d.jra 2.2- review of the existing protocol structure in large clinical

D.JRA 2.2 – Review of the existing protocol structure . . . Dissemination level PU

Project co-funded by the European Commission within the FP7 (2007 – 2013)

Grant agreement no.: 228436

ULICEUnion of Light-Ion Centres in Europe

Project type: Combination of CP & CSAIntegrating Activities / e-Infrastructures / Preparatory phase

Start date of project: 1st September 2009 Duration: 48 months

D.JRA 2.2 – Review of the existing protocol structure in large clinical researchorganisations (national and international) as collected by WP 10

Delivery date: M 18 2011/02/28

WP n{ and title: WP 2 – Concepts and terms for dose volume parameters and for out-come assessment in hadron-therapy integrating applied biology, medi-cal physics and clinical medicine in ULICE

WP leader: Ramona Mayer, Jacques Balosso

Reporting period: 1st

Name Partner

2011/02/28Author(s): Ulrike Mock MEDAContributor(s): Ramona Mayer, Thomas Schreiner,

Piero Fossati, Stephanie CombsMEDA,CNAO, UKL-HD

Pillar coordinator: Richard Pötter MUWApproved by TPB and CPO signature

Dissemination LevelPU Public XPP Restricted to other programme participants (including the Commission Services)RE Restricted to a group specified by the consortium (including the Commission Services)CO Confidential, only for members of the consortium (including the Commission Services)

ULICE-GA n{228436 of 22


TABLE OF CONTENTS

PUBLISHABLE SUMMARY 5

CONTENTS AND SPECIFIC DOCUMENT STRUCTURE 6

1 Study protocol analysis 61.1 Methodology of study protocol analysis . . . . . . . . . . . . . . . . . . . . . . . . 61.2 Analysis of photon based clinical study protocols . . . . . . . . . . . . . . . . . . . 61.3 Analysis of carbon ion based clinical study protocols (HIMAC) . . . . . . . . . . . . 61.4 Analysis of clinical study protocols used at the HIT, Germany . . . . . . . . . . . . 71.5 Analysis criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.6 Results of study protocol analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.7 Results and conclusion of study protocol analyses . . . . . . . . . . . . . . . . . . . 8

2 Analysis of study protocol guidelines 202.1 Analysed study protocol guidelines . . . . . . . . . . . . . . . . . . . . . . . . . . . 202.2 Results of study protocol guidelines analyses . . . . . . . . . . . . . . . . . . . . . 202.3 Conclusion of study protocol guideline analyses . . . . . . . . . . . . . . . . . . . . 20

CONCLUSIONS 22



LIST OF ABBREVIATIONS AND DEFINITIONS

CTCAE Common Terminology Criteria for Adverse Events

ECCO-AACR-ASCO European Cancer Organisation – American Association for Cancer Research– American Society of Clinical Oncology

EORTC European Organisation for Research and treatment of Cancer

GCP Good Clinical Practice

HIMAC Heavy Ion Medical ACcelerator

HIT Heidelberg Ion Therapy Centre

ICH International Conference on Harmonisation

IMRT Intensity Modulated Radiation Therapy

NIRS National Institute of Radiological Science

NSCLC Non Small Cell Lung Cancer

RTOG Radiation Therapy Oncology Group

TNM Classification of Malignant Tumours is a cancer staging system that describesthe extent of cancer in a patient’s body. T describes the size of the tumour andwhether it has invaded nearby tissue; N describes regional lymph nodes thatare involved; M describes distant metastasis (spread of cancer from one bodypart to another).



PUBLISHABLE SUMMARYMain activities of WP 2.2 were focused on the analyses of different clinical study protocols fromlarge clinical research organisations and different treatment facilities in order to define and outlinemain protocol structure characteristics. Determination included photon based treatment protocols de-signed by international organisations like EORTC, RTOG, and treatment protocols currently used ation beam facilities like the National Institute of Radiological Science (NIRS) in Chiba, Japan or atthe Heidelberg Ion Therapy Centre (HIT), Heidelberg, Germany. For all these protocols principalstructures were determined with regard to aspects like background and introduction, objective of thetrial, patient selection criteria, trial design/therapeutic regimen, etc. Results specified according tothe different analysed protocols are shown in detail. As a conclusion it can be stated that the gen-eral structures and/or the main topics of protocols appear to be relatively similar in all protocols but– going more in detail – there are several open questions like study protocol design organisation,main protocol organisation, data monitoring or quality assurance programme, etc. These challengeshave to be further discussed and solved within the future activities of the ULICE WP 2.2. Analysisof clinical study protocols was followed by a structure analysis of different existing study protocolguidelines. Determination referred to the ECCO-AACR-ASCO Methods in Clinical Cancer ResearchPhase I/II/III studies, the EORTC guidelines for writing protocols for clinical trials of radiotherapy(1995), the EORTC Investigator’s Handbook (2002), the International Conference on Harmonisation(ICH), GCP (Good clinical practice) Guidelines for Clinical Trial Protocol development, the ICHTopics E3/E6/E9; European medicines Agency, the harmonised ICH-criteria for EU, Japan and theUnited States), the Southwest oncology group (USA): Protocol guidelines and the Masterprotokoll(Deutschen Krebsgesellschaft e.V. and Deutsche Krebshilfe) Detailed results of this analysis is shownin tables. In conclusion it can be stated that all study protocol guidelines showed an enumeration ofdifferent aspects of clinical studies. In the Masterprotokoll headlines were elaborated more in detailand the most detailed description of Phase I/II and III studies was given in the ECCO-AACR-ASCOstudy protocol guidelines.



CONTENTS AND SPECIFIC DOCUMENT STRUCTURE

1 Study protocol analysis

1.1 Methodology of study protocol analysis

Main activities of WP 2.2 were focused on the analyses of different clinical study protocols from largeclinical research organisations and different treatment facilities in order to define and outline mainprotocol structure characteristics. Selection of study protocols was predominantly based on factorslike the availability of study protocols and radiotherapy as a main treatment option.

1.2 Analysis of photon based clinical study protocols

Determination included the following photon based study protocols:

1. EORTC 40013-22012: randomised phase II/III study comparing gemcitabine followed by gem-citabine plus concomitant radiation (50.4 Gy) versus control after curative pancreaticoduodenec-tomy for pancreatic head cancer;

2. RTOG 0618: phase II trial of stereotactic radiation therapy in patients with operable stage I/IINon small cell lung cancer;

3. RTOG 0915: a randomised phase II study comparing two stereotactic body radiation therapyschedules for medically inoperable patients with stage I peripheral NSCLC;

4. Prospektive randomisierte Vergleichsstudie zur präoperativen Kurzzeit-Radiotherapie versusLangzeit-Radiochemotherapie beim uT2-3 Rektumkarzinom.

1.3 Analysis of carbon ion based clinical study protocols (HIMAC)

Clinical study protocols being performed at the Heavy Ion Medical Accelerator (HIMAC) locatedat the National Institute of Radiological Science (NIRS) in Chiba, Japan were determined. Theseprotocols include the application of carbon-ion treatment as the radiotherapeutic treatment option.

