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

Study Overview
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Brief Summary
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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.

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

Conditions
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Relapsed / Recurrent Germ Cell Tumors

Intervention / Treatment
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* Drug: Erlotinib
* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib + sirolimus<br> | Drug: Erlotinib<br> <br> Drug: Sirolimus<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The PFR, Defined as the Proportion of Patients With Refractory Germ Cell Tumors Free of Objective Disease Progression After 4 Cycles (16 Weeks) of Therapy With Erlotinib and Sirolimus | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions: Progressive Disease (PD), >= 20% increase in the sum of the longest diameter of target lesions or the development of any new lesions | 16 weeks | 
| The Toxicities of the Combination of Sirolimus and Erlotinib Administered on This Schedule. | The number of patients with drug related grade III, IV, or V adverse events according to the Common Terminology Criteria for Adverse Events version 4.0. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Incidence of EGFR and mTOR Pathway Activation in Banked Tumor Specimens. |  | 3 years | 
| The Progression-free Interval (PFI) for Patients With Germ Cell Tumors With and Without Evidence of EGFR/mTOR Pathway Activation With This Drug Combination. |  | 3 years |