During dose escalation (phase I), standard 3+3 design will be followed.

Retinoblastoma

Clear Cell Sarcoma

Renal Cell Carcinoma

Rhabdoid Tumor

Wilms Tumor

Hepatoblastoma

Neuroblastoma

Germ Cell Tumors

Ewings Sarcoma

Non-rhabdomyosarcoma Soft Tissue Sarcoma

Osteosarcoma

Rhabdomyosarcoma

The starting dose of simvastatin will be 140 mg/m^2/dose BID for 21 days for the first group. Dose escalation for subsequent groups will be 180 mg/m^2/dose BID, 225 mg/m^2/dose BID, and 290 mg/m^2/dose BID. If the maximum tolerated dose (MTD) has been exceeded at the first dose level, then the subsequent cohort of subjects will be treated at a dose of 100 mg/m2/dose BID (dose level 0). Simvastatin will be administered orally twice daily, approximately 12 hours apart. Feeding tube (nasogastric tube or gastrostomy tube, NOT a jejunum localized tube) administration is allowed. If a subject vomits a dose of simvastatin, it will not be repeated.

Simvastatin

The dose of cyclophosphamide will be fixed at 250 mg/m^2/dose. Cyclophosphamide will be administered intravenously over 30 minutes once daily for 5 days every 21 days.

Cyclophosphamide

The dose of topotecan will be fixed at 0.75 mg/m^2/dose. Topotecan will be administered, after cyclophosphamide, intravenously over 30 minutes once daily for 5 days every 21 days.

Topotecan

Myeloid growth factor (G-CSF or pegylated G-CSF) will be initiated 24-48 hours after the completion of topotecan and cyclophosphamide for all subjects, which would be day 6 or 7. Myeloid growth factor should continue until the absolute neutrophil count is greater than 2,000/mm^3

Myeloid growth factor

Children's Healthcare of Atlanta/Emory University

Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

A Phase 1 Study Using Simvastatin in Combination With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

MTD will be the maximum dose at which fewer than one-third of subjects experience dose-limiting toxicities (DLTs) during Cycle 1 of therapy.

DLT will be defined as any of the following events that are possibly, probably, or definitely attributable to study drug:
Non-hematological dose-limiting toxicity: Any Grade 3 or 4 non-hematological toxicity (excluding nausea, alanine transaminase (ALT) or aspartate aminotransferase (AST) that returns to baseline or ≤ grade 1 within 7 days of study drug interruption, fever, infection, hypophosphatemia, hypokalemia, hypocalcemia, hypomagnesemia, or creatinine phosphokinase (CPK) elevation that returns to baseline or ≤ grade 1 within 7 days of study drug interruption), Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered sufficiently medically significant or sufficiently intolerable by subjects that it requires treatment interruption, or hematological dose-limiting toxicity, defined as neutropenia or thrombocytopenia that precludes initiation of the next cycle of therapy within 14 days of the scheduled start date.

Response is defined as CR (Complete Response) or PR (Partial Response) per Response Evaluation Criteria in Solid Tumor (RECIST criteria). Possible evaluations include: CR: Disappearance of all target lesions. PR: At least a 30% decrease in the size of target lesions.
Response rate (%) = (number of patients with CR+PR/number of patients)*100

Change in serum total cholesterol level after treatment with simvastatin. A decrease from baseline to the end of treatment, a negative value, indicates an improvement.

Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the IL-6 will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.

Change in serum interleukin-6 (IL-6) level after treatment with simvastatin. Serum levels of the sIL-6r will be assayed using by enzyme-linked immunosorbent assay (ELISA). Higher levels are typically interpreted as worsening of condition.

Change in STAT-3 expression after treatment with simvastatin. STAT-3 will be measured using phospho-specific flow cytometry, or phospho-flow.

Change in phospho-STAT3 expression after treatment with simvastatin. Phospho-STAT3 expression will be measured using phospho-specific flow cytometry, or phospho-flow.

Kelly Goldsmith

Assistant Professor

Emory University

Children's Healthcare of Atlanta

Non-small Cell Lung Cancer (NSCLC)

Istituto Clinico Humanitas

Pemetrexed in Advanced Non-small Cell Lung Cancer

Retrospective Study of Molecular Predictors of Sensitivity and Resistance to Pemetrexed in Advanced Non-Small Cell Lung Cancer

Armando Santoro, MD

Patients receive erlotinib hydrochloride PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients receive oral erlotinib hydrochloride once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
erlotinib hydrochloride: Given orally

Arm I

Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
pemetrexed disodium: Given IV

Arm II

Total

Sex: Female, Male

Region of Enrollment

Estimated using the method of Kaplan-Meier survival curves to compare PFS between the erlotinib and pemetrexed arms using an intent-to-treat (ITT) analysis. Due to the small sample size (21 of the required 954 patients ~2%), analyses within the FISH(+) and FISH(-) groups were not performed, and no formal analyses for the primary or the secondary efficacy outcomes were performed.

Progression-free Survival (PFS)

The distribution of all time to event data will be estimated using the method of Kaplan-Meier survival curves.

Time to Treatment Failure

Will be estimated using the method of Kaplan-Meier survival curves. A 1-sided stratified log rank test [accounting for all the stratification factors except FISH status and cooperative group] will be used to compare overall survival between the erlotinib and pemetrexed arms within the FISH(+) and FISH(-) subgroups, compare overall and progression free survival between the erlotinib and pemetrexed arms within the subgroups defined on the basis of the epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC), and EGFR gene mutation status (MUT). Cox proportional hazards model will be used to assess potential differences.

