ࡱ>   !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~Root EntryF ǒؽplo!Book Y+_VBA_PROJECT>$m>$mdir+   } }  }  }  } } !! } "" } ## } $$} %% } && } '' } (( ))T0)b)b ))eb))) ) b )  )b ) )))E)))K )@)e)bE)KE)))T0)) b))b))erProtocol Number Design Type "Course1 Course 2   Course 3   Course 4 Course 5 Course 6 0Course 7 Course 8 !"Course 9 #%& Course 10 '(#Patient I. D. Dose Level Dose Level Worst Dose Level Dose Level Worst   Dose Level  Dose Level  Worst  Dose Level Dose Level Worst Dose Level Dose Level Worst Dose Level Dose Level Worst Dose Level Dose Level Worst Dose Level Dose Level  Worst!" Dose Level# Dose Level $Worst%& Dose Level' Dose Level (Worst $  Start Da  Worksheet&Tools&WindowChart&Tools&WindowVisual Basic Module&Tools&Window\pzhaoy Freidlin B ChangeViewPort Module1.runprogram ShowTextScroller=xZ$e8T@"1Arial1Arial1Arial1Arial1Arial1 Arial1 Arial1 Arial1 Arial1Arial1 Arial1Tahoma"$"#,##0_);\("$"#,##0\)"$"#,##0_);[Red]\("$"#,##0\) "$"#,##0.00_);\("$"#,##0.00\)%""$"#,##0.00_);[Red]\("$"#,##0.00\)5*2_("$"* #,##0_);_("$"* \(#,##0\);_("$"* "-"_);_(@_),))_(* #,##0_);_(* \(#,##0\);_(* "-"_);_(@_)=,:_("$"* #,##0.00_);_("$"* \(#,##0.00\);_("$"* "-"??_);_(@_)4+1_(* #,##0.00_);_(* \(#,##0.00\);_(* "-"??_);_(@_) 0.00000.000 0.000000.0 General\  #,##0\ 0\ \ 0.0.\ # "This is line"\ 0\ "of the text"                + ) & ( , *      @  @   @   @  @  @  $ @"X "X "X "X !X !X !X "X  !X  !X  $ @     !X  "X Comma [0]_YAHTZEE2Comma_YAHTZEE2Currency [0]_YAHTZEE2Currency_YAHTZEE28 ``i̜̙3f3333f3ffff333ff333f33f33BBB: Module1 Module2  Sheet1 ScrollTextDlgScrollTextSheet Sheet2 Sheet3 Sheet4 !Sheet5 ;Sheet6 U Sheet7 o!Sheet8 "Sheet9#Sheet10$Sheet11%Sheet12&Sheet13 (Sheet14%)Sheet15?*Sheet16 "ff3f??f=xZ$e8T> xZ$e8 "Z??f=xZ$e8T> xZ$e8  (G)>Sh}Ғ  dMbP?_*+%&APage &PMFHP LaserJet 4/4M Plus PS 600e pD; odXX"dX??U} }  }  }  } }  }  }  } } m } } } } }  }  } } I }  }  } }  }  }  } }  }  } te Administered Recommended!Toxicity Start Date Administered Recommended!Toxicity  Start Date Administered Recommended !Toxicity  Start Date Administered Recommended!Toxicity Start Date Administered Recommended!Toxicity Start Date Administered Recommended!Toxicity Start Date Administered Recommended!Toxicity Start Date Administered Recommended !Toxicity! Start Date" Administered# Recommended$!Toxicity% Start Date& Administered' Recommended(!Toxicity 2% % %  % % %  %  %! $%%(% % %        ! $%( 1 % %      ! $% ( % %       ! $% ( %        ! $% ( % % %      ! $% ( %        ! $% (%          ! $%(% %         ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(%          ! $%(          ! $%(          ! $%(          ! $%(          ! $%(BXt )T0!)b")b#)$)eb%)&)')() b)) *)b+),)-).)E/)0)1)K 2)@3)e4)bE5)KE6)7)8)T09):) b;)<)b=)>)er?)e         ! $% (! ! ! !  ! ! ! ! ! ! !$%!(" " " "  " " " " " ! "$%"(# # # #  # # # # # ! #$%#($ $ $ $  $ $ $ $ $ ! $$%$(% % % %  % % % % % ! %$%%(& & & &  & & & & & ! &$%&(' ' ' '  ' ' ' ' ' ! '$%'(( ( ( (  ( ( ( ( ( ! 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RL Arialt$P tD$PD$L$D$t$P_$t$\t$Vt$ t PUf t$ VO^t$QVt$ h8EeVC tD$L$QP+t$Vt-^ AfAAA fAASVWd% TAACLminor deviations from the recommended dose, failure to follow the      T#!AA#:L recommended dose schedule may invalidate the future dose  <   T#%2AA#Lp recommendations.   RLArial$PhEeW uD$t$$L$ PdD$t$lD$P u+ P*M uSD$P u2t$D$t$Pk uD$L$PD$$L$D$t$P_^VWfL$D$ fL$t$fD$ >u:j[V u+j]V u^% T4ETAAEQLThis program provides assistance in dose level assignment for e  TVeAAVCLAccelerated Titration Designs for Phase I Clinical Trials @    TgrvAAg>L[Simon, Freidlin, Rubinstein, Arbuck, Collins, Christian    <   TxAAxHLJournal of National Cancer Institute 1997; 89 1138-47]. For additional  TAACLassistance or clarification, Drs. Richard Simon (rs10m@nih.gov) and[     TAA=LLarry Rubinstein (rubinstein@ctep.nci.nih.gov) are available.P   RL Arial t-|$t&t$WA ujjjjjjjL$4t$/t$N` t Us]_^[l$b l$d VWTuDD$ ;r D$9HtDt$u!|$ 9>s  t t$_^ VDt$\ tu% TIAAI3LBrief Description o<f Accelerated Titration Design 2$     RLArialDPV D$HtL$ Qt$P}D$ t~D$ D$,PjD$L$jtD$0L$0P4 D$FD$,t$DPWteD$$ |$0D$0L$QhhEet$8 ur|$kD$L$tjL$Q L$$QL$PD$tRP( u % TAAJLThe dose escalation/de-escalation rules for design 2 are based on genericT AANLdefinitions of life threatening toxicity (LT), dose limiting toxicity (DLT),   % % " !  % % 6Ml!??% 6Ml!??& <WMFC )"% 6"Ml"!??3% 63Ml3!??D% 6DMlD!??U% 6UMlU!??f% 6fMlf!??w% 6wMlw!??% 6Ml!??% 6Ml!??% 6Ml!??% 6Ml!??% 6Ml!??% 6Ml!??% 6Ml!??%< 6Ml!??% 6Ml!??% % % " !  % "   ''', -- @ !- @ !--' ,-' ,- @ !"   Arial???????????????????????-l2 Cminor deviations from the recommended dose, failure to follow the t      ^2 #: recommended dose schedule may invalidate the future dose     "2 # recommendations.    Arial?????????????????????????-2 EQThis program provides assistance in dose level assignment for   l2 VCAccelerated Titration Designs for Phase I Clinical Trials    d2 g><[Simon, Freidlin, Rubinstein, Arbuck, Collins, Christian       s2 xHJournal of National Cancer Institute 1997; 89 1138-47]. For additional  l2 Cassistance or clarification, Drs. Richard Simon (rs10m@nih.gov) andi     c2 =Larry Rubinstein (rubinstein@ctep.nci.nih.gov) are available.v     Arial?A????????????Ujj%jjU??-T2 I3Brief Description of Accelerated Titration Design 2      Arial?????U????????????????-v2 JThe dose escalation/de-escalation rules for design 2 are based on generic|2 Ndefinitions of life threatening toxicity (LT), dose limiting toxicity (DLT),   -"Systemf%``'-', -- @ !- @ !"-" @ !"3-3 @ !3D-D @ !DU-U @ !<Uf-f @ !fw-w @ !w- @ !- @ !- @ !- @ !- @ !- @ !- @ !- @ !- @ !-- -' ,-'Q =xZ$e8T> "  $Km 8  dMbP?_*+%&APage &PMFHP LaserJet 4/4M Plus PS 600 pD; odXX"dX??U} A T0@b@@b@bb  b b D b;0;0b b000b~bb0b(D(<Accelerated Titration Designs for Phase I Clinical Trials&(Biometric Research Branch, NCI(R)JWarning: this program provides only general guidance related to proposed U)M accelerated titration designs for phase I clinical trials. It is not meantL4Dto substitute for professional medical judgement in the treatment ofJ4Bindividual patients. All dose level assignments should be verifiedM4E independently. In addition, while an effort was made to accommodateK 4Cminor deviations from the recommended dose, failure to follow the B 4: recommended dose schedule may invalidate the future dose  4 recommendations.  