In this context the following protocols were analysed:

1. a phase I/II clinical trial of carbon-ion therapy in four fractions per week for patients with stageI non-small cell lung cancer;

2. a phase II clinical trial of carbon-ion radiotherapy combined with chemotherapy for mucosalmalignant melanoma of the head and neck;

3. a phase I/II clinical trial of carbon-ion therapy for patients with epithelial malignant tumour oflacrimal gland.



1.4 Analysis of clinical study protocols used at the HIT, Germany

Moreover study protocols being used at the Heidelberg Ion Therapy Centre (HIT), a treatment facilityoffering protons and/or carbon ions were assessed. This analysis referred to the following clinicalstudy protocols:

1. NCT 01182753: randomised trial of proton versus carbon ion radiation therapy in patients withlow and intermediate grade chondrosarcoma of the skull base, clinical phase III study;

2. NCT 01166321: treatment of patients with atypical meningiomas Simpson grade 4 and 5 witha carbon ion boost in combination with postoperative photon radiotherapy: the MARCIE trial;

3. NCT 01182779: randomised trial of protons versus carbon ion radiation therapy in patients withchordoma of the skull base, clinical phase III study HIT-1-study;

4. NCT 01154270: combined treatment of malignant salivary gland tumours with intensity mod-ulated radiation therapy (IMRT) and carbon ions (COSMIC);

5. NCT 01165671: randomised phase II study evaluating a carbon ion boost applied after com-bined radiochemotherapy with temozolomide versus a proton boost after radiochemotherapywith temozolomide in patients with primary glioblastoma: the CLEOPATRA trial;

6. NCT 01166308: randomised phase I/II study to evaluate carbon-ion radiotherapy versus frac-tionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CIN-DERELLA trial.

1.5 Analysis criteria

For all these protocols principal structures were determined with regard to the following aspects:

• background and introduction;

• objective of the trial;

• patient selection criteria;

• trial design/therapeutic regimen;

• clinical evaluation and follow-up/endpoints;

• data collection/statistical considerations;

• patient registration and randomisation procedure;

• references;

• appendices (TNM classification, toxicity grading scale (CTCAE), flowsheet, informed consentstatement, patient information sheet, etc.).

1.6 Results of study protocol analyses

Results specified according to the different analysed protocols are shown in the following tables:

• Tables 1 to 3: analysis of photon based study protocol;



• Tables 4 to 6: analysis of study protocol performed at HIMAC, Chiba, Japan;

• Tables 7 to 11: analysis of study protocols performed at HIT, Heidelberg, Germany.

1.7 Results and conclusion of study protocol analyses

Performed analysis showed that several aspects like background and introduction, objective of a trial,patient selection criteria, trial design/therapeutic regimen, clinical evaluation and follow-up, end-points, etc. can regularly be found in all protocols.

Nonetheless major differences can be found with regard to:

• radiotherapy procedure/volume definition, dose prescription;

• forms and procedures of data collection;

• patient registration and randomisation procedure;

• investigator authorisation procedure.

As a conclusion it can be stated that the general structure and/or the main topics of protocols appearto be relatively similar in all protocols but – going more in detail – there are several open questionslike the study protocol design organisation, the main protocol organisation (i. e. review committee,data monitoring, quality assurance programme, etc.) or radiotherapy treatment planning includingdelineation of target volumes, dose prescription to the target volume, dose limits to organs at risk etc.These challenges have to be further discussed and solved within the future activities of the ULICEWP 2.2.



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of p

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Table 1: Analysis of photon based study protocol.



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lly a

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End

poi

nts

Feas

ibili

ty st

udy:

feas

abili

ty, t

oler

abili

ty

Ph

ase

III p

art:

over

all s

urvi

val,

DFS

, site

of

recu

rren

ce to

xici

ty; Q

ol

loca

l con

trol,

treat

men

t rel

ated

side

ef

fect

s to

xici

ty a

nd lo

cal t

umou

r con

trol

Phas

e III

pro

spek

tive

rand

omis

ed, d

isea

se fr

ee in

terv

al (

loca

l un

d di

stan

t met

asta

ses)

, Loc

al re

curr

ent f

ree

surv

ival

, ove

rall

surv

ival

, per

cent

age

of sp

hinc

ter p

rese

rvin

g op

erat

ions

, R0

rese

ctio

n ra

te, m

orbi

dity

(acu

te si

de e

ffect

s of t

he R

T/C

H,

post

oper

ativ

e co

mpl

. + lo

ng te

rm si

de e

ffect

s, co

mpl

ianc

e,

qual

ity o

f life

und

er th

erap

y an

d af

ter t

reat

men

t

Prim

ary

endp

oint

Fe

asib

ility

stud

y: fe

asab

ility

, tol

erab

ility

Phas

e III

par

t: ov

eral

l sur

viva

l, 2

year

s loc

al c

ontro

l,

rate

of 1

-yea

r Gra

de 3

or h

ighe

r ad

vers

e ev

ents

lo

cal c

ontro

l, re

curre

nce

free

surv

ival

Seco

ndar

y en

dpoi

nts

Phas

e III

par

t: di

seas

e fre

e su

rviv

al, s

ites

of re

curr

ence

s, a

cute

and

late

toxi

city

, Q

ualit

y of

life

rate

s of t

reat

men

t rel

ated

gra

de 3

-4

adve

rse

effe

cts

1yea

r loc

al c

ontro

l rat

e, 1

yea

r ov

eral

l sur

viva

l and

dis

ease

free

su

rviv

al, A

sses

smen

t of F

DG

PET

SU

V c

hang

es a

as a

mea

sure

of

treat

men

t res

pons

e an

d ou

tcom

es,

Pulm

onar

y fu

nctio

n ch

ange

s by

treat

men

t arm

and

resp

onse

R0

rese

ctab

ilitä

t, pe

rcen

tage

of s

phin

kter

pre

serv

ing

rese

ctio

ns,

met

asta

ses f

ree

surv

ival

, pro

gres

sion

free

surv

ival

, ove

rall

surv

ival

, (tim

e ra

ndom

isat

ion

to d

eath

) acu

te to

xici

ty a

ccor

ding

to

CTC

, lat

e m

orbi

dity

acc

ordi

ng to

WH

O, q

ualit

y of

life

ac

cord

ing

to E

OR

TC c

riter

ia)

Tabl

e I:

