Protocol Abstract and Schema

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1 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 Prtcl Abstract and Schema PBTC-042: Phase I study f CDK 4-6 inhibitr PD (palbciclib; IBRANCE) in children with recurrent, prgressive r refractry central nervus system tumrs Descriptin This is a multicenter, Phase I trial fr children with Retinblastma Prtein 1 (Rb1) psitive recurrent, prgressive r refractry central nervus system tumrs. In the recent years there have been several clinical trials in adults with cancer utilizing small mlecule inhibitrs targeting cell cycle regulatry genes such as CDKs (cyclin-dependent kinase). In nrmal cells, these kinases are kept under cntrl by a gene, hwever, this gene is frequently deleted in cancers and these tw kinases are uncntrllably activated which drives the cell t divide and frm cancer. This trial is using PD (palbciclib; IBRANCE), a selective CDK inhibitr, t be evaluated in children with CNS tumrs. PD (Pfizer Crpratin, USA) is an rally active, water sluble, cell-permeable highly specific inhibitr f CDK4 and 6. It is designed t shut dwn the activity f mlecules, CDK4 and 6 that drive cell divisin. PD is expected t wrk nly if the cancer cells demnstrate expressin f the tumr suppressr retinblastma (Rb1) prtein which is needed t cntrl cell grwth even if CDK4/6 is inhibited. A screening test fr presence r absence f Rb1 will therefre be perfrmed in all types f CNS tumrs except diffuse pntine glima (DIPG), medullblastma, r Atypical Teratid Rhabdid Tumr (ATRT) t cnfirm eligibility fr this trial. Ratinale: Survival fr children with recurrent CNS tumrs is dismal and nvel therapeutic ptins need t be develped in rder t imprve utcme. Cancer initiatin and prgressin is dependent n deregulatin f the cmpnents and phases f the cell cycle. Ample evidence exists n alteratins f CDKs, Cyclins, cell cycle inhibitrs, and checkpint prteins in pediatric CNS tumrs. The presence f specific mutatins in the prteins invlved in G1-S phase transitin f the cell cycle in these tumrs is particularly relevant fr the use f a specific CDK4/6 inhibitr like PD Furthermre, it is likely that ver 60% f pediatric CNS tumrs are likely t have intact Rb-prtein, a pre-requisite fr the efficacy f this cell cycle inhibitr. PD has nt been tested in children with cancer thus far. A Phase I study is therefre needed t assess the txicity, MTD, pharmackinetics, and preliminary evidence f efficacy f this agent in this patient ppulatin. Since myelsuppressin is the predminant side effect f this agent, the Phase I study will first evaluate the txicities in children wh have nt been heavily pre-treated previusly. With the MTD identified in less-heavily pre-treated patients (stratum I), this phase I study will be expanded t include heavily pre-treated patients (defined as thse wh have received mre than 4 prir regimens (either myelsuppressive chemtherapy r bilgic) ± cranispinal irradiatin ± myelablative chemtherapy plus stem cell rescue) in a separate chrt (stratum II). Treatment f these patients will be initiated at 50 mg/m 2 /day (ne dse level belw the ptential MTD in stratum I) as the starting dse level. Stratum II is likely t mstly include patients with recurrent medullblastma, ther central PNETs, ATRT, and germ cell tumrs. Recent genmic studies f medullblastma and ATRT have demnstrated that Rb1 prtein is intact in these tumrs. Therefre, patients with medullblastma r ATRT will nt be required t have their tumrs screened fr Rb1 expressin. Versin 7.0 1