'Y *QThis program provides assistance in dose level assignment for K*CAccelerated Titration Designs for Phase I Clinical Trials F*>[Simon, Freidlin, Rubinstein, Arbuck, Collins, Christian P*HJournal of National Cancer Institute 1997; 89 1138-47]. For additionalK*Cassistance or clarification, Drs. Richard Simon (rs10m@nih.gov) andE*=Larry Rubinstein (rubinstein@ctep.nci.nih.gov) are available.'';&3Brief Description of Accelerated Titration Design 2+R,JThe dose escalation/de-escalation rules for design 2 are based on genericV,Ndefinitions of life threatening toxicity (LT), dose limiting toxicity (DLT), P3Hmoderate' toxicity (MOD), 'mild' toxicity (MILD) and no toxicity (NONE).T,LDefinitions of these events must be specified for each protocol for Phase I ,clinical trials.,Q,IThe method used for dose assignment for the first course of a new patientS,Kdepends on whether the patient is entered during the early accelerated modeU,Mor the later standard mode of the trial. During the early mode, there is one D' l H* VYPNQOF ]OJTOI ? VZTX UW T0!b"b#$%&'b(b)*b+b,D-b./;00;01b 2b3045060b7~8b9b:;<0=>b?Y ,Qpatient per cohort, and the dose for each patient is one dose level (a factor of U!,M1.4) higher than that used for the first course of the previous patient. The S",Kaccelerated mode ends when one patient experiences DLT or worse during the V#,Nfirst course of treatment or when two patients experience 'moderate' toxicity -$,%during the first course of treatment.%,P&,HWhen the accelerated mode ends, the dose assignment for the first courseR',Jof a new patient is the same as that of the standard Phase I design. Two W(,Oadditional patients are placed on the dose level at which the last new patient X),Pwas treated, and subsequently, cohorts of three to six patients are started at [*,Seach dose level. If zero of three experience first course DLT or worse, the next ^+,Vcohort starts one dose level higher (a multiplicative factor of 1.4). If one of three X,,Pexperience first course DLT or worse, up to three more patients are started at U-,Mthe same dose level. If two or more experience first course DLT or worse, no W.,Ofurther patients are started at that dose. The largest dose level at which lessR/,Jthan two patients experience first course DLT or worse is expanded to six 0, patients.1,K2,CThe intra-patient dose modification options are defined as follows:3* Option A:  +4,#No intra-patient dose escalation. X5,PIf the worst toxicity is DLT or worse during a course, the dose is reduced one 76,/dose level for the next course of that patient.7* Option B:  X8,PIf the worst toxicity is DLT or worse during a course, the dose is reduced one ]9,Udose level for the next course of that patient. If the worst toxicity is 'moderate' Z:,Rthe dose level remains the same for the next course. If the worst toxicity is lessN;,Fthan 'moderate', the dose is increased one level for the next course. <,=,;>&3Brief Description of Accelerated Titration Design 4?,D l]YWZ1 TV[\_b\Y[V O/\;\a^R ?@T0AbBbCDEFGbHbIJbKbLDMbNO;0P;0Qb RbS0TU0V0bW~XbYbZ[\0]^b_T@,LThe dose escalation/de-escalation rules for design 4 also assume that there ^A,Vare protocol-specific definitions of life threatening (LT), DLT, 'moderate', 'mild' PB,Hand no toxicity. Single dose steps represent 40% increments (as above),YC,Qbut during the early acceleration phase of the trial, double dose steps are used 3D,+(approximately 100% increments; 1.4 x 1.4).E,RF,JThe method used for a dose level assignment for the first course of a new RG,Jpatient depends on whether the patient enters during the early acceleratedWH,Omode or the later standard mode of the trial. During the early mode, there is VI,None patient &per cohort and the first-course dose for each patient is twice theUJ,Mdose used for the first course of the previous patient. The accelerated mode MK,Eends when one patient experiences DLT or worse during any course of XL,Ptreatment or when two different patients experience 'moderate' toxicity during WM,Oany course of treatment (so long as the dose level does not exceed that of the TN,Lfirst course of the most recent patient). The accelerated mode is suspended UO,Mwhen the initial instance of 'moderate' toxicity occurs (so long as the dose TP,Llevel does not exceed that of the first course of the most recent patient), XQ,Pif two additional patients have not been treated at that dose level, or higher,UR,Mwith no worse than mild toxicity. During the suspension, the dose is assignedWS,Ofor new patients, or for additional courses of ongoing patients, as in the non-ST,Kaccelerated phase (except that ongoing patients treated below the level at LU,Dwhich moderate toxicity was seen continue to be escalated as in the OV,Gaccelerated mode). The suspension is resolved by resuming accelerationQW,Iif two patients (other than the one who had toxicity which triggered the WX,Othe suspension), treated at the current dose, or higher, for any course, show RY,Jno worse than mild toxicity. Otherwise, the suspension will be resolved byRZ,Jending acceleration, since there will have been a case of DLT or two cases[,of 'moderate' toxicity.\,S],KWhen the accelerated mode ends, the dose assignment for the first course ofQ^,Ia new patient is the same as that of the standard method described above _,under Design 2.DQ lXbT]7 VV[ZYQ\[XYX\Y[WPSU[VV# WU`T0abbbcdefgbhbijbkblDmbno;0p;0qb rbs0tu0v0bw~xbybz{|0}~b`,La,DThe intra-patient dose modification options are defined as follows: b* Option A:  +c,#No intra-patient dose escalation. Xd,PIf the worst toxicity is DLT or worse during a course, the dose is reduced one 7e,/dose level for the next course of that patient.f* Option B:  Xg,PIf the worst toxicity is DLT or worse during a course, the dose is reduced one ]h,Udose level for the next course of that patient. If the worst toxicity is 'moderate' Zi,Rthe dose level remains the same for the next course. If the worst toxicity is lessYj,Qthan 'moderate', the dose is increased for the next course. The increase is two Vk,Ndose levels during the early accelerated mode of the trial, and one dose levell, otherwisem,n&Spreadsheet Layouto-Qp,IEach row corresponds to one patient. It contains a patient ID field and aQq,Isection for each treatment course. The program supports up to ten coursesVr,Nper patient. Each course section consists of four columns: the date the courseQs,Ibegins, the administered dose level, the recommended dose level, and the Wt,Oworst toxicity. The 'worst toxicity' is defined to be the severity of the