Anal

ysis

of p

hoto

n ba

sed

stud

y pr

otoc

ol

Table 2: Analysis of photon based study protocol.ULICE-GA n{228436 of 22


Tri

al r

egis

trat

ion

E

OR

TC

400

13-2

2012

R

TO

G 0

618

RT

OG

091

5 C

hari

te B

erlin

C

ontr

act p

erio

d of

the

stud

y

3 ye

ars r

ecru

itmen

t, 2

mor

e ye

ars o

f fo

llow

-up

afte

r clo

sing

recr

uitm

ent

at a

bout

24

mon

ths r

ecru

itmen

t ac

crua

l will

be

com

plet

ed a

fter 4

.5

year

s tim

e fo

r pat

ient

incl

usio

n: 4

year

s, fo

llow

up

perio

d: 5

yea

rs,

final

stat

istic

al a

naly

sis:

afte

r 9 y

ears

Stat

istic

al c

onsi

dera

tions

St

atist

ical

met

hods

des

crib

ed in

det

ail

Stat

istic

al m

etho

ds d

escr

ibed

in d

etai

l St

atist

ical

met

hods

des

crib

ed in

de

tail

St

atist

ical

met

hods

des

crib

ed in

det

ail

Ref

eren

ces

yes

yes

yes

yes

Sam

ple

cons

ent f

orm

ye

s ye

s ye

s ye

s St

udy

para

met

ers

Feas

ibili

ty st

udy

Phas

e III

ove

rall

surv

ival

, DFS

, site

of r

ecur

renc

e to

xici

ty; Q

ol

Phas

e II

stud

y

rand

omiz

ed P

hase

II st

udy

pr

ospe

ctiv

e ra

ndom

ised

Perf

orm

ance

stat

us sc

orin

g

Kar

nofs

ky in

dex

Zubr

od p

erfo

rman

ce st

atus

0-1

Zu

brod

per

form

ance

stat

us 0

-1

Kar

nofs

ky in

dex

Stag

ing

syst

em

TNM

A

JCC,

TN

M

AJC

C, T

NM

TN

M

Com

orbi

dity

scor

ing

Es

tro Q

lQ -C

30 v

ersi

on 3

C

TCA

E 3.

0 C

TCA

E 3.

0 C

TC (a

cute

side

effe

cts)

, LEN

T - S

OM

A (l

ate

toxi

city

) Sp

ecim

en c

olle

ctio

n in

stru

ctio

ns

no

yes

yes

Follo

w u

p

defin

ed in

det

ail

defin

ed in

det

ail

defin

ed in

det

ail

EOR

TC Q

LQ D

30 u

nd Q

LQ D

38 in

itial

, 3, 6

, 12,

36,

60

mon

ths

post

oper

ativ

ely,

ana

mne

sis,

phys

ical

exa

min

atio

n, T

umou

r m

arke

r, A

bdom

inal

sono

grap

hy, R

ö Th

orax

, Rek

tosk

opie

, En

doso

nogr

aphi

e, K

olos

kopi

e, C

T B

ecke

n (u

nter

schi

edlic

he

Abs

tänd

e 3,

6, 1

2, 1

8, 2

4, 3

6, 4

8, 6

0 M

onat

e

Info

rmed

con

sent

ye

s ye

s ye

s ye

s In

depe

nden

t Eth

ics C

omm

ittee

ye

s ye

s ye

s ye

s R

ando

mis

atio

n ce

ntra

l ran

dom

isat

ion

no

ce

ntra

l ran

dom

isat

ion

R

ando

mis

atio

n th

roug

h ce

ntra

l stu

dy o

ffic

e,

birth

dat

e,

stra

tific

atio

n ac

cord

ing

to tr

eatm

etn

faci

lity,

tum

our

loca

lisat

ion,

infil

tratio

n de

pth,

inte

nded

ope

ratio

n pr

oced

ure

Exa

min

atio

n of

the

docu

men

ts

yes

yes

yes

repo

rt ev

ery

6 m

onth

s abo

ut n

umbe

r of t

reat

ed p

atie

nts b

y m

ain

resp

onsi

ble

pers

ons

Parti

cipa

ting

depa

rtm

ents

au

thor

isat

ion

proc

edur

e

auth

oris

atio

n pr

oced

ure

au

thor

isat

ion

proc

edur

e

with

nam

e / a

ddre

ss

Mon

itori

ng

cons

iste

ncy

chec

k at

dat

a m

onito

ring

cent

er

yes

yes

Aud

it qu

ality

ass

uran

ce

yes

yes,

all p

lans

hav

e to

be

send

in fo

r QA

pu

rpos

es

yes,

all p

lans

hav

e to

be

send

in fo

r Q

A p

urpo

ses

Hyp

othe

sis

to

det

erm

ine

whe

ther

radi

othe

rapy

in

volv

ing

high

bio

logi

cal d

ose

to li

mite

d tre

atm

ent v

olum

e ac

hiev

es a

ccep

tabl

oe

loca

l con

trol i

n op

erab

le p

atie

nts w

ith

early

stag

e N

SCLC

com

paris

on o

f tw

o st

ereo

tact

ic

fract

iona

tion

sche

dule

s (34

Gy/

1fr.

Vs.

48G

y/4f

r.) in

inop

erab

le

NSC

LC

zero

hyp

othe

sis,

prim

ary

+ se

cund

ary

endp

oint

s, cl

inic

al

rele

vant

diff

eren

ces

Dro

p ou

t rat

e

5%

not l

iste

d in

det

ail

not l

iste

d in

det

ail

lost

in fo

llow

up

10%

rela

ted

to 5

yea

rs

Stat

istic

al a

naly

sis

de

scrib

ed in

det

ail

desc

ribed

in d

etai

l de

scrib

ed in

det

ail

Kap

lan

Mey

er C

urve

s Log

-Ran

k-Te

st, B

resl

ow T

est

Mul

tivar

iat C

ox R

egre

ssio

n,

Tabl

e I:

Anal

ysis

of p

hoto

n ba

sed

stud

y pr

otoc

ol

Table 3: Analysis of photon based study protocol.



H

IMA

C, J

apan

N

ame

of th

e st

udy

A

pha

seⅠ

/II c

linic

al tr

ial o

f car

bon-

ion

ther

apy

in ４

fra

ctio

s per

wee

k fo

r pat

ient

s with

stag

e I n

on-s

mal

l cel

l lu

ng c

ance

r

A p

hase

II c

linic

al tr

ial o

f Car

bon-

ion

radi

othe

rapy

com

bine

d w

ith c

hem

othe

rapy

for

muc

osal

mal

igna

nt m

elan

oma

of th

e he

ad a

nd

neck

.

A p

hase

I/II

clin

ical

tria

l of C

arbo

n-io

n th

erap

y fo

r pat

ient

s with

ep

ithel

ial m

alig

nant

tum

or o

f lac

rimal

gla

nd

Typ

e of

stud

y / P

roto

col

Phas

e I/I

I clin

ical

tria

l Ph

ase

II no

n-ra

ndom

ized

tria

l Ph

ase

I/II c

linic

al tr

ial

Prot

ocol

com

ittee

√

√ √

Tum

or e

ntity

St

age

I (T1

-T2)

Non

smal

l cel

l lun

g ca

ncer

hi

stol

ogic

ally

pro

ven

muc

osal

mal

igna

nt

mel

anom

a

lacr

imal

gla

nd tu

mou

rs

Stag

e

Stag

e I

n=60

pat

ient

s enr

olle

d Tx

N0M

0;

n

=60

patie

nts

n=15

pat

ient

s Q

uest

ion

of p

roto

coll

To

test

effi

cacy

and

safe

ty o

f CIR

T (4

frac

tions

in 1

w

eek)

for s

tage

I N

SCLC

, per

iphe

ral t

ype.