2 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 Schema This is a dse escalatin trial f PD t determine the maximum tlerated dse in children with recurrent brain tumrs. PD is taken rally nce a day fr 21 days fllwed by a week rest. One curse is therefre equivalent t 28 days. Therapy may cntinue fr up t tw years (26 curses) in the absence f disease prgressin r unacceptable txicity. Dsing is based n BSA calculated at the beginning f each curse. The starting dse is 50 mg/m 2 fr stratum I and stratum II. PD dse escalatins will be perfrmed accrding t the table belw until the maximum tlerated r recmmended Phase II dse is reached. Since myelsuppressin is the main dse limiting txicity (DLT) f this drug, patients wh have been mre heavily pretreated are likely t experience hematlgic txicity with this agent. Therefre, patients will be divided int tw strata; stratum I- patients wh have received either fcal raditherapy (RT) nly r fcal RT ± 4 prir myelsuppressive chemtherapy and/ r bilgic therapy regimens r stratum II- thse wh have received > 4 prir regimens (either chemtherapy r bilgic agent), ± cranispinal irradiatin, and ± myelablative chemtherapy plus bne marrw r peripheral bld stem cell rescue. Enrllment t Stratum I is currently nging and has accrued 12 patients at dse level 1 (n=3), 2 (n=3), and 3 (n=6). Tw patients enrlled at dse level 3 were inevaluable fr DLT. Of the 10 evaluable patients, 2 f 4 patients at dse level 3 experienced a DLT f grade 4 neutrpenia. Hence the MTD was exceeded at dse level 3, and 3 additinal patients have been enrlled at dse level 2. The maximum tlerated dse (MTD) fr stratum I is expected t be dse level 2 (75 mg/m 2 /day fr 21 days). Since the pssibility f myelsuppressin is expected t be mre in patients enrlled in stratum II (heavily pretreated patients), we cnsider it mre prudent t cmmence enrllment f patients at dse level 1 which is 50 mg/m 2 /day. An MTD will be separately determined fr this stratum. Stratum I and II - PD (IBRANCE) Dsing Regimen and BSA Restrictins Dse Level Dse (mg/m 2 ) BSA (m 2 ) 1* ** *Starting dse fr stratum II ** Current enrllment fr stratum I OBJECTIVES Primary Objectives T determine the maximum tlerated dse (MTD)/Phase II recmmended dse and describe txicities related t PD in children with Retinblastma Prtein 1 (Rb1) psitive recurrent, prgressive, r refractry primary CNS tumrs. MTD will be determined separately in less-heavily pre-treated vs. heavily pre-treated patients. T determine plasma pharmackinetics f PD in children with Rb1 psitive recurrent, prgressive r refractry primary CNS tumrs Secndary Objectives T recrd preliminary evidence f efficacy f PD in children with recurrent CNS tumrs T evaluate CDK4/6, cyclin D1-3, Ink4a-ARF cpy-number variatins in available tumr tissue by array cmparative, genmic hybridizatin (acgh) Versin 7.0 2

3 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 T explre the ptential relatinships between the pharmackinetics f PD and pharmacdynamic respnse (e.g. percentage change in abslute neutrphil cunt (ANC), platelet cunts) T explre the pharmacgenetic plymrphisms in PD metablizing enzymes and transprters and relate these plymrphisms t PD pharmackinetics PATIENT SELECTION Screening Criteria All subjects must meet the fllwing criteria withut exceptin. Screening Cnsent Patients wh are candidates fr enrllment are willing t sign a screening cnsent and prvide pre-trial tumr material fr Rb1 testing. Screening applies t patients with all types f CNS tumrs except DIPG, medullblastma, r ATRT. Tumr Patients must have recurrent, prgressive r refractry central nervus system (CNS) tumrs. Patients with secndary malignant glimas will be eligible fr this study but shuld cnfrm t the strict prir treatment expsure criteria irrespective f the number f individual tumrs treated previusly. Patients with lw grade glimas are excluded. Prir Therapy Stratum I: Less-Heavily Pretreated Stratum Patients wh have received the fllwing: 4 prir treatment regimens* with either myelsuppressive chemtherapy r bilgic agents and/r fcal raditherapy Stratum II: Heavily Pretreated Stratum Patients wh have received the fllwing: 4 prir treatment regimens* with either myelsuppressive chemtherapy r bilgic agents and/r cranispinal irradiatin and/r myelablative chemtherapy with autlgus stem cell rescue *A treatment regimen is defined as a single agent (chemtherapeutic r bilgic), r a sequential cmbinatin f therapies that can include raditherapy (with r withut cncurrent radisensitizer, chemtherapy, r bilgic therapy) fllwed by maintenance therapy (either single r cmbinatin) given ver a perid f time at either diagnsis r relapse. Age Patient must be 4 years and 21 years f age. Patient must be able t swallw capsules. Pre-Trial Tumr Tissue availability Frmalin fixed paraffin embedded tumr tissue (preferably frm the mst recent recurrence) must be available t assess Rb1 prtein status prir t enrllment. Only Versin 7.0 3