worstWu,Otoxicity in any organ system, judged to be definitely or probably drug related,@v,8and observed for that treatment course in that patient. w,Ex,= NA means not expected to ever be available (e.g., due to the;y,3death of the patient from non-drug related causes).z,{,|&Operating Instructions}.Q~/IA separate Excel workbook file must be used for each Phase I trial. FilesW/Ofor different phase I trials must be saved under different file names, to avoidD l P/\;\a^]Z  UUZU[[D I? " UT0bbbbbbDb;0;0b b000b~bb0bM/Eoverwriting previously accumulated data. The main spreadsheet in eachO/Gworkbook must be initially devoid of data from any other trial or test./X,PTo begin using the program, enter a protocol identifier (up to 8 characters) andT,La design (2A, 2B, 4A or 4B). When a new patient has consented to treatment, W,Oa dose level recommendation is obtained by clicking on an "Assign dose level" [,Sbutton. The program will request a patient identifier. A patient identifier may be T,Lany label up to 8 characters. The program will then provide the recommended Z,Rdose level, according to the design used, for the first course of the new patient.L,DThe program automatically records the recommended dose level in the V,Nappropriate column for the new patient. At that point you may save the updated,spreadsheet and exit. ,T,LBetween runs of the spreadsheet macro, you should update the fields giving V,Nstart dates of the treatment courses, dose levels actually administered, and \,Tworst toxicities for all previously entered patients. The program checks that: (a) S,Kall patients' courses for which recommended dose level have been assigned [,Shave been updated with start dates and administered dose levels; and (b) that U,Mall courses starting more than 30 days before the current date contain worst E,=toxicity evaluation. (Dates must be given in mm/dd/yy form).,M,EThe program will also recommend dose levels for subsequent courses ofV,Npreviously entered patients. After clicking on the "Assign dose level" button Y,Qwhen prompted for patient identification, provide the ID of a previously entered ,patient.,U,MThe program works based on dose level, not dose. It assumes that the protocolG,?defines the dose levels based on approximately 40% increments.,V,NIt is important that the information entered into the worst toxicity fields beR,Jbased on careful assessment and complete observation of the at-risk periodZ,R(at least 15 days). The observation of dose limiting toxicity, however, should be D lQS \X[_X^PZ# XZ`W_YI QZ] YK ZVT0bbbbbbDb;0;0b b000b~bO,Grecorded as soon as it is observed even if at-risk period has not been T,Lcompleted. No lower grades of toxicity should be recorded, however, until V,Nthe full at-risk period has been completed. If a patient is not evaluated for [,Stoxicity because of death (not drug related) or inaccessibility, the worst toxicityU,Mshould be recorded as NA (not available). Toxicities should be recorded usingR,Jone of the following short codes: LT, DLT, MOD, MILD, NONE or NA. EitherU,Mupper or lower case characters may be entered, but will be converted to upper ,case.,''''''''''''''''6SXZ_YVY =xZ$e8T> "     dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>      dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>      dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>      dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>       dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    !  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    :"  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    T#  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    n$  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    %  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    &  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    '  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    (  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    )  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>    +  dMbP?_*+%&APage &P"Pag??chU =xZ$e8T>  2360d1a49 4360d1a49-SummaryInformation(DocumentSummaryInformation8LJ4J*.$( LXp6,&.  <,\:80,DL@:0 :<.x06.,(\4.,, @ 4X . , * !4,!.`!,!(!!F!8D"2|"(".",#4#8D#.|#,# #8#0$0L$ |$8$.$0%4%:D%4%0% %8%0(&.X&,&8&0&('(D'2l'''6''L'LH(0("(0( ($)4<)4p)6)8),*>@*H*F*H+8X+@+0+,B,\,>|,,2,-,-.4-d-h----p......`.,L/x/|//.///:/040(1D1H111101(2D2`2x2,|2P2L2D3&T3>|3B3"4$4 842D4 x4 4 04 4 4 4 4 55 25 555>6DH66N6R6NL7.77L7(8@8JP8H889*949P9X92t9999299B9L9ND:J:L:*,;X;`;h;tp;;;F;*@<l<X<<< P< 8=H=L=P=.X==B=,==  =  r= d> t>  x> > ">>X? h? l?eN[ s NN \ 60 @AT JstT  `atj  t F in ow  +   1 Cr  ot sR F *sC 4Fi @ JP<@8 T ` j t       M sR  sC  Fid@"r    t\ =   L ID  C K   (1  * L 4ro@ elJ T ` j t  M   tP: LTɂ duɂ Crɂ  tɂ  inɂ  0otɂ @lɂ*  *M 4  gnɂ@   wPɂ@ tiɂ ivɂ*   H<, KɂJ ur h ZL T ox ` K zK  jmp tAc L 4ox gB Kh\, @ɂ <deɂ L@ɂj m  hHɂ enɂt I   M x4   4 4  (   *@`@[ɂ Pɂt     H   M   @ * ɂ@ N J TM ` j t    M j   N   tM   MEv8@LHTP28JlN*L4LNJ>hNPRHN6J$RpN,L@(JLDLHNF(NpL2 J@  4  N L Jl J   H$ Dl J L NH H L P, J| L JF`F 6LLTJLPLhLLdN|&L@HXFFL0"|JJJ8H>N L\LJH@NNL(Pt4NJlNHLPLt?x? ?,?@? @<@T@ d@ p@ @ t@ A,A0ALATA"\A"A A:A(AB(BL,B6xBDBBCZCpCCCChD pDDDDE"E E EEEEE2EFL$FPpF"FFFF FFG0(G"XG8|G2GG"GH(HOP Q Q Q( QHQPQ`Q|QFQQQQ QQ RR R(RRRRSFS`SpStSFxSSSS (S LT  LT `T hT  TT0U HULUR\UUU  U U U JU   V V V &V  V xV  tW8W WWWWWW2X4DXxXX XbXX  Y   YYY Y$Y2,Y`YBhY lY*xY&Y.YYZ0ZZ [[[ [$[([00[`[Bh[l[ |[[[[[[[[[[[\ \ \(\\\\B\\ \\ ]]$],]<]D]T]\]l]t] ] ]]t^^^^0^^B^^ ^ ^ _ _ _ $_ 0_ <_ H_ T_`_ p_|___@_____6_0`B8` <`H`P`X```h`p`x`8``2`B`88apaaa"a^a Hb Xb `b hblbpb@tb4bbc cp2$q2XqNqqqprJr:rsH$sLlsLst t t0tL@t0tFtuu(u8u6Ď Ԏ "  0 @D L @X  @PFT6 Ԑ   " P0< :Б :  8H     " Ԓ J `Dp@      N0P  Д L"< ` p   NL4H  |   B v  d t x @  ė Lܗ"(  L \ p   8   Ę ؘ     L"\       0  @  0  v4     ĚJК 8 HD2   ț ܛ H  @ >L        tĜ  8  H L 0X  @ȝ t̝  @PTNX  F"   ,  ȟ  ̟ ܟ   @ D TX\`4h$Ƞ"Р"Ԡ*(@$h86ġ4*04\88:6T:ȣУأ<,T<   " (̤      8  <\dl t   $   8 8  ,   80 8h  ĦԦ"(P8  $ا:$(0PJT8ب ( @ X8x (4ة 48H\` p tF ܪ (DH:P ̫ ثN4PԬ@6@xF$  D8N|B̮L  \ l  N2  ( <LPLT$48<@1 Module1 - Workbook ATDPH1.XLSF This Excel (Version 5) workbook analyzes dose and toxicity data fromN phase I clinical trials of chemotherapy agents, and provides recommendationsI for treatment dose levels. See Module2 for additional information about+ the dose escalation models employed here.C Module1 contains functions and subroutines which analyze dose andG toxicity