PBTC-026: A Feasibility Study of SAHA Combined with Isotretinoin and Chemotherapy in Infants with Embryonal Tumors of the Central Nervous System

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1 PBTC-026: A Feasibility Study f SAHA Cmbined with Istretinin and Chemtherapy in Infants with Embrynal Tumrs f the Central Nervus System PURPOSE: This clinical trial is studying the side effects f giving vrinstat and istretinin tgether with cmbinatin chemtherapy and t see hw well it wrks in treating yung patients wh have undergne surgery fr embrynal tumrs f the central nervus system. Study Type: Interventinal Masking: Open Label Primary Purpse: Treatment OBJECTIVES: Primary Secndary T determine the bjective respnse rate t the cmbinatin f cixutumumab and temsirlimus in patients with relapsed r refractry stesarcma, Ewing sarcma, rhabdmysarcma, r nnrhabdmysarcma sft tissue sarcma. T further describe the txicities (including dse-limiting txicities) f cixutumumab and temsirlimus administered n this schedule. T assess the prgressin-free survival fr patients treated in each disease stratum with this drug cmbinatin. T assess the incidence f insulin-like grwth factr 1 receptr (IGF-1R), insulin receptr, ERK, RON, and mammalian target f rapamycin (mtor) pathway activatin in archival tumr material, and crrelate with respnse. T evaluate minimal residual disease and IGF-1R tumr cell expressin in the bld and bne marrw f Ewing sarcma patients using flw cytmetry. OUTLINE: This is a multicenter study. Patients are stratified accrding t diagnsis (stesarcma vs Ewing sarcma/pnet vs rhabdmysarcma vs nn-rhabdmysarcma sft tissue sarcma). Patients receive cixutumumab IV ver 1 hur and temsirlimus IV ver 30 minutes n days 1, 8, 15, and 22. Treatment repeats every 28 days fr up t 25 curses in the absence f disease prgressin r unacceptable txicity. Archived tumr tissue samples frm mst recent bipsy are cllected and analyzed fr IGF-1R, insulin receptr, AKT, ERK, mtor, and S6 kinase pathway activatin by immunhistchemistry (IHC) and banked fr future crrelative studies. Bld and bne marrw samples, frm patients with Ewing sarcma, may be cllected at baseline and peridically during treatment fr minimal residual disease analysis by flw cytmetry.

2 After cmpletin f study treatment, patients are fllwed up peridically fr 5 years. AGES ELIGIBLE FOR STUDY: up t 3 Years DISEASE CHARACTERISTICS: Patients with any f the fllwing tumrs wh have experienced relapse fllwing frnt-line therapy, r wh are refractry t frnt-line therapy, are : Ostesarcma Ewing sarcma/peripheral primitive neurectdermal tumr (PNET) Rhabdmysarcma Nn-rhabdmysarcma sft tissue sarcma Patients must have had histlgic verificatin f malignancy at riginal diagnsis r relapse All patients are required t submit archival tumr samples fr immunhistchemical analysis (either paraffin-embedded tumr blcks r unstained slides) Tissue samples cllected at riginal diagnsis r at relapse r at any subsequent resectins r bipsies shuld be available and ready fr shipment t the Bipathlgy Center (BPC) at time f study enrllment; the samples are required even if tissue samples have previusly been sent t the BPC fr ther purpses r studies; blcks r slides shuld be shipped t the BPC within 7 days f study enrllment Patients must have radigraphically measurable disease Measurable disease is defined as the presence f at least ne lesin n magnetic resnance imaging (MRI) r cmputed tmgraphy (CT) scan that can be accurately measured with the lngest diameter a minimum f 10 mm in at least ne dimensin (CT scan slice thickness n greater than 5 mm) The fllwing d nt qualify as measurable disease: Malignant fluid cllectins (e.g., ascites, pleural effusins) Bne marrw infiltratin Lesins nly detected by nuclear medicine studies (e.g., bne, gallium, r psitrn emissin tmgraphy [PET] scans) Elevated tumr markers in plasma r cerebrspinal fluid (CSF) Previusly radiated lesins that have nt demnstrated clear prgressin pst radiatin