4 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 patients with recurrent diffuse intrinsic brain stem glima (DIPG), medullblastma, r ATRT can be enrlled withut the need fr available tumr tissue fr Rb1 prtein status cnfirmatin. BSA: Patients enrlled n dse level 1 (50mg/m2) must have BSA 1.20m2 Patients enrlled n dse level 2 (75mg/m2) must have BSA 0.93m2 Patients enrlled n dse level 3 (95mg/m2) must have BSA 0.70m2 Eligibility fr Treatment Criteria All subjects must meet the fllwing inclusin and exclusin criteria. N exceptins will be given. Eligible Diagnsis Tumr type: Histlgically cnfirmed retinblastma prtein (Rb1) psitive primary recurrent, prgressive, r refractry central nervus system tumrs. Patients with lw grade glimas are excluded. Frmalin fixed paraffin embedded tumr tissue (preferably frm the mst recent recurrence) must be available t assess Rb1 prtein status prir t enrllment. Patients with recurrent diffuse intrinsic brain stem glima (DIPG), medullblastma, r ATRT can be enrlled withut the need fr available tumr tissue fr Rb1 prtein status cnfirmatin. Measureable Disease Patients must have measurable disease (in 2-dimensins) n MRI scan f brain and/r spine t assess preliminary evidence f respnse. Age BSA: Patient must be 4 years and 21 years f age at the time f enrllment. Patients enrlled n dse level 1 (50mg/m2) must have BSA 1.20m2 Patients enrlled n dse level 2 (75mg/m2) must have BSA 0.93m2 Patients enrlled n dse level 3 (95mg/m2) must have BSA 0.70m2 Prir Therapy - Stratum I: Less-Heavily Pretreated Stratum Patients wh have received the fllwing: 4 prir treatment regimens* with either myelsuppressive chemtherapy r bilgic agents and/r fcal raditherapy. - Stratum II: Heavily Pretreated Stratum Patients wh have received the fllwing: > 4 prir treatment regimens* with either myelsuppressive chemtherapy r bilgic agents and/r cranispinal irradiatin and/r myelablative chemtherapy with autlgus stem cell rescue Versin 7.0 4