data contained in the worksheets, and calculates recommended# dose levels. These functions are:F runprogram() - this driver function runs when the user presses anE "Assign dose level" button on the main worksheet.H findnumpt() - counts consecutive records that contain administeredD or recommended dose information to determine the7 number of patients in the worksheetG patid() - queries the user for a patient id and classes it asI either existing or new to the worksheet. Also, checksK that all existing patient id's are unique and not blankH datachk() - checks existing data and handles queries to the user0 about problems with the dataD dosecheck() - checks dose levels (should be positive integers)K toxint() - converts short standard strings (used in the worksheet)G to integer codes for toxicity (used by the program)% toxstr() - inverse of toxintE CurrentDose()- scans existing spreadsheet data to initialize the" 'current dose'C design2b() - contains code for actions specific to design 2bE standardmsg()- updates the worksheet with a new recommended dose= level and notifies the user of it as wellB courseb() - called by design2b() and design4b() to handleH dose assignments for successive intrapatient courses@ phase2() - called by design2b() and design4b() to scanG existing data to adjust the current dose level, andE to assign a dose level for a new patient once the, accelerated mode is overC design4b() - contains code for actions specific to design 4b- Notes on NomenclatureG - Previously, phase 1 was used to describe accelerated dose escalationE mode, and phase 2 was used to describe the standard, unacceleratedD mode of dose escalation. 'Mode' is now used instead of 'phase' inD this context to avoid confusion with phases (e.g., I, II, III) of clinical trialsA - The 'current' patient refers to a patient in the worksheet who> received the 'current dose': i.e., the base dose from whichD escalation or de-escalation will occur to obtain the first courseF dose for a new patient. There is a potential ambiguity with respectG to the patient selected for a dose recommendation by the user of theA program. This patient is now called the 'selected patient'. ToF describe the set of patients already listed in the spreadsheet, theI term 'existing' is now used. Thus the 'selected' patient can be eitherC new, or known (because they already exist in the worksheet), butE cannot be the (previous) 'current' patient until the next time theD program runs. Data that can potentially be used to write into the? selected patient's spreadsheet row at the end of the current@ run is accumulated in variables preceded by New; i.e., NewDL, NewPatRow, NewMode/ To do's, Q's, and NotesF - arrow up and down and page up and down keys should work with scroll text in Module2C - scrolltext incorrectly cites an 8 character limit for some namesE - instructions for clicking on button/scroll bar (re inactive clicks and arrow keys)F - entering a date in the patient field resets the cell format to dateE - should trim leading and trailing spaces for tox (and patient) info - printing issuesE - spreadsheets wider than one page are a hassle - e.g., print pages 1, 6, and 11MH - its easy to unintentionally print out the entire program in addition to pages of the spreadsheetE - suggest reorder columns in order of use: patid, doserec, dosedate, doseadm, toxB - suggest reorder worksheets: Sheet1, Module1, Module2, Scroll...? - suggest codes for reccol for stopping treatment and/or trial? - findnumpt() design is not compatible with entering a list ofE (potential) patients: but we do not want protocol driven treatment prior to reccommendation@C - checks on 'other' patients' data may be considered irrelevant byC users who are focussed on their own patient. Also, it may not beD reasonable to request this data prior to 30 days after the courseB start date. However, the recommended dose for their patient may8 depend on the completeness of the available data set.G - When accelerated mode is suspended, downcourse escalations for earlyF patients may creep along one step at a time at doses well below theF 'current' dose. However, this is a real consequence of the rule forC suspending acceleration until additional patients can be treated@A at the current dose to resolve the suspension. Eventually, theG downcourse assignments for early patients may reach the current dose@G by intracourse escalation, albeit one dose level at a time while theF suspension is in effect. At this point they should be capped at theI current dose level. Should doses for patients already at a higher dose be frozen?- Global Declarations@H Global variables are declared here at the top of the module. In VisualC Basic for Applications (VBA), variables are made available acrossH functions within a module by declaring them (public, or private = dim)B outside of any function (e.g., at the top of the module). GlobalF variables can be initialized (assigned an initial value) only withinF some function in the body of the module. Public makes them availableE outside the module, and private (or dim) limits their visibility toD within the module. Booleans (logical variables) can be initializedC within a function using the integer values 0 (False), or 1 (True)YCurrent Date, verified by userY &" Names of main and aux. worksheetsY$ MainSheet locationsY0<YHT`lxMYY % Memvars representing values of cells% Variables to hold values obtained by analyzing the worksheet at the' beginning of the current program runY Current Dose LevelY Dose recommendation complianceY. Row of Patient with Current Dose (not offset)Y, Current Mode of Treatment (1 = accelerated,* 2 = standard, 3 = acceleration suspended)YD  suspension doseY8 New Dose Level (to be recommended for selected patient)Y3 Row of Selected Patient with New Dose (not offset)4 Dim NewMode As Integer ' New Mode of TreatmentY * Number of patients, patient idY,- Redim to size numpt later on (in datachk()).' Used to tabulate the number of courses) undertaken by each patient, according to the main spreadsheetYX* True if patient is found on the worksheet( patid() sets it false if the patient is! previously unknown (new or typo)Yd( True if course date, dose administered,' and toxicity evaluations are completed& for the first course of treatment for& all existing patients with previously recommended dosesYp( True if course date, dose administered,' and toxicity evaluations