To

ass

ess t

he sa

fety

and

effe

ctiv

enes

s of

com

bine

d C

IRT

and

Chem

othe

rapy

in th

e tre

atm

ent o

f H&

N m

ucos

al m

elan

oma

dose

esc

alat

ion

trial

Tre

atm

ent

carb

on io

n ra

diot

hera

py

Che

mo

with

CIR

T; C

IRT:

3.6

GyE

per

fra

ctio

n、１

fract

ion

per d

ay、

from

8 to

a

min

imum

of 6

frac

tions

ove

r 2 w

eeks、

for a

to

tal o

f16

fract

ions、

Tota

l dos

e 57

.6

GyE

、To

tal t

reat

men

t dur

atio

n of

CIR

T 25

〜39

day

s

carb

on io

n th

erap

y w

ith d

ose

esca

latio

n

Elig

ibili

ty c

heck

list

yes

yes

yes

Intr

oduc

tion

ye

s ye

s ye

s O

bjec

tives

ye

s ye

s ye

s Pa

tient

sele

ctio

n in

clus

ion

crite

ria

H

isto

logi

cally

(bio

psy

or c

ytol

ogy)

pro

ven

NSC

LC S

tage

I,

inop

erab

le o

r pat

ient

refu

ses s

urge

ry, M

easu

rabl

e tu

mor

, PS

0-2,

The

pat

ient

(or h

is tu

tor f

or p

atie

nt

youn

ger t

han

18) i

s aw

are

of th

e di

agno

sis a

nd is

abl

e to

gi

ve c

onse

nt

His

tolo

gica

lly (b

iops

y or

cyt

olog

y) p

rove

n m

alig

nant

muc

osal

mel

anom

a,

PS 0

-2, T

he

patie

nt (o

r his

tuto

r for

pat

ient

you

nger

than

18

) is a

war

e of

the

diag

nosi

s and

is a

ble

to

give

con

sent

, no

hear

t-, re

nal-,

hep

atic

dis

ease

, no

rmal

blo

od m

arro

w fu

nctio

nalit

y, n

o pr

evio

us tr

eatm

ent,

mea

sura

ble

tum

our

His

tolo

gica

lly p

rove

n m

alig

nant

epi

thel

ial t

umor

of t

he la

crim

al

glan

d, N

0M0

inop

erab

le (w

ith e

ye p

rese

rvat

ion)

or p

ost o

pera

tive

recu

rren

t dis

ease

, Tum

or v

isib

le o

n im

agin

g ex

ams,

age

15-8

0 ye

ars,

Kar

nofs

ky in

dex

equa

l or h

ighe

r tha

n 70

(PS:

0-2

), A

t lea

st

6 m

onth

s of e

xpec

ted

surv

ival

, no

othe

r mal

igna

nt d

isea

se, p

atie

nt

is a

ble

to u

nder

stan

d st

udy

Patie

nt se

lect

ion

excl

usio

n cr

iteri

a

prev

ious

radi

othe

rapy

, che

mot

hera

py, p

rogn

osis

of l

ess

than

6 m

onth

s, o

ther

act

ive

canc

er, i

nabi

lity

to

unde

rsta

nd a

ims o

f stu

dy

Prev

ious

radi

othe

rapy

of t

he a

ffect

ed a

rea,

Pr

evio

us c

hem

othe

rapy

, Act

ive

non

resp

onsi

ve

infe

ctio

n in

the

affe

cted

are

a, P

atie

nts j

udge

d in

adeq

uate

for m

edic

al, p

sych

olog

ical

or o

ther

fa

ctor

s by

the

exam

inin

g do

ctor

.

Prev

ious

radi

othe

rapy

in th

e af

fect

ed a

rea,

tum

our i

nvas

ion

beyo

nd

the

orbi

t bon

es, p

atie

nt re

ceiv

ing

chem

othe

rapy

less

than

2 w

eeks

be

fore

, inf

ectio

n in

the

area

to b

e irr

adia

ted,

med

ical

con

ditio

ns

whi

ch d

isqu

alify

for R

T tre

atm

ent

Pret

reat

men

t eva

luat

ions

H

isto

ry, p

hysi

cal f

indi

ngs,

bloo

d te

sts,r

espi

rato

ry fu

nctio

n te

sts,

bloo

d ga

s, C

T, c

hest

x-ra

ys, b

one

scin

tigra

phy,

br

onch

osco

py, a

bdom

inal

CT,

MR

I hea

d an

d ne

ck re

gion

hi

stor

y, o

phth

alm

olog

ical

exa

min

atio

n, b

iops

y, b

lood

test

s, C

T/M

RI e

xam

inat

ion

Reg

istr

atio

n pr

oced

ure

in

hou

se st

udy

in

hou

se st

udy

in

hou

se st

udy

Tabl

e II:

Ana

lysi

s of

stu

dy p

roto

col p

erfo

rmed

ad

NIR

S, C

hiba

, Jap

an

Table 4: Analysis of study protocol performed at HIMAC/NIRS, Chiba, Japan.



Nam

e of

the

stud

y

A p

haseⅠ

/II c

linic

al tr

ial o

f car

bon-

ion

ther

apy

in ４

frac

tios p

er w

eek

for

patie

nts w

ith st

age

I no

n-sm

all c

ell l

ung

canc

er

A p

hase

II c

linic

al tr

ial o

f Car

bon-

ion

radi

othe

rapy

com

bine

d w

ith

chem

othe

rapy

for

muc

osal

mal

igna

nt

mel

anom

a of

the

head

and

nec

k.

A p

hase

I/II

clin

ical

tria

l of C

arbo

n-io

n th

erap

y fo

r pa

tient

s with

epi

thel

ial m

alig

nant

tum

or o

f lac

rim

al g

land

Rad

iatio

n th

erap

y

carb

on io

n th

erap

y in

four

frac

tions

with

13,

2 G

yE fo

r T1

tum

ours

, 15G

yE fo

r T2

tum

ours

C

arbo

n io

n ra

diot

hera

py:3

.6 G

yE p

er

fract

ion、

１fra

ctio

n pe

r day、

from

8 to

a

min

imum

of 6

frac

tions

ove

r 2 w

eeks、

for a

to

tal o

f 16

fract

ions、

Tota

l dos

e 57

.6

GyE

、To

tal t

reat

men

t dur

atio

n of

CIR

T 25〜

39 d

ays

One

frac

tion

per d

ay 6

-8 fr

actio

ns in

2 w

eeks

12

fract

ions

in

tota

l. St

artin

g do

se o

f 4 G

yE p

er fr

actio

n (to

tal d

ose

48 G

yE).

Thre

e ca

ses w

ill b

e irr

adia

ted

with

the

sam

e do

e an

d fo

llow

ed u

p fo

r 6 m

onth

s, if

no to

xici

ty g

reat

er th

an G

2 ac

cord

ing

to N

CI-

CTC

scor

e is

obs

erve

d a

10%

dos

e es

cala

tion

will

be

perfo

rmed

on

the

next

3 p

atie

nt. I

f Gra

de 3

toxi

city

is o

bser

ved

the

case

will

be

exa

min

ed b

y th

e pr

otoc

ol o

pera

tive

boar

d.

