A Phase II Study of Sirolimus and Erlotinib in Recurrent/Refractory Germ Cell Tumors

Inclusion Criteria:

- Patients must be greater than 12 months and less than 50 years of age at the time of
study enrollment.

- Patients must have had histologic verification of an extracranial germ cell tumor that
is not a pure mature teratoma.

- Patients must have sufficient tumor tissue available to allow assessment of EGFR and
mTOR pathway activation (see Section 5.2.3 for sample requirements)

- Patients must have relapsed or refractory disease following at least two prior
cisplatin containing chemotherapy regimens.

- Patients must have measurable disease, documented according to RECIST criteria, or
evaluable disease with a standard tumor marker (AFP and/or HCG) greater than 10 times
the upper limit of normal.

- Patients must have a Lansky or Karnofsky performance status score of ≥ 50. Use
Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age.

- Patients must have a life expectancy of greater than 8 weeks.

- Patients must have fully recovered from the acute toxic effects of all prior
anti-cancer therapy.

- Patients must not have received myelosuppressive chemotherapy within 3 weeks of
enrollment.

- Patients must be > 7 days since treatment with hematopoetic growth factors (>14
days for Neulasta).

- Patients must be >7 days since therapy with a biologic agent and beyond the
period for which adverse events of the biologic agent are known to occur if
longer.

- Patients must be >3 half-lives since therapy with a monoclonal antibody.

- Patients must be >42 days since completion of any immunotherapy (i.e. tumor
vaccines).

- Patients must be greater than 2 weeks since most recent palliative XRT and
greater than 6 weeks since substantial bone marrow irradiation.

- Patients must be greater than 8 weeks since prior stem cell transplant or
infusion and without evidence of active graft vs. host disease.

- Adequate bone marrow function defined as:

- Peripheral absolute neutrophil count (ANC) of at least 1,000/ L

- Platelet count of at least 100,000/ L (transfusion independent, defined as not
receiving platelet transfusions within a 7-day period prior to enrollment)

- Hemoglobin 8.0 g/dL (may receive RBC transfusions).

- Adequate renal function defined as:

- Creatinine clearance or radioisotope GFR 70 mL/min/1.73 m2 or

- Maximum serum creatinine (mg/dL) based on age/gender

- Adequate liver function defined as:

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age

- SGPT (ALT) ≤ 2.5 x ULN (for the purpose of this study, the ULN for SGPT is 45
U/L)

- Serum albumin ≥ 2 g/dL.

- Adequate central nervous system function defined as:

o Patients with seizure disorder may be enrolled if receiving non-enzyme inducing
anticonvulsants and well controlled.

- Serum cholesterol levels must be less than Grade 2 (< 300 mg/dL), and serum
triglyceride levels must be less than Grade 2 (< 2.5 x ULN).

Exclusion Criteria:

- Patients with active brain metastases are not eligible as lethal intratumoral
hemorrhages have been reported with erlotinib therapy. Patients with brain metastases
that have been treated and stable for > 30 days following treatment will be eligible.

- Patients who are pregnant or breast feeding will not be entered into the study as
erlotinib is teratogenic. Pregnancy tests must be obtained in females who are
post-menarchal. Post-menarchal females with HCG secreting tumors will be excluded as
pregnancy can't be excluded. Males or females of reproductive potential may not
participate unless they have agreed to use an effective contraceptive method for the
duration of the study.

- Concomitant medications

- Investigational Drugs: Patients who are currently receiving another
investigational drug are not eligible.

- Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
are not eligible.

- Anticonvulsants: Patients who are receiving enzyme-inducing anticonvulsants are
not eligible (see Appendix 1 for a list of enzyme- inducing anticonvulsants).

- Anticoagulants: Use of warfarin is not allowed while on study. Patients already
on warfarin should use alternative anticoagulants while on this study. Warfarin
must not have been administered within 7 days of enrollment.

- Smoking: Smoking induces CYP3A4/5 enzymes and decreases exposure to sirolimus and
erlotinib. Thus, patients must not smoke for 10 days prior to enrollment and for
the duration of therapy.

- Infection: Patients who have an uncontrolled infection are not eligible.

- Drug interactions: Sirolimus and erlotinib are primarily metabolized by the CYP3A4/5
enzymes. Drug exposure is substantially effected by CYP inhibitors (increased
exposure) and inducers (decreased exposure). Thus, concomitant administration of
strong CYP3A4/5 inhibitors or inducers is prohibited while on therapy. See Appendix 1
for a list of these medications. Patients must not have received these medications for
a minimum of 10 days prior to enrollment.

- Patients who have received prior therapy targeting EGFR with small molecule tyrosine
kinase inhibitors or monoclonal antibodies are NOT eligible.

- Prior treatment with mTOR or TORC1/2 inhibitors (eg, rapamycin, temsirolimus,
everolimus, sirolimus) is NOT allowed.

- Patients who have had major surgery within 3 weeks prior to enrollment are not
eligible. Procedures such as placement of a central vascular catheter, or limited
tumor biopsy, are not considered major surgery.

- Patients who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.