are completed% for all courses of treatment for the# selected patient with a previously recommended doseY|( True if course date, dose administered,' and toxicity evaluations are completed% for all courses of treatment for all" existing patients with previously recommended doses? Only patients with a 'legal' dose are used in the counts belowY+ Number of patients with level 2 toxicities, in any course. If this is greater than one," then accelerated mode is ended in( design4b. If this is greater than zero,& then accelerated mode is suspended in design4bY+ Number of patients with level 2 toxicities' in their first course only. If this is& greater than one, accelerated mode is endedY+ Number of patients with level 2 toxicities) at the current dose level in their first* course only. If this is greater than one, accelerated mode is endedY+ Number of patients with level 3 toxicities' in their first course only. If this is) greater than zero, then accelerated mode is endedYD+ Number of patients with level 3 toxicities- in any course. If this is greater than zero,) then accelerated mode is ended in design 4bY+ Number of patients with level 3 toxicities) at the current dose level in their first' course only. This statistic is used to& decide when the trial should be endedY+ Number of patients with level 3 toxicities* at one level above the current dose level! in their first course only. This! statistic is used to decide when+ additional patients should be added at the current dose0 Subroutine runprogram()E Runprogram() is called when the user presses an "Assign dose level"F button on the main worksheet. It serves as the driver for subsequent) downstream functions within this moduleY#$ Working var - T when cell was emptyY# Temporary variable Initialize global variablesSheet1'J Main worksheet, for user access J$B@  The active sheet is Mainsheet'( Rows 1-7 (MainSheet)are header material  '$ Row 8 contains data for 1st patient' Patient ID's are in column 1'/ Treatment Dates (for course 1) are in column 2': Dose Level(s) administered (for course 1) are in column 3'7 Recommended Dose Levels (for course 1) are in column 4'9 Observed worse toxicities (for course 1) are in column 5'* Width of one course, in worksheet columns$'4/ Calls function findnumpt to count all existing* patients with either an administered or a recommended dose'T3 Protocol Number (id) is in the (MainSheet) cell at'j row 1, column 2'`0 Design (2B or 4B) is in the (MainSheet) cell at't row 2, column 2+ Workbook Initialization (and some checks) T j % $ ' Specify A Protocol IDATDPH1$*'` T j % 'g Message supressed tv1 = MsgBox("This Worksheet Is For Protocol ID: " + Protocol + Chr(13) + Chr(10) + Chr(13) + Chr(10) + "(OK Continues Program, Cancel Ends Program)", 1) If tv1 = 2 Then End 'program End If T j ,  ` t % $ ' Specify An Accelerated "Titration Design: 2A, 2B, 4A or 4B ATDPH1$*'% Should we clear the worksheet here?` ` t % 'g $4/ force upper case $4'g 2B 4B 2A 4A Message supressed r tv1 = MsgBox("This Worksheet Will Use Design: " + Design +' Chr(13) + Chr(10) +' Chr(13) + Chr(10) +' "(OK Continues Program, Cancel Ends Program)", 1)" If tv1 = 2 Then End 'program`Design  Is Not Available. ?Available Designs Are 2A, 2B, 4A And 4B, This Program Is Ending A@@c programg ` t ,  % $ (New worksheet)'8 Initialize '8 global varsM CurrMode = 1g& Have the user verify the system dateI If Cancel is pressed, or if an invalid date is entered, end the programE A correct current date is required to enforce the 30 day data entry "window" Date is a built-in VBA function J'@/() Crdate is a global date variable:If This Is Not Today's Date, Please Enter The Correct Date'T T Verify Date J$*' EcfM  $` #...# indicates a date literal '@ @v@ $Date Is Not Valid: Program is EndingA@@c programg @ J Using @ As The Current Date: $j $j *Your Computer's (CMOS) Date Should Be Set 'Correctly By Your System Administrator A@@g`&Input Is Not A Date: Program Is EndingA@@c programg`% End programProgram CancelledA@@% on entry of a blank date,c <program ' since the InputBox default was theg% current system dateG Call function patid to query the user for the selected patient id andK to check the input. New vs. existing patient is set in the global booleanG variable KnownPatient. The worksheet row of the user-selected patient( is set in the global boolean NewPatRow t'@()E Call function datachck to perform various checks on the data in the main worksheetMA()C Call function CurrentDose() to analyze the data and determine theB current dose, the patient with the current dose, and the current mode of escalationA@$ Route program flow based on design 2B 2AA 4B 4AaA& Checking for 2b|4b already done abovegk, Function findnumpt() F This stops if a row is 'dose-blank' for course 1, even if additionalG non-blank rows exist. But now we check to see if there are additionalD non-blank rows (if so, complain and quit). This count may disagreeE with patid() because different columns are used to obtain the blank# field which is interpreted as eofYLYXM'  %    %    %   '@ Check down 10 more rows - if they are not empty, warn and quit'Initialize boolean to false       %    %  '  M$One or More Rows Have Missing Data: Program Is Ending A@@c programgeM( Function patid()d& Check existing patids for uniqueness  4@  % $   Patient ID in Row   Is Missing: $j $j Program Ending A@@cprogram`  % 't   4  %  t Error: Patient t# Is Already Entered More Than Once! $j $j Program Is Ending A@@cprogramg @g  Get patient ID from userEnter A Patient I.D.ATDPH1$*'t: Format has no restrictions. Exit on cancel or null input t/No Patient Was Specified: The Program Is EndingA@@c program 4a t  ,   , .By Definition, The Recommended Dose Level For +The First Course For The First Patient is 1 A@@c Programg Check for uniqueness''  %   %  t  '  '*!