A Phase II Study of Sirolimus and Erlotinib in Recurrent/Refractory Germ Cell Tumors
Condition: Relapsed / Recurrent Germ Cell Tumors
MeSH terms: Neoplasms, Germ Cell and Embryonal; Recurrence
Intervention: Erlotinib; Sirolimus
Intervention MeSH terms: Sirolimus; Erlotinib Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 12 Months
Maximum age: 50 Years
Healthy volunteers: No

Summary:

      The purpose of this study is to find out if the combination of an mTOR inhibitor (sirolimus)
      with an EGFR inhibitor (erlotinib) is effective at treating relapsed or refractory germ cell
      tumors, and to find out what the side-effects of this regimen are.
    

Eligibility criteria:

        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.