Dru

g th

erap

y no

D

TIC

, AC

NU

, VC

R c

hem

othe

rapy

no

Surg

ery

no

no

no

Oth

er th

erap

y no

no

no

Dat

a co

llect

ion

in

hou

se st

udy

in

hou

se st

udy

in

hou

se st

udy

End

poi

nts

early

toxi

city

loca

l con

trol

surv

ival

, loc

al c

ontro

l, lo

cal r

epon

se, t

oxic

ity

toxi

city

, loc

al re

spon

se, o

vera

ll su

rviv

al

Prim

ary

endp

oint

ea

rly to

xici

ty lo

cal c

ontro

l S

urvi

val r

ate

Ove

rall

surv

ival

, Dis

ease

free

surv

ival

, dea

th

and

recu

rren

ce a

re c

ount

ed fr

om d

ay o

f sta

rt of

tre

atm

ent

early

toxi

city

, loc

al re

spon

se

Seco

ndar

y en

dpoi

nts

loca

l res

pons

e ra

te, s

urvi

val

loca

l con

trol r

ate,

Prim

ary

loca

l and

syst

emic

ef

fect

s (re

spon

se ra

te),

Toxi

city

lo

cal c

ontro

l, la

te to

xici

ty, o

vera

ll su

rviv

al

Con

trac

t per

iod

of th

e st

udy

2

year

s for

recr

uitm

ent

accr

ual t

ime

3 ye

ars,

follo

w u

p 2

year

s ac

crua

l tim

e 3

year

s, fo

llow

up

2 ye

ars

Stat

istic

al c

onsi

dera

tions

no

t des

crib

ed

not d

escr

ibed

Ref

eren

ces

yes

yes

yes

Sam

ple

cons

ent f

orm

ye

s ye

s ye

s

stud

y pa

ram

eter

s to

xici

ty, l

ocal

con

trol,

to

xici

ty, l

ocal

con

trol,

resp

onse

rate

,

toxi

city

, loc

al c

ontro

l, re

spon

se ra

te ,

Perf

orm

ance

stat

us sc

orin

g

PS 0

-2

Kar

nofs

ky in

des >

60, P

S 0-

2 K

arno

fsky

inde

s >60

, PS

0-2

Stag

ing

syst

em

TNM

Tx

N0M

0 Tx

N0M

0

Com

orbi

dity

scor

ing

R

TOG

acu

te m

orbi

dity

scor

ing

RTO

G/E

OR

TC la

te

mor

bidi

ty sc

orin

g

For e

arly

toxi

city

NC

I – C

TC (V

ersi

on 2

.) Fo

r la

te to

xici

t RTO

G/E

OR

TC L

ate

Radi

atio

n M

orbi

dity

Sco

ring

Syst

em

For e

arly

toxi

city

NC

I – C

TC (V

ersi

on 2

.) Fo

r lat

e to

xici

t R

TOG

/EO

RTC

Lat

e R

adia

tion

Mor

bidi

ty S

corin

g Sy

stem

Spec

imen

col

lect

ion

inst

ruct

ions

no

no

no

Tabl

e II:

Ana

lysi

s of

stu

dy p

roto

col p

erfo

rmed

ad

NIR

S, C

hiba

, Jap

an




Nam

e of

the

stud

y

A p

haseⅠ

/II c

linic

al tr

ial o

f car

bon-

ion

ther

apy

in 4

frac

tios p

er w

eek

for

patie

nts w

ith st

age

I no

n-sm

all c

ell l

ung

canc

er

A p

hase

II c

linic

al tr

ial o

f Car

bon-

ion

radi

othe

rapy

com

bine

d w

ith

chem

othe

rapy

for

muc

osal

mal

igna

nt

mel

anom

a of

the

head

and

nec

k.

A p

hase

I/II

clin

ical

tria

l of C

arbo

n-io

n th

erap

y fo

r pa

tient

s with

epi

thel

ial m

alig

nant

tum

or o

f lac

rim

al g

land

Follo

w u

p

mon

thly

than

eve

ry 2

mon

ths,

……

mon

thly

(firs

t 6 m

onth

s), e

very

3 m

onth

s (en

d of

yea

r 3),

ther

eafte

r ev

ery

6 m

onth

s In

form

ed c

onse

nt

yes

yes

yes

Inde

pend

ent E

thic

s Com

mitt

ee

yes

yes

yes

Ran

dom

isat

ion

no

no

no

Exa

min

atio

n of

the

docu

men

ts

no

rese

arch

exe

cutiv

e of

fice/

prot

ocol

stud

y bo

ard

prot

ocol

stud

y bo

ard

Pa

rtici

patin

g de

part

men

ts

in h

ouse

stud

y

in h

ouse

stud

y

in h

ouse

stud

y

Mon

itori

ng

not d

escr

ibed

pr

otoc

ol st

udy

boar

d

prot

ocol

stud

y bo

ard

A

udit

qual

ity a

ssur

ance

no

(in

hous

e)

rese

arch

exe

cutiv

e of

fice/

prot

ocol

stud

y bo

ard

prot

ocol

stud

y bo

ard

Hyp

othe

sis

eval

utat

e ef

ficac

y an

d to

xici

ty o

f car

bon

ion

ther

apy

in

NSC

LC

eval

uate

effi

cacy

and

toxi

city

of c

ombi

ned

chem

othe

rapy

and

car

bon

ion

RT

in m

ucos

al

mal

igna

nt m

elan

oma

eval

utat

e ef

ficac

y an

d to

xici

ty o

f car

bon

ion

ther

apy

in

lacr

imal

gl

and

tum

ours

Dro

p ou

t rat

e

not d

escr

ibed

no

t des

crib

ed

not d

escr

ibed

St

atis

tical

ana

lysi

s

not d

escr

ibed

K

apla

n M

eyer

Cur

ves

Kap

lan

Mey

er C

urve

s In

terim

ana

lysi

s no

t des

crib

ed

yes t

wic

e pe

r yea

r pe

riodi

c ch

eck

once

per

yea

r A

band

onm

ent o

f the

stud

y

not d

escr

ibed

de

scrib

ed (o

ne o

r mor

e G

4 si

de e

ffect

s)

desc

ribed

(one

or m

ore

G4

side

effe

cts)

A

band

onm

ent c

rite

ria

not d

escr

ibed

de

scrib

ed (o

ne o

r mor

e G

4 si

de e

ffect

s)

desc

ribed

(one

or m

ore

G4

side

effe

cts)

D

ata

anal

ysis

, Doc

umen

tatio

n bi

omet

ric

cont

rol

in h

ouse

stud

y

in h

ouse

, tw

ice

per y

ear

in h

ouse

stud

y

Qua

lity

cont

rol

not d

escr

ibed

no

t des

crib

ed

not d

escr

ibed

A

dver

se e

ffec

t rep

ortin

g cr

iteri

a R

TOG

/EO

RTC

C

TC, R

TOG

-EO

RTC

C

TC, R

TOG

-EO

RTC

Stor

age

of st

udy

docu

men

ts

in h

ouse

no

furth

er sp

ecifi

catio

n

in h

ouse

no

furth

er sp

ecifi

catio

n

in h

ouse

no

furth

er sp

ecifi

catio

n

Dec

lara

tion

of H

elsi

nki

not d

escr

ibed

no

t des

crib

ed

not d

escr

ibed

E

thic

s com

miss

ion

yes f

or e

ach

patie

nt

yes f

or e

ach

patie

nt

yes f

or e

ach

patie

nt

Insu

ranc

e po

licy

no

t des

crib

ed

not d

escr

ibed

no

t des

crib

ed

Fin

anci

ng o

f the

stud

y no

t des

crib

ed

not d

escr

ibed

no

t des

crib

ed

Lite

ratu

re

yes

yes

yes

Tabl

e II:

