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

Summary

This will be a phase ii study to determine the response rate of children, adolescents, and young adults with relapsed / refractory germ cell tumors to the combination of sirolimus and erlotinib. Patients will be treated with these medications daily on a continuous schedule. The initial dose of sirolimus will be 1mg/m2 daily (max 2mg) and adjusted to obtain trough plasma concentrations of 10-15ng/mL. The initial dose of erlotinib will be 85mg/m2 daily (max 150mg/day). The initial dose of erlotinib will be higher than used in the pediatric phase ii study of sirolimus and erlotinib for low grade gliomas. The dose of 65mg/m2/day used in the prior phase ii study was empirically chosen and not a defined MTD. it was very well tolerated with no grade iV or V adverse events and only two grade iii adverse events: cellulitis without neutropenia in one patient and neutropenia in one patient. The dose of 85mg/m2/day used in this study was chosen given that there are suggestions that erlotinib concentration correlates with efficacy in nSCLC patients, especially those with wildtype eGFR. Further, erlotinib clearance is faster in pediatric patients and the incidence of the on target rash is lower, both again suggesting the need for a higher dose in this population. This dose was the pediatric MTD in the Children's oncology Group phase i study of erlotinib in combination with temozolamide, and equivalent to the well tolerated adult dose of 150mg/day in the adult phase ii study of sirolimus and erlotinib. note that the maximum dose of 150mg/day is equal to the adult phase ii study and FDa approved dose, so this only represents a dose increase for pediatric patients.

as there is significant inter-patient variability in the pharmacokinetics of erlotinib and drug exposure and the development of low grade rash have been shown to correlate with outcome in adult studies of this agent, patients who do not develop grade ii or greater drug-related rash (which is maximal at 2-3 weeks of therapy) or any dose limiting toxicities during cycle 1 will be dose-escalated to 120mg/m2/day (max 200mg) for the second and subsequent cycles (the MTD of erlotinib in combination with radiotherapy and approximately the MTD of single agent erlotinib (125mg/m2/day) in two studies pediatric brain tumor patients.)

To assess biological correlates of efficacy, we will assess banked tumor specimens (from the enrolled patients) for evidence of mToR pathway activation by immunohistochemical staining for eRBB1 and eRBB2 receptors (peRBB2, paKT1, peRK1/2, pmToR, p70S6, and pRPS6.) expression of these targets will be correlated with response to therapy. Pharmacodynamic assessment of mToR pathway inhibition will be obtained by measuring activity of the downstream pathways in peripheral blood mononuclear cells (paKT, peRK, pS6) prior to starting therapy, and at the end of cycle 1, and cycle 2 if the erlotinib dose is escalated. Trough sirolimus and erlotinib levels will be obtained simultaneously to correlate pathway inhibition with drug exposure.

Participant Eligibility


* 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 teratoma (mature or immature), pure germinoma, or pure seminoma.

* 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 platinum 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.

* Adequate bone marrow function

* Adequate renal function

* Adequate liver function

* Adequate central nervous system

* 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).