& Assign NewPatRow for existing patientg" (new patient is assigned below)  'F Notes: - second MsgBox parameter = 1 specifies ok and cancel buttons0 retvals are 1 for ok and 2 for cancel= - Chr(13) + Chr(10) equals newline in output (CR/LF)  'T  .Error: This Patient Is Entered More Than Once!Program Is Ending A@@c program a Message Blocked tmv2 = MsgBox("Patient ID Found" + Chr(13) + Chr(10) + Chr(13) + Chr(10) + "(OK Continues Program, Cancel Ends Program)", 1)' Ecfprogram aM Message Blocked@  tmv2 = MsgBox ("This Patient ID Is New" + Chr(13) + Chr(10) + Chr(13) + Chr(10) + "(OK Continues Program, Cancel Ends Program)", 1)'  user cancelledcprogram`D  '*gge@, Subroutine datachk()F datachk() checks all the data in the main sheet (which may have beenI altered by the user) before proceeding with analysis and recommendationYYYY(MY4@LXYdp| 4J* Originally dimmed () at top* of module to make it global  4$$ Convention is: numpt does not count +J$ a new patient yet (this run)  Initialize global booleans'` True'j True' True Initialize global counters   Check data for all ten courses   '   '   '   '  4 % Check data for all existing patients  % '*< First check single pieces, then later look at combos Check Rec data' initialize negative@   % $ 'T@ T      $J  *Ag Check Date Data'j   % $ '@ @   % '=variant $` '  ' DoseDate is a date var, cdt is variant'j  +J` Start Date For Course  For Patient * Is Invalid: $j $j Program Is Ending A@@cprogramgg& Check here for integer DoseAdm't Initialize boolean   % $ 'J J     t $J  *Ag0 Check tox data and rewrite in upper case' Initialize boolean   % $ '` `   % '4 4 4$4@ 4$4'4 4   , g 4  *$'7 force the check (which quits A)# the program if there is a problem)'gF if there is neither rec or admin dose but tox is given end program T J `  No Dose Level Given For Course  Of Patient * $j $j Program Is Ending A@@cprogramgM Prompt for Missing Course Dates (where DoseRec or DoseAdm is present)E Check for Entry of Course Date within 30 days of Current Date T J ` @ * @ T  ` 'If Available Enter The Date For Course  Of Patient  *# Otherwise Press Cancel To Continue. For Example, "For January 1, 1997 Enter 01/01/97 Course Date Is Missing$*' '@ $` T' - DoseDate is a date var'j  +J    , `A Valid Date Was Not Entered: Program Ending A@@cprogramgg` Enter The Date For Course  Of Patient  *. For Example, "For January 1, 1997 Enter 01/01/97  Course Date Is Missing$*' '@ $` T' - DoseDate is a date var'j  +J    , `A Valid Date Was Not Entered: Program Ending A@@cprogramg`A Valid Date Was Not Entered: Program Ending A@@cprogramggg (Not RecEmpty or Not DoseEmpty)F If course date is present, dose administered should be entered @ J@' )Enter Dose Level Administered For Course  of patient  * Evaluation Is Due Within 30 Days$*'     ,      t $J  *A` * @MProgram Cannot Proceed Without Administered Dose Level A@@cprogramgggg `   @ @    Worst Toxicity For Course  Of Patient  * Is Lower Than DLT,7 Evaluation Is Due After 15 Days: The Program Is EndingA@@cg ` @ @   ' Enter Worst Toxicity For Course  Of Patient  * Evaluation Is Due Within 30 Days$*' 2 Force check and rewrite as uppercase'` '4 4 4$4 4$4'4g 4   ,  4$', force the check (which quits A,# the program if there is a problem)'  +J`*Worst Toxicity Evaluations Are Due Within 30 days: The Program Is Ending A@@cprogramgg  k, Function DoseCheck()Y\h@   % '  variant '*$ to integer (truncates) *'4 back to variant (for comparison in the next line) 4     Dose Level For Course  For Patient  * $j $j ! Must Be A Non-Negative Integer: $j $j  Program Is Ending: A@@cprogram`' ' ge* Function toxintm()t @$4'@M' @NONE' @MILDa' @MODa' @DLTa' @LTa@' @NAa'M @a  Illegal Value For Toxicity: | @|. 7Valid Values Are: NONE, MILD, MOD, DLT, LT And NA: Program Ending A@@c programge @$4'@' @NONE' @MILDa' @MODa' @DLTa' @LTa' @NAa' @a   Illegal Value For Toxicity: | @| For Course   Patient  *. 8 Valid Values Are: NONE, MILD, MOD, DLT, LT and NA: Program Ending A@@c programge) Function toxstr() ' default JNONE' JaMILD' JaMOD' JaDLT' JaLT'M JaNA'@ Ja'`3Illegal Internal Value For Toxicity: Program EndingA@@c  programge/ Function CurrentDose()HYt''''''''* Compute Current Dose from 1st Course Data' '$ initialize low, cycle top to bottom  4!' Use first course data for all existing $J $ patients with first course data  % '*  % '   % '  % $'        1Legal' dose present  ' ''qgg 3(patient loop) ' Now count Toxes re Current Dose   Check data for all ten courses   '   '   '   '  4 % Check data for all existing patients  % '*   % '    % '   % $'   *! Now 'Legal' dose is a tad looser @GP7 (note + 1 above)    '@   '@    '@gggIP  M  ' M  '  M  'gg    a@  'gjg (patient loop)  (course loop)3 Mode is a design-specific decision, so wait on ite- Subroutine design2b() Calls to courseb(), phase2()Y temp variableY& holds treatment course number for the selected patientY, was step mode (now use as step and refer to# public variable CurrMode for mode)Y# var to hold toxicities as integersY var to hold toxicity stringsY# vars to hold info about (previous)# current patientI step = 2 ' vestigial - to indicate mode 1 (acceleration)'t* even though in design 2b single steps are+ used during accelerated and standard modes? Consider the first-course toxicities of patients treated withK the highest 'per-protocol' dose. If there was a dlt, then the acceleratedG mode will end. Also consider the number of such patients with a worstB first-course toxicity of moderate. If there are two or more, theD accelerated mode will end for protocol 2b. Also note the number ofF first course grade 3 (dlt) toxicities at the next higher dose. TheseH doses may not be 'per-protocol', but if there are two or more of them,D there is no use accelerating, since the ultimate goal of the trialB is to find the dose one step below the (unacceptable) dose levelF where there are 2 dlts in six or less patients. Use this information9 to decide if accelerated mode is over. This is true if:2 (ntox3course1 > 0) - any 1st course dlts? (ntox2course1 > 1) - two or more 1st course moderates? (ntox3ACDcourse1 > 1) - two or more 'next level' dlts? - trial may be almost complete      't NewMode = 2' `'  NewMode = CurrModegG Handle recommendation for this course (by calling function courseb())I Step is not global: courseb() gets it as the second parameter, which isE set here to 1 for protocol 2b, in which there is no double stepping 2B@ * A`D * AgD courseb() doesn't make 1st course recommendations. (If there is no? first course information for the selected patient, it returns> after taking no action.) However, it handles all actions forB subsequent courses, and then ends the program, so all code below5 here in sub design2b() refers to 1st course actions'j4 Unpack Tox info for the previous (current) patient  % '4 4$'M: If step = 1 Then ' Mode is 2, accelerated mode is over $ Mode is 2, accelerated mode is over7 Case of: accelerated mode is over, so call step to+ recommend an appropriate dose A! program ends somewhere in phase2G Case of: previous patient is