Ana

lysi

s of

stu

dy p

roto

col p

erfo

rmed

ad

NIR

S, C

hiba

, Jap

an




H

IT H

eide

lber

g

Nam

e of

the

stud

y

Ran

dom

ised

tria

l of p

roto

n vs

. C

arbo

n io

n ra

diat

ion

ther

apy

in

patie

nts w

ith lo

w a

nd

inte

rmed

iate

gra

de

chon

dros

arco

ma

of th

e sk

ull b

ase,

cl

inic

al p

hase

III s

tudy

Trea

tmen

t of p

atie

nts w

ith

atyp

ical

men

ingi

omas

Si

mps

on g

rade

4 a

nd 5

with

a

carb

on io

n bo

ost i

n co

mbi

natio

n w

ith

post

oper

ativ

e ph

oton

ra

diot

hera

py: T

he M

AR

CIE

Tr

ial

Ran

dom

ized

tria

l of p

roto

ns v

s. C

arbo

n io

n ra

diat

ion

ther

apy

in

patie

nts w

ith c

hord

oma

of th

e sk

ull b

ase,

clin

ical

pha

se II

I stu

dy

HIT

-1-S

tudy

Com

bine

d tre

atm

ent o

f mal

igna

nt

saliv

ary

glan

d tu

mou

rs w

ith

inte

nsity

mod

ulat

ed ra

diat

ion

ther

apy

(IMR

T) a

nd c

arbo

n io

ns

(CO

SMIC

)

Ran

dom

ized

pha

se II

stud

y ev

alua

ting

a ca

rbon

ion

boos

t ap

plie

d af

ter c

ombi

ned

radi

oche

mot

hera

py w

ith

tem

ozol

omid

e ve

rsus

a p

roto

n bo

ost a

fter r

adio

chem

othe

rapy

w

ith te

moz

olom

ide

in p

atie

nts

with

prim

ary

glio

blas

tom

a:

The

CLE

OPA

TRA

Tria

l

Ran

dom

ised

pha

se I/

II st

udy

to

eval

uate

car

bon

ion

radi

othe

rapy

ver

sus f

ract

iona

ted

ster

eota

ctic

radi

othe

rapy

in

patie

nts w

ith re

curr

ent o

r pr

ogre

ssiv

e gl

iom

as: T

he

CIN

DER

ELLA

tria

l

Tri

al r

egis

trat

ion

N

CT

0118

2753

N

CT

0116

6321

: N

CT

0118

2779

: N

CT

0115

4270

N

CT

0116

5671

N

CT0

1166

308:

T

ype

of st

udy

/ Pro

toco

l pr

ospe

ctiv

e ra

ndom

ised

act

ive-

cont

rolle

d cl

inic

al p

hase

III t

rial,

mon

ocen

tric

sing

le c

ente

r one

-arm

ed

phas

e II

stud

y

pros

pect

ive

rand

omiz

ed p

hase

III

trial

, mon

ocen

tric,

dou

ble

arm

st

udy

pros

pect

ive

mon

o-ce

ntric

pha

se II

tri

al

sing

le c

ente

r, tw

o-ar

med

ra

ndom

ized

Pha

se II

stud

y

Sing

le c

ente

r: Ph

ase

I/II s

tudy

: Ph

ase

I: do

se e

scal

atio

n sc

hem

e,

Phas

e II

part:

car

bon

ions

vs.

FSR

T

Prot

ocol

com

ittee

ye

s ye

s ye

s ye

s ye

s ye

s H

ypot

hesis

lo

w a

nd in

term

edia

te

chon

dros

arco

ma

of th

e sc

ull b

ase

at

ypic

al m

enin

giom

a sc

ull b

ase

chor

dom

a

mal

igna

nt sa

livar

y gl

and

tum

ours

gl

iobl

asto

ma

mul

tifor

me

re

curr

ent g

liobl

asto

ma

mul

tifor

me

Stag

e

154

patie

nts i

n to

tal

40 p

atie

nts i

n to

tal

154

patie

nts i

n to

tal

54 p

atie

nts

inco

mpl

ete

rese

cted

(m

acro

scop

ic tu

mou

r)n=1

50

patie

nts /

75

patie

nts p

er a

rm

recu

rren

t glio

blas

tom

a m

ultif

orm

e Ph

ase

I: 56

pat

ient

s;

Phas

e II

n=15

2 FS

RT,

n=2

28

carb

on io

ns

Que

stio

n of

pro

toco

ll

to e

valu

ate

if th

e in

nova

tive

ther

apy

(car

bon

ions

) is n

ot

rele

vant

ly in

ferio

r to

the

stan

dard

pr

oton

trea

tmen

t with

resp

ect t

o th

e 5

year

Loc

al p

rogr

essi

on fr

ee

surv

ival

to e

valu

ate

in a

Pha

se II

de

sign

the

impa

ct o

f a

carb

on io

n bo

ost i

n co

mbi

natio

n w

ith p

hoto

n R

T in

aty

pica

l men

ingi

oma

to e

valu

ate

if th

e in

nova

tive

ther

apy

(car

bon

ions

) is s

uper

ior

to th

e st

anda

rd p

roto

n tre

atm

ent

with

resp

ect t

o th

e lo

cal

prog

ress

ion

free

surv

ival

to e

valu

ate

feas

ibili

ty a

nd to

xici

ty

of tr

eatm

ent

to c

ompa

re a

car

bon

ion

boos

t to

a p

roto

n bo

ost d

eliv

ered

to

the

mac

rosc

opic

tum

or in

co

mbi

natio

n w

ith c

ombi

ned

radi

oche

mot

hera

py w

ith T

MZ

eval

uatio

n of

the

reco

mm

ende

d do

se (P

hase

I) /C

ompa

rison

of

carb

on io

ns a

nd F

SRT

(Pha

se

II)

Tre

atm

ent

prot

ons v

s. Ca

rbon

ions

afte

r op

erat

ion

co

mb.

Pho

tons

+ c

arbo

n io

ns

afte

r inc

ompl

ete

rese

ctio

n

prot

ons v

s. Ca

rbon

ions

afte

r op

erat

ion

co

mbi

ned

IMR

T/ca

rbon

ions

in

inco

mpl

ete

rese

cted

/inop

erab

le

mal

igna

nt sa

livar

y gl

and

tum

ours

surg

ical

rese

ctio

n, B

oost

Pr

oton

s or c

arbo

n io

ns,

conv

entio

nal p

hoto

n R

T (5

0Gy)

+ C

hem

othe

rapy

radi

othe

rapy

for r

ecur

rent

gl

iom

a

Elig

ibili

ty c

heck

list

yes

yes

yes

yes

yes

yes

Intr

oduc

tion

ye

s ye

s ye

s ye

s ye

s ye

s

Obj

ectiv

es

yes

yes

yes

yes

yes

yes

Tabl

e III

: Ana

lysi

s of

stu

dy p

roto

cols

per

form

ed a

t HIT

, Hei

delb

erg,

Ger

man

y

Table 7: Analysis of study protocols performed at HIT, Heidelberg, Germany.