3 Leptmeningeal lesins that d nt meet the measurements nted abve Patient's current disease state must be ne fr which there is n knwn curative therapy r therapy prven t prlng survival with an acceptable quality f life Patients with knwn central nervus system metastases are excluded unless treated surgically r with raditherapy and stable with n recurrent lesins fr at least 3 mnths PATIENT CHARACTERISTICS: Patients must have a Lansky r Karnfsky perfrmance status scre f 50%, crrespnding t Eastern Cperative Onclgy Grup (ECOG) categries 0, 1, r 2; use Karnfsky fr patients > 16 years f age and Lansky fr patients 16 years f age Patients wh are unable t walk because f paralysis, but wh are up in a wheelchair, will be cnsidered ambulatry fr the purpse f assessing the perfrmance scre Fr patients with slid tumrs withut bne marrw invlvement: Peripheral abslute neutrphil cunt (ANC) 1,000/μL Platelet cunt 100,000/μL (transfusin independent, defined as nt receiving platelet transfusins within a 7-day perid prir t enrllment) Hemglbin 8.0 g/dl (may receive red bld cell [RBC] transfusins) Fr patients with slid tumrs and knwn bne marrw metastatic disease: ANC 750/μL Platelet cunt 50,000/μL (may receive platelet transfusins) Hemglbin 8.0 g/dl (may receive RBC transfusins) Fr patients with knwn bne marrw metastatic disease, transfusins are permitted t meet bth platelet and hemglbin criteria; patients must nt be knwn t be refractry t red bld cell r platelet transfusins Creatinine clearance r radiistpe GFR 70 ml/min OR a serum creatinine based n age/gender as fllws: 0.6 mg/dl (1 t < 2 years f age) 0.8 mg/dl (2 t < 6 years f age) 1.0 mg/dl (6 t < 10 years f age) 1.2 mg/dl (10 t < 13 years f age) 1.5 mg/dl (males) r 1.4 mg/dl (females) (13 t < 16 years f age) 1.7 mg/dl (males) r 1.4 mg/dl (females) ( 16 years f age)

4 Ttal bilirubin 1.5 times upper limit f nrmal (ULN) Serum glutamic pyruvate transaminase (SGPT) (alanine amintransaminase [ALT]) 2.5 times ULN (fr the purpse f this study, the ULN fr SGPT is 45 U/L) Serum albumin 2 g/dl Patients with seizure disrder may be enrlled if receiving nn-enzymeinducing anticnvulsants and well cntrlled Patients with knwn type I r type II diabetes mellitus are nt Serum glucse values must be within the nrmal limits fr age; if the initial bld glucse is a randm sample that is utside nrmal limits, then a fllw-up fasting bld glucse shuld be btained and must be within the nrmal limits fr age Serum chlesterl levels must be < grade 2 (< 300 mg/dl), and serum triglyceride levels must be < grade 2 (< 2.5 times ULN) Patients wh are pregnant r breast-feeding are nt fr this study Negative pregnancy tests must be btained in girls wh are pstmenarchal Males r females f reprductive ptential may nt participate unless they have agreed t use an effective cntraceptive methd fr the duratin f the study and fr 3 mnths after the last dse f cixutumumab Patients wh have an uncntrlled infectin are nt Patients wh, in the pinin f the investigatr, may nt be able t cmply with the safety mnitring requirements f the study are nt PRIOR CONCURRENT THERAPY: See Disease Characteristics There is n limit t the number f prir treatment regimens; hwever, patients must have fully recvered frm the acute txic effects f all prir chemtherapy, immuntherapy, r raditherapy prir t study enrllment Patients must nt have received myelsuppressive chemtherapy within 3 weeks f enrllment (6 weeks if prir nitrsurea) At least 7 days must have elapsed since the cmpletin f therapy with a grwth factr; at least 14 days must have elapsed after receiving pegfilgrastim At least 7 days must have elapsed since the cmpletin f therapy with a bilgic agent; fr agents that have knwn adverse events ccurring beynd 7 days after administratin, this perid prir t enrllment must be extended beynd the time during which adverse events are knwn t ccur At least 3 half-lives must have elapsed since prir therapy that included a mnclnal antibdy

5 2 weeks must have elapsed since lcal palliative raditherapy (XRT) (small prt); 3 mnths must have elapsed if 50% radiatin f pelvis; 6 weeks must have elapsed if therapeutic dses f metaidbenzylguanidine (MIBG) r ther substantial bne marrw irradiatin was given N evidence f active graft-vs-hst disease and 2 mnths must have elapsed since stem cell transplant r rescue Grwth factrs that supprt platelet r white cell number r functin must nt have been administered within the 7 days prir t enrllment (14 days if Neulasta ) Patients receiving crticsterids wh have nt been n a stable r decreasing dse f crticsterid fr the 7 days prir t enrllment are nt Patients wh are currently receiving anther investigatinal drug are nt Patients wh are currently receiving ther anti-cancer agents, including chemtherapy, raditherapy, immuntherapy, r bilgic therapy, are nt Patients receiving insulin r grwth hrmne therapy are nt Patients wh are receiving enzyme-inducing anticnvulsants are nt Use f warfarin is nt allwed while n study; patients already n warfarin shuld use alternative anticagulants while n this study; warfarin must nt have been administered within 7 days f starting prtcl therapy Patients wh have received prir therapy targeting IGF-1R with either mnclnal antibdies r small mlecule tyrsine kinase inhibitrs are NOT Prir treatment with mtor inhibitrs (e.g., rapamycin, temsirlimus, everlimus, deferlimus) is NOT allwed Patients wh have had majr surgery within 3 weeks prir t enrllment are nt ; prcedures such as placement f a central vascular catheter r limited tumr bipsy are nt cnsidered majr surgery Fr mre infrmatin cntact: Cincinnati Children s Hspital Medical Center Divisin f Hematlgy/Onclgy 3333 Burnet Ave., Cincinnati, OH Phne: cancer@cchmc.rg