not eva      "#%,-./012$lueted: Issue warning and stop a3Cannot Assign A Dose For A New Patient Until First 5Course Toxicity For The Previous Patient Is Evaluated A@@c programD Case of: accelerated mode is still in force. In design 2b, that3 means cohorts can be a single patient  a@A Case of: toxicity information for previous (current) patientF will not ever be available - so keep 1st course dose theF same. Advise user, add new values to worksheet, and quit '   jAc program aF Case of: Toxicity was reported for the (previous) current patient) Accelerate with a step of 1@ Advise user, add new values to worksheet, and quit  '   jA@c program`/ Case of: Toxstring = "": Complain and quit> (this case should now be preempted by datachk())3Cannot Assign A Dose For A New Patient Until First 5Course Toxicity For The Previous Patient Is Evaluated A@@c programgk. Function StandardMsg()H Called by subroutines design2b() and design4b(), courseb(), and step().G StandardMsg updates the main worksheet, informs the user about the new< recommended dose for the selected patient. DoseLevel (DL),E RecCol (RC), and course of treatment (tcourse) are parameterized for5 flexibility of use. Parameters are dimmed implicitly  @ * , @  *  ,  Suggested Dose Level For Course j Of Patient  @ Is:  A@@eM, Subroutine courseb()E Called by sunbroutines design2b() and design4b(). Subroutine Courseb5 handles intrapatient dose escalation in courses 2-10h+ ptnum should refer to the selected patientG step should specify the step size (not indicate the acceleration mode)YYYMY+ Walk out to a new column for this patient. Test cols 3, 7, 11, etc. (Look at DoseAdm's)'   %   'M Etf( return from sub - 1st course is handled elsewhere  4This Worksheet Supports Only Ten Courses Per PatientA@@c programg '*  '   '    '4   '  '  '   % '*   % $'    % $ 0 Case of: previous intrapatient toxcol empty; (this should be unneccessary after datachk())0Previous Worst Toxicities For This Patient Must -Be Entered Before The Next Course Is Assigned A@@c program  a1 Case of: previous intrapatient toxcol severe> De-escalate one dose level from base of previous intrapatient dose   %   4 %    %  '`D  4 % 'g  $Cannot Decrement Dose Level Below 1:,Therefore, No Dose Level Can Be Recommended !For Further Treatment of Patient *A@@cprogram`   Acprogramg a@1 Case of: previous Tox is -1 (not available)- maintain dose at current level.   % '   Acprogram a* Case of: previous Tox is 2 (moderate)- maintain dose at current level.   % '   Acprogram`I Case of: default - escalate one step's worth, which could be 2 unitsG for accelerated mode in design 4b. Cap increase at CurrDL2 if accelerated mode is in suspension   % '     'tg  t '   Ac+ program ' restore accelerated modegk, Subroutine coursea()E Called by sunbroutines designab() and design4a(). Subroutine Coursea5 handles intrapatient dose escalation in courses 2-10 + ptnum should refer to the selected patientG step should specify the step size (not indicate the acceleration mode)YlxY@YY+ Walk out to a new column for this patient. Test cols 3, 7, 11, etc. (Look at DoseAdm's)'   %   ' Etf( return from sub - 1st course is handled elsewhere  4This Worksheet Supports Only Ten Courses Per PatientA@@c programg '*  '   '    '4   '  '  '   % '*   % $'    % $ 0 Case of: previous intrapatient toxcol empty; (this should be unneccessary after datachk())0Previous Worst Toxicities For This Patient Must -Be Entered Before The Next Course Is Assigned A@@c program  a1 Case of: previous intrapatient toxcol severe> De-escalate one dose level from base of previous intrapatient dose   %   4 %    %  '`D  4 % 'g  $Cannot Decrement Dose Level Below 1:,Therefore, No Dose Level Can Be Recommended !For Further Treatment of Patient *A@@cprogram`   AMcprogramg a1 Case of: previous Tox is -1 (not available)- maintain dose at current level.   % '   Acprogram`* Case of: previous Tox is 2 (moderate)- maintain dose at current level.   % '   Acprogramgk+ Subroutine phase2(). Called by functions design2b() and design4b()2 cd is the adjusted 'current dose', i.e., the dose( given to the previous (current) patientY) num patients (tox<>-1) at the dose levelY & num patients (tox<>-1) one dose belowY,) num patients (tox<>-1) at the dose aboveY8& num patients at current dose who have reported dltsYD* num patients at current dose + 1 who have reported dltsYP\ temporary variablesYh' # evaluated patients at the dose levelYt@Y' initalize'J'T'`'t'j'j- phase2 handles only first course assignments4 Limit the current dose based on first course dlt's  @ " scan doses below the current dose'0 accumulate dlt's separately for each dose level  4  % '   % $'      '@g   '@2 this can put cd on a level where 2 dlt's occurredqg  @ $Cannot Decrement Dose Level Below 1:)Therefore, No Additional Patients Should Be Added To This Trial A@@cprogramg@ Accumulate various counts of patients with reported toxicities0 at, below, or above the new current dose level 4  4M  % '   % $'MI If (Tox = -2) Then ' remmed - in filling out cohort, this is ok6 MsgBox ("Missing Toxicity: Program Ending") End If  @  E T 'Tf  @  E ` '`f  @   E t 'tf  @  J 'JM E  'f  E j 'jfMg g jMC Case of: No dlts at the newly adjusted (previous) current dose J = Case of: Less than three patients at the current dose: Add a(nother) patient at the current dose @'   jAc program JaH Case of: Three patients, no dlt's at the current dose. This is aI transition point. (What if we jump from 2 to 4 at once?)  t F Case of: Less than 2 dlt's at next dose level means room to escalate @ ' @  jAc program  taH Case of: Two or more dlt's at next dose level means expand toF six patients at the current dose level (final dose. could even be lower still) @'   jAc program`9 Is Tox well defined here? Is it the last one in the row?.Cannot Enter A New Patient Until First Course -Toxicity Is Available For The Previous Cohort A@@c programg J a9 Case of: expanding past three toward six patients  t F Case of: Less than 2 dlt's at next dose level means room to escalateM @ '   jAMc program`1 Case of: No room or reason to escalate @'   jAc programg Ja  t F Case of: Less than 2 dlt's at next dose level means room to escalate @ '   jAc program a* Case of: time to quit the trial3No Further Patients Should Be Treated On This TrialA@@`.Cannot Enter A New Patient Until First Course -Toxicity Is Available For The Previous Cohort A@@c programgg jaC Case of: One first