5 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 *A treatment regimen is defined as a single agent (chemtherapeutic r bilgic), r a sequential cmbinatin f therapies that can include raditherapy (with r withut cncurrent radisensitizer, chemtherapy, r bilgic therapy) fllwed by maintenance therapy (either single r cmbinatin) given ver a perid f time at either diagnsis r relapse. Patients must have fully recvered frm the acute treatment- related txicities f all prir therapies prir t entering this study. Fr thse acute baseline adverse events attributable t prir therapy, patients must meet rgan functin criteria (sectin ) in the Inclusin and Exclusin Criteria. Chemtherapy: Patients must have received their last dse f knwn myelsuppressive anticancer chemtherapy at least three (3) weeks prir t enrllment in the study r at least six (6) weeks fr thse receiving nitrsurea. Bne marrw/stem Cell Infusin: 3 mnths since autlgus bne marrw/stem cell infusin prir t enrllment (stratum II nly) Bilgic therapy: Patients shuld have received their last dse f bilgic agent 7 days prir t enrllment. In the event the patient has received anther bilgic agent and has experienced Grade 2 myelsuppressin, then at least three (3) weeks must have elapsed prir t enrllment. If the investigatinal r bilgic agent has a prlnged half-life then at least three (3) weeks interval is required. Fr patients n mnclnal antibdies including Bevacizumab, please refer t list f half-lives available n the PBTC webpage under Generic Frms and Templates. Raditherapy: Patients must have had their last fractin f: Fcal irradiatin > 2 weeks prir t enrllment Cranispinal irradiatin > 3 mnths prir t enrllment (stratum II nly) Crticsterids: Patients wh are receiving dexamethasne r ther crticsterids must be n a stable r decreasing dse fr at least 1 week prir t enrllment. It is recmmended that patients be ff all sterid therapy r receive the least dse that will cntrl their neurlgic symptms Grwth factrs: All clny frming grwth factr(s) have been discntinued fr at least ne week prir t enrllment (filgrastim, sargramstim, and erythrpietin). Fr patients n lng acting grwth factrs, the interval shuld be tw weeks. Inclusin f Wmen and Minrities Bth males and females f all races and ethnic grups are eligible fr this study. Neurlgic Status Patients with neurlgical deficits that are stable fr a minimum f ne week prir t enrllment. Patients must be able t swallw capsules. Perfrmance Status Karnfsky Perfrmance Scale (KPS fr > 16 years f age) r Lansky Perfrmance Scre (LPS fr 16 years f age) assessed within tw weeks f enrllment must be 60. Versin 7.0 5

6 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 Organ Functin Patients must have nrmal rgan and marrw functin as defined belw: Abslute neutrphil cunt >1,000/mm3 Platelets >100,000/ mm3 transfusin independent (n platelet transfusin ne week prir t enrllment ) Hemglbin 8g/dl Ttal bilirubin 1.5 times upper limit f institutinal nrmal (ULN) fr age AST (SGOT)/ALT(SGPT) < 3 x institutinal upper limit f nrmal fr age Serum albumin 3g/dL Creatinine clearance r radiistpe GFR 70 ml/min/1.73 m2 r a serum creatinine based n age/gender as fllws: Serum Creatinine fr age/gender Age Maximum Serum Creatinine (mg/dl) Male Female 1 t < 2 years t < 6 years t < 10 years t < 13 years t < 16 years years The threshld creatinine values in this Table were derived frm the Schwartz frmula fr estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC. Pregnancy Status Female patients f childbearing ptential must have a negative serum pregnancy test at the time f enrllment. Pregnancy Preventin Patients f childbearing r child fathering ptential must agree t use adequate cntraceptive methds while being treated n this study and fr 97 days after cmpleting therapy. Infrmed Cnsent Patient and/r guardian have the ability t understand and the willingness t sign a written infrmed cnsent dcument accrding t institutinal guidelines. Versin 7.0 6

7 NCI Prtcl #: PBTC-042 Lcal Prtcl #: PBTC-042 Exclusin Criteria Patients with any clinical significant unrelated systemic illness (serius infectins r significant cardiac, pulmnary, hepatic r ther rgan dysfunctin) that is likely t interfere with the study prcedures r results Patients with lw grade glimas and Rb1 negative tumrs Patients with QTc interval f > 450 msec r thse n medicatins knwn t prlng QTc interval (see Errr! Reference surce nt fund.) Prir treatment n a CDK inhibitr (e.g. Flavpiridl) Patients wh are receiving drugs that are strng inducers r inhibitrs f CYP3A4 (seeerrr! Reference surce nt fund.) Patients wh are receiving any ther investigatinal therapy Patients wh require enzyme inducing anti-cnvulsants t cntrl seizures Patients with cataracts n phthalmlgic examinatin. The phthalmlgy reprt frm the institutin shuld clearly specify the presence r absence f cataracts per slit lamp examinatin. Versin 7.0 7