients <18 years of age, children are excluded from this study, but will be
eligible for the pediatric phase I single-agent trials, when available.

- Performance Status: ECOG 0-1 at study entry.

- Life Expectancy: Patients must have a life expectancy of greater than 12 weeks.

- Required Laboratory Values:

- absolute neutrophil count ≥1,500/mm3

- platelets ≥100,000/mm3

- hemoglobin ≥9.0 g/dL

- total bilirubin ≤1.5 x ULN

- AST/ALT ≤3.0 x ULN

- alkaline phosphatase ≤2.5 x ULN

- creatinine ≤2.0 x ULN OR

- creatinine clearance ≥60 mL/min/1.732 for patients with creatinine levels above 2.0
mg/dl

- serum cholesterol ≤350 mg/dL /9.0 mmol/L (fasting)

- triglycerides ≤300 mg/dL (fasting)*

- PT/INR ≤1.5, unless the patient is on full dose warfarin or stable
dose of 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.

- Temsirolimus is primarily metabolized by CYP3A4. Patients cannot be receiving
enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine,
phenobarbital) nor any other CYP3A4 inducer such as rifampin or St. John's wort, as
these may decrease temsirolimus levels. A partial list of agents which interact with
cytochrome P450 (CYP3A) is found in Appendix AB. Use of agents that potently inhibit
CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is
discouraged, but not specifically prohibited. Temsirolimus can inhibit CYP2D6, and
may decrease metabolism (and increase drug levels) of drugs that are substrates for
CYP2D6, such as codeine. The appropriateness of use of such agents is left to
physician discretion. A list of drugs that may have potential interactions with
CYP2D6 is found in Appendix A. If there is any doubt about eligibility based on
concomitant medication, the Principal Investigator, Dr. Andrea Wang-Gillam, should be
contacted. All concomitant medications must be recorded.

- Known Allergies: Patients with known hypersensitivity reactions to macrolide
antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible
for this trial.

- 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. Pregnant and nursing women are
not eligible.

- HIV-Positive Patients: Patients receiving anti-retroviral therapy (HAART) for HIV
infection are excluded from the study because of possible pharmacokinetic
interactions. Appropriate studies will be undertaken in patients receiving HAART
therapy, when indicated.

- Neurologic Status: Patients must not have active CNS disease.

- Recovery from Intercurrent Illness: 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.

- Informed Consent: Patients must have signed a Washington University Human Research
Protection Office (HRPO) approved informed consent. The patient should not have any
serious medical or psychiatric illness that would prevent either the giving of
informed consent or the receipt of treatment.

- Inclusion of Women and Minorities: Entry to this study is open to both men and women
and to all racial and ethnic subgroups.