course dlt at this dose level means room to escalate J A Case of: have to expand cohort toward six patients before, escalating or de-escalating @'   jAc program t aB Case of: expanded cohort with less than 2 next level dlt's 8 Case of: 6 patients evaluated, OK to escalate @ '   jAMc program`,Cannot Enter New Patient Until First Course -Toxicity Is Available For The Previous Cohort A@@c programg a* Case of: time to quit the trial3No Further Patients Should Be Treated On This TrialA@@`,Cannot Enter New Patient Until First Course -Toxicity Is Available For The Previous Cohort A@@c programg`G Case of: (not zero or one dlt this dose level - must be 2 or more) T @ Case of: Cohort at one dose level down is expandable, so de-escalateM @$Cannot Decrement Dose Level Below 1:)Therefore, No Additional Patients Should Be Added To This Trial A@@c programg @ '   jAMc program`3No Further Patients Should Be Treated On This TrialA@@c programggk- Subroutine design4b() Calls to courseb(), phase2()Y maximum toxicityY temp variablesY number of grade 2 toxicitiesY # of grade3+ at 2 steps upY  # of grade3+ at step upY +# of grade3+ at one step up at the course2+Y *# of grade3+ at 2 steps up at the course2+Y$ ' # of patients at the current dose with# mild toxicities. Two are needed to'& restore accelerated mode after it was' suspended') indicator of mod toxicity for suspension'* dose level of mod toxicity for suspension'+ indicates that suspension dose is currdl+1'' # of the previous patient for restores', # number of the pat with MOD for suspension't't'''  (should pat loop be inside intrapat loop?  4M count only if: recom. dose used, the dose is less or equal to current  '   % '    % $'   E  'f@   E 'fg    ' ' '   E'fg  First course only     E t 'tf     E  'f`     E  ' f     E  'fg    4@   '   % '    % $'          ' 'g      t't' 3 NewMode = 2 ' acceleration ends`'  NewMode = CurrModegD If (NewMode <> 2) Then ' if acceleration is on or suspended "# if acceleration is on or suspended M  " evaluate conditions' 9 NewMode = 3 ' acceleration suspended T" if not first course't") escalate (or not) below in standard mode`" for first course of new patient ' "& add at current dose towards resolving  A( suspension`  '   Agc programg`" resume accelerated mode@ NewMode = 1 ' fall through to continue with' " assignmentggg 4B * tA`D * tAg'j4 Unpack Tox info for the previous (current) patient  % '4@ 4$' If step = 1 Then  A@G Case of: previous patient is not evalueted: Issue warning and stop  a3Cannot Assign A Dose For A New Patient Until First 5Course Toxicity For The Previous Patient Is Evaluated A@@c program  a: Case of: CurrTox for (previous) current patient is NA/ (not ever going to be available) '   jAMc program aM@ Case of: CurrTox for (previous) current patient not missing t    Case of:> - no first course dlts at current dl (accel mode ok),H - < 2 first course dlts at next double step up (escalation ok),; - no downcourse dlts at current dl (accel mode ok)E - < 2 downcourse dlts at next double step up (escalation ok)  '   jA@c program`H Case of: step is not 1 (must be 2), but some other consideration, prevents a double dose jump  ' M  jAc programg`F Case of: Problem evaluating CurrTox of (previous) current patient+Cannot Assign Dose For A New Patient Until ;First Course Toxicity For The Previous Patient Is Evaluated A@@c programgkNNN-\ 6|  * 4 P@D + ple $PME""@ \ | "  6Y@Y gBYti$ ScrollTextDlg J%T. @Viewport %`.* TextScroller %j.4 4(tA B@kP TextScroller %j.4 4!t'  'ScrollTextSheet!$B$ :$B$  *(kOh+'0@HXATDPH1:Accelerated Titration Designs for Phase 1 Clinical Trials_Boris FreidlinrBoris FreidlinrMicrosoft Excel՜.+,0h0 8@ H - ortTextScrollerShowTextScrolleroThisWorkbookcDialogSheetsPicturesScrollBarsValueChangeViewPortShowFirstLastFormulaH   +  $Sheet1ScrollTextSheetSheet2Sheet3Sheet4Sheet5Sheet6Sheet7Sheet8Sheet9Sheet10Sheet11Sheet12Sheet13Sheet14Sheet15Sheet16ScrollTextDlg  WorksheetsDialogs FMicrosoft Excel WorksheetBiff8Excel.Sheet.59qCompObjf`j t09%iÅ@G |0 b*30I(H("`*^n2\@^DIl H-iN㣀Xblxb)\}ReÂeeߐz?WJMUD F(c0[8vD5NyO\|nK|><K"zbhqYVBAExcelATDPH1.XLTstdoleModule1_EvaluateCrdateMainSheetMainProtRowMainDesRowMainProtColMainDesCollZRowdFirstRowPatColDatColCourseColsnAdmColRecColToxColProtocolDesignCurrDLDRecCompCurrPatRowCurrModesusdlNewDLNewPatRownumptpatientCoursesActiveKnownPatient Course1CompleteThisPatCompleteAllPatsCompletentox2anycoursentox2course1ntox2CDcourse1ntox3course1ntox3anycourse ntox3CDcourse1ntox3ACDcourse1runprogramWasEmptyttv1SheetstActivaterfindnumptIsEmptyActiveSheetCellsInputBox$UCaseMsgBoxDatecouMessageIsDateMChrpatiddatachkCurrentDosedesign2b design4btempproblemtv2icount(tmv1tmv2ToxcdttvaDoseAdmDoseRecDoseDate1locpatid ToxstringDateEmptyDoseEmptyRecEmptyToxEmptyDateGoodDoseGoodRecGoodToxGoodactiveWorksheetCompletea] k*\G{000204F3-0000-0000-C000-000000000046}#1.0#9#C:\WINDOWS\SYSTEM\VBAEN32.OLB#Visual Basic For Applications>*\G{00020813-0000-0000-C000-000000000046}#1.0#409#xl5en32.olb#\*\G{00020430-0000-0000-C000-000000000046}#2.0#0#C:\WINDOWS\SYSTEM\stdole2.tlb#OLE AutomationQ \ 6 2360d1a49 1360d1a49*D* 4360d1a49 3360d1a49*D`T 4J @t` `j*t@ t*`T*@J Jt*4 T t4J @jj`jT4*+ J`bT  (@ 2V:D@etPM*\$jhH t3zUcna ST]4@]Je{54#*- ;M2 TQq&kb 4$DeQjT d(jd'tJ"L(((  |@ J%N  5 4*R0 ;8@2HK~TP^ T*Z JbSnxRq`lH֪I֠=})4<K"zbhqYVBAExcelATDPH1.XLTstdoleModule1_EvaluateCrdateMainSheetMainProtRowMainDesRowMainProtColMainDesCollZRowdFirstRowPatColDatColCourseColsnAdmColRecColToxColProtocolDesignCurrDLDRecCompCurrPatRowCurrModesusdlNewDLNewPatRownumptpatientCoursesActiveKnownPatient Course1CompleteThisPatCompleteAllPatsCompletentox2anycoursentox2course1ntox2CDcourse1ntox3course1ntox3anycourse ntox3CDcourse1ntox3ACDcourse1runprogramWasEmptyttv1SheetstActivaterfindnumptIsEmptyActiveSheetCellsInputBox$UCaseMsgBoxDatecouMessageIsDateMChrpatiddatachkCurrentDosedesign2b design4btempproblemtv2icount(tmv1tmv2ToxcdttvaDoseAdmDoseRecDoseDate1locpatid ToxstringDateEmptyDoseEmptyRecEmptyToxEmptyDateGoodDoseGoodRecGoodToxGoodactiveWorksheetCompletelocdatcollocadmcol locreccolloctoxcolDoseCheck(toxintmtoxstrVtoxintColumnDoseGoodCourseActintcheckvarchecktoxwordtoxnumcDoseLegalDoseCurrenttcoursestepCurrToxprevdoseprevptcoursebcourseaphase2StandardMsgDLRCptnumnewcoursenewdoscolnewreccolprevdoscolprevtoxcolPrevToxprevcourseprevreccolcdcdpcdbpcdapcdt3gncdat3cdpetx3maxtoxnumpt2cda2t3dact3cdac2t3restorersnumpt2csdli1ptnum2cptnum22spacercdact3Module2ScrollTextViewP