Overall Survival

Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. The proportion of patients with confirmed CR and PR will be computed within each treatment arm and exact binomial confidence intervals for the true proportion computed. Chi-square test and Fisher's exact test will be used to compare the response rates between the treatment arms within the subgroups defined by FISH status, IHC, and MUT.

Confirmed Response Rate Defined as Complete Response (CR) or a Partial Response (PR) Per Response Evaluation Criteria In Solid Tumors (RECIST)

Overall Study

Alex A. Adjei, M.D., Ph.D

Recurrent Non-Small Cell Lung Carcinoma

Stage IIIA Non-Small Cell Lung Cancer

Stage IIIB Non-Small Cell Lung Cancer

Stage IV Non-Small Cell Lung Cancer

Erlotinib Hydrochloride

Pemetrexed Disodium

Mayo Clinic in Arizona

Sparks Regional Medical Center

Kaiser Permanente-Deer Valley Medical Center

Kaiser Permanente-Fremont

Fremont - Rideout Cancer Center

Kaiser Permanente-Oakland

Valley Care Health System - Pleasanton

Kaiser Permanente-Redwood City

Kaiser Permanente-Richmond

Kaiser Permanente-Roseville

University of California Davis Comprehensive Cancer Center

Kaiser Permanente-South Sacramento

Kaiser Permanente - Sacramento

Kaiser Permanente-San Francisco

Kaiser Permanente-Santa Teresa-San Jose

Kaiser Permanente San Leandro

Kaiser Permanente-San Rafael

Kaiser Permanente Medical Center - Santa Clara

Kaiser Permanente-Santa Rosa

Kaiser Permanente-South San Francisco

Kaiser Permanente-Stockton

Tahoe Forest Cancer Center

Kaiser Permanente Medical Center-Vacaville

Kaiser Permanente-Vallejo

Kaiser Permanente-Walnut Creek

The Medical Center of Aurora

Boulder Community Hospital

Penrose-Saint Francis Healthcare

Porter Adventist Hospital

Exempla Saint Joseph Hospital

Presbyterian - Saint Lukes Medical Center - Health One

Rose Medical Center

Colorado Cancer Research Program CCOP

Swedish Medical Center

Saint Mary's Hospital and Regional Medical Center

North Colorado Medical Center

Saint Anthony Hospital

Sky Ridge Medical Center

Longmont United Hospital

McKee Medical Center

Saint Mary Corwin Medical Center

North Suburban Medical Center

SCL Health Lutheran Medical Center

Bristol Hospital

Middlesex Hospital

Lynn Regional Cancer Center - West

Boca Raton Comprehensive Cancer Center

Mayo Clinic in Florida

MacNeal Hospital and Cancer Center

Saint Joseph Medical Center

Illinois CancerCare-Bloomington

Graham Hospital Association

Illinois CancerCare-Canton

Illinois CancerCare-Carthage

Memorial Hospital

Hematology and Oncology Associates

Northwestern University

University of Chicago Comprehensive Cancer Center

Decatur Memorial Hospital

Eureka Hospital

Illinois CancerCare-Eureka

Galesburg Cottage Hospital

Illinois CancerCare Galesburg

Illinois CancerCare-Cottage

Illinois CancerCare-Havana

Mason District Hospital

Hematology Oncology Associates of Illinois-Highland Park

Hopedale Medical Complex - Hospital

Midwest Center for Hematology Oncology

Illinois CancerCare-Kewanee Clinic

NorthShore Hematology Oncology-Libertyville

Illinois CancerCare-Macomb

Mcdonough District Hospital

Loyola University Medical Center

Holy Family Medical Center

Illinois CancerCare-Monmouth

DuPage Medical Group-Ogden

Illinois Cancer Specialists-Niles

Bromenn Regional Medical Center

Community Cancer Center Foundation

Illinois CancerCare-Community Cancer Center

Illinois CancerCare-Ottawa Clinic

Ottawa Regional Hospital and Healthcare Center

Illinois CancerCare-Pekin

Pekin Cancer Treatment Center

Pekin Hospital

Methodist Medical Center of Illinois

Proctor Hospital

OSF Saint Francis Medical Center Radiation Oncology Service at the Central Illinois Comprehensive CC

Illinois CancerCare-Peoria

Illinois Oncology Research Association CCOP

OSF Saint Francis Medical Center

Illinois CancerCare-Peru

Illinois Valley Hospital

Illinois CancerCare-Princeton

Perry Memorial Hospital

Hematology Oncology Associates of Illinois - Skokie

Illinois CancerCare-Spring Valley

Saint Margaret's Hospital

Memorial Medical Center

Pemetrexed Disodium or Erlotinib Hydrochloride as Second-Line Therapy in Treating Patients With Advanced Non-small Cell Lung Cancer

MARVEL: Marker Validation of Erlotinib in Lung Cancer- A Phase III Biomarker Validation Study of Second-Line Therapy in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Randomized to Pemetrexed Versus Erlotinib

reductase/sarcoma

Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors

Pemetrexed in Advanced Non-small Cell Lung Cancer

Pemetrexed Disodium or Erlotinib Hydrochloride as Second-Line Therapy in Treating Patients With Advanced Non-small Cell Lung Cancer

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