H

IT H

eide

lber

g

Tri

al r

egis

trat

ion

N

CT

0118

2753

N

CT

0116

6321

: N

CT

0118

2779

: N

CT

0115

4270

N

CT

0116

5671

N

CT0

1166

308:

Pa

tient

sele

ctio

n in

clus

ion

crite

ria

K

arno

fsky

per

form

ance

sc

ore>

60%

Age

18-

80, i

nfor

med

co

nsen

t sig

ned,

hist

olog

ical

co

nfira

mtio

n of

low

/inte

rmed

iate

gr

ade

chon

dros

arco

ma

with

in

filtra

tion

of th

e sc

ull b

ase

hist

olog

ical

con

firm

ed

atyp

ical

men

ingi

oma,

su

btot

al re

sect

ion

Sim

pson

4/

5, p

rior p

hoto

n R

T, R

T no

t la

ter t

han

12 w

eeks

afte

r su

rger

y, a

ge 1

8-80

, K

arno

fsky

Sco

re >

60, a

bilit

y to

und

erst

and

stud

y, w

ritte

n in

form

ed c

onse

nt

hist

olog

ical

con

firm

ed c

hord

oma

with

infil

tratio

n of

the

scul

l ba

se,a

ge 1

8-80

, Kar

nofs

ky S

core

>6

0, w

ritte

n in

form

ed c

onse

nt

hist

olog

ical

ly c

onfir

med

or

surg

ical

ly re

mov

ed m

alig

nant

sa

livar

y gl

and

tum

ours

G2/

3,

>T3/

4, p

erin

eura

l inv

asio

n, w

ritte

n in

form

ed c

onse

nt a

ge 1

8-80

, ef

fect

ive

cont

race

ptio

ns

hist

olog

ical

ly c

onfir

med

un

ifoca

l, su

prat

ento

rial

prim

ary

glio

blas

tom

a,

mac

rosc

opic

tum

our a

fter

biop

sy/re

sect

ion,

indi

catio

n fo

r com

b. R

T/Ch

emo

(Tem

ozol

omid

e), p

rior p

hoto

n R

T, A

ge <

18 y

ears

, K

arno

fsky

> 6

0, a

dequ

ate

cont

race

ptio

n, a

bilit

y to

un

ders

tand

stud

y, w

ritte

n in

form

ed c

onse

nt

unifo

kal s

upra

tent

oria

l rec

urre

nt

glio

ma

WH

O G

II-IV

, prio

r Ph

oton

RT,

Kar

nofs

ky >

60,

adeq

uate

con

trace

ptio

n, a

bilit

y to

und

erst

and

aim

s of s

tudy

, w

ritte

n in

form

ed c

onse

nt

Patie

nt se

lect

ion

excl

usio

n cr

iteri

a

no in

form

ed c

onse

nt, i

nabi

lity

to

unde

rsta

nd a

ims o

f stu

dy, P

rior

RT

of th

e sc

ull b

ase,

oth

er

mal

igna

ncie

s with

dis

ease

free

su

rviv

al le

ss th

an 5

yea

rs,

parti

cipa

tion

in a

noth

er tr

ial,

preg

nanc

y, si

mul

tane

ous C

HT

or

Imm

unot

hera

py

patie

nts r

efus

al, p

revi

ous

RT,

opt

ic m

erve

shea

th

men

ingi

oma,

par

ticip

atio

n in

an

othe

r tria

l,

no in

form

ed c

onse

nt, i

nabi

lity

to

unde

rsta

nd a

ims o

f stu

dy, P

rior

RT

of th

e sc

ull b

ase,

oth

er

mal

igna

ncie

s with

dis

ease

free

su

rviv

al le

ss th

an 5

yea

rs,

parti

cipa

tion

in a

noth

er tr

ial,

preg

nanc

y, si

mul

tane

ous C

HT

or

Imm

unot

hera

py

prio

r RT/

Chem

o fo

r Hea

d an

d ne

ck

tum

ours

, oth

er m

alig

nanc

ies w

ithin

th

e pa

st 5

yea

rs, s

igni

fican

t ne

urol

ogic

al o

r psy

chia

tric

cond

ition

s, le

gal i

ncap

acity

, or

limite

d le

gal c

apac

ity, p

regn

ancy

, dr

ug a

buse

refu

sal o

f pat

ient

, pre

viou

s RT

to th

e br

ain,

> 5

2 G

y ap

plie

d du

ring

phot

on R

T, >

12

wee

ks

afte

r prim

ary

diag

nosi

s, cl

inic

al a

ctiv

e di

seas

e of

the

liver

, kid

ney

or c

ardi

a, o

ther

ca

rcin

oma

requ

iring

im

med

iate

trea

tmen

t in

terfe

ring

with

stud

y th

erap

y,

preg

nanc

y

mul

tifoc

al g

liom

a, re

fusa

l of

patie

nt, p

revi

ous r

e-irr

adia

tion,

le

ss th

an 6

mon

ths a

fter p

rimar

y R

T, p

regn

ancy

, oth

er c

linic

al

trial

par

ticip

atio

n

Pret

reat

men

t eva

luat

ion

Tum

or re

late

d ex

amin

atio

ns

(his

tory

, phy

sica

l exa

min

atio

n,

neur

olog

ical

stat

us, h

isto

logi

cal

conf

irmat

ion,

oph

thal

mol

ogic

ex

amin

atio

n, M

R Im

agin

g

Tum

or re

late

d ex

amin

atio

ns

(his

tory

, phy

sica

l ex

amin

atio

n, n

euro

logi

cal

stat

us, h

isto

logi

cal

conf

irmat

ion,

op

htha

lmol

ogic

exa

min

atio

n,

MR

Imag

ing

hist

ory

and

phys

ical

exa

min

atio

n in

clud

ing

neur

olog

ical

stat

us,

hist

olog

ical

con

firm

atio

n,

opht

halm

olog

ic e

xam

inat

ion

by

optic

ner

ve, a

udio

met

ry,

endo

crin

olog

ical

exa

min

atio

n,

MR

Imag

ing

befo

re a

nd a

fter

oper

atio

n

not

spec

ified

in

clus

ion/

excl

usio

n cr

iteria

pa

tient

his

tory

tria

l rel

evan

t pa

ram

eter

s

MR

I

Reg

istr

atio

n pr

oced

ure

ce

ntra

l HIT

tria

l cen

ter

cent

ral H

IT tr

ial c

ente

r ce

ntra

l HIT

tria

l cen

ter

cent

ral H

IT tr

ial c

ente

r ce

ntra

l in

hous

e ra

ndom

isat

ion

ce

ntra

l in

hous

e ra

ndom

isat

ion

Dru

g th

erap

y no

no

no

no

Te

moz

olom

ide

no

Su

rger

y

no fu

rther

des

crip

tion

no fu

rther

des

crip

tion

no

furth

er d

escr

iptio

n

if po

ssib

le

if po

ssib

le

no

Tabl

e III

: Ana

lysi

s of

stu

dy p

roto

cols

per

form

ed a

t HIT

, Hei

delb

erg,

Ger

man

y




H

IT H

eide

lber

g

Tri

al r

egis

trat

ion

N

CT

0118

2753

N

CT

0116

6321

: N

CT

0118

2779

: N

CT

0115

4270

N

CT

0116

5671

N

CT0

1166

308:

Rad

iatio

n th

erap

y

Plan

ning

CT

/MR

I 3 m

m sl

ices

, C

TV1

incl

udes

CTV

(ent

ire

resid

ual t

umou

r) an

d 1-

2mm

sa

fety

mar

gin,

C

TV2=

CTV

1+in

divi

dual

safe

ty

mar

gin

PTV

= C

TV +

indi

vidu

al

safe

ty m

argi

n fo

r eac

h pa

tient

O

AR

: eye

s, op

tic n

erve

s, ch

iasm

, br

ains

tem

, spi

nal c

ord,

tem

pora

l lo

bes,

man

dibl

e, sa

livar

y gl

ands

, N

o ov

erla

p of

OA

R a

nd C

TV

Plan

ning

CT

/MR

I ex

amin

atio

n, O

AR

co

nstra

ins E

mam

i et a

l. B

rain

stem

, opt

ic n

erve

s, ch

iasm

, spi

nal c

ord,

GTV

: lt

MR

, CTV

(car

bon)

G

TV+5

mm

, CTV

(pho

ton)

: G

TV, +

pre

oper

ativ

e tu

mou

r pe

ritum

oral

ede

ma,

hy

pero

stot

ic c

hang

es e

tc. +

1c

m sa

fety

mar

gin,

Car

bon

ion

dose

pre

scrip

tion:

3G

yE

to th

e m

axim

um o

f the

ca

lcul

ated

dos

e di

strib

utio

n,

Cov

erag

e of

the

targ

et

volu

me

by th

e 90

% is

odos

e

Plan

ning

CT

/ MR

I exa

min

atio

n,

3mm

slic

es, P

TV1:

incl

ude

the

GTV

, and

1-2

mm

safe

ty m

argi

n,

PTV

2: P

TV1+

indi

vidu

al sa

fety

m

argi

n w

hole

cliv

us, p

reve

rtebr

al

mes

cles

, OA

R: e

yes,

optic

ner

ves,

chia

sm, b

rain

stem

, spi

nal c

ord,

te

mpo

ral l

obes

, man

dibl

e,

saliv

ary

glan

ds, n

o ov

erla

p of

O

AR

and

PTV

Plan

ning

CT

/ MR

I exa

min

atio

n,

3mm

slic

es, C

TV1:

(car

bon

ion

boos

t) in

clud

es th

e m

acro

scop

ic

tum

our/

prio

r tum

our b

ed, s

peci

al

focu

s on

the

R1 re

sect

ion

and

resp

ectiv

e ne

ural

pat

hway

s. Fo

r pa

rotid

gla

nd tu

mou

rs: w

hole

fo

rmer

par

otid

are

a/if

poss

ible

m

andi

bula

r joi

nt is

kep

t out

side

the

CTV

1, P

TV1:

3m

m m

argi

n ar

ound

th

e C

TV1,

24G

yE b

y ca

rbon

ions

, co

verin

g C

TV1

by th

e 95

%

isod

ose,

// C

TV 2

con

sists

of C

TV1

+ sa

fety

mar

gin

alon

g ty

pica

l pa

thw

ays o

f spr

eas,

ipsi

late

ral

noda

l lev

els I

I/III,

CTV

2 ta

kes i

nto

acco

unt o

f set

-up

(CTV

2=PT

V2)

CT

/MR

I im

agin

g, 4

8-52

Gy

phot

on R

T ap

plie

d to

the

rese

ctio

n ca

vity

, are

a of

co

ntra

st e

nhan

cing

, inc

ludi

ng

a sa

fety

mar

gin

of 2

-3 c

m,

OA

R: b

rain

stem

, opt

ic

nerv

es, c

hias

m, s

pina

l cor

d,

Prot

on o

r Car

bon

ions

: GTV

: ar

ea o

f con

trast

enh

anci

ng

CTV

: GTV

+ 5

mm

safe

ty

mar

gin,

Dos

e ca

rbon

arm

: 3G

yE/1

8GyE

90%

iosd

ose

Dos

e pr

oton

arm

: 5x2

GyE

90

% io

sdos

e

Phas

e I:

dose

esc

alat

ion;

car

bon

ions

10x

3GyE

esc

alat

ed u

p to

16

x3G

yE

Phas

eII:

rand

omis

atio

n in

two

arm

s:

Car

bon

ions

(up

to th

e do

se

eval

uate

d in

Pha

se I

vs. F

SRT

18x2

Gy

othe

r th

erap

y ra

diot

hera

py

radi

othe

rapy

ra

diot

hera

py a

fter o

pera

tion

no

ye

s no

Dat

a co

llect

ion

el

ectro

nic

data

pro

cess

ing

at th

e st

udy

offic

e at

HIT

el

ectro

nic

data

pro

cess

ing

at

the

stud

y of

fice

at H

IT

elec

troni

c da

ta p

roce

ssin

g at

the

stud

y of

fice

at H

IT

in h

ouse

in

hou

se st

udy

in

hou

se st

udy

End

poi

nts

5 ye

ars l

ocal

pro

gres

sion

free

su

rviv

al (p

rimar

y en

dpoi

nt),

Ove

rall

surv

ival

, pro

gres

sion

free

su

rviv

al, m

etas

tasi

s fre

e su

rviv

al,

pattt

erns

of r

ecur

renc

es, l

ocal

co

ntro

l rat

e, m

orbi

dity

are

se

cond

ary

endp

oint

s

5 ye

ars l

ocal

pro

gres

sion

fre

e su

rviv

al (p

rimar

y en

dpoi

nt),o

vera

ll su

rviv

al,

safe

ty a

nd to

xici

ty

to d

emon

stra

te th

at io

n th

erap

y (e

xper

imen

tal t

reat

men

t) is

not

rele

vant

ly in

ferio

r to

prot

on

radi

othe

rapy

(sta

ndar

d tre

atm

ent)

with

resp

ect t

o th

e 5

year

LPF

S ra

te.

feas

ibili

ty a

nd to

xici

ty o

f tre

atm

ent,

effic

acy

of tr

eatm

ent

over

all s

urvi

val

prim

ary

endp

oint

: Pha

se I:

to

xici

ty, P

hase

II: s

urvi

val a

fter

12 m

onth

s

Prim

ary

endp

oint

5

year

s loc

al p

rogr

essi

on fr

ee

surv

ival

(prim

ary

endp

oint

),

5 ye

ars l

ocal

pro

gres

sion

fre

e su

rviv

al (p

rimar

y en

dpoi

nt)

5 ye

ars l

ocal

pro

gres

sion

free

su

rviv

al (p

rimar

y en

dpoi

nt)

feas

ibili

ty a

nd to

xici

ty (w

ith a

fo

cus o

n m

ucos

itis C

TCA

E III

ov

eral

l sur

viva

l to

xici

ty (P

hase

I) su

rviv

al (P

hase

II)

Seco

ndar

y en

dpoi

nts

Ove

rall

surv

ival

, pro

gres

sion

free

su

rviv

al, m

etas

tasi

s fre

e su

rviv

al,

pattt

erns

of r

ecur

renc

es, l

ocal

co

ntro

l rat

e, m

orbi

dity

are

se

cond

ary

endp

oint

s

over

all s

urvi

val,

safe

ty a

nd

toxi

city

A

sses

smen

t of o

vera

ll su

rviv

al,

prog

ress

ion

free

and

met

asta

sis

free

surv

ival

, pat

tern

s of

recu

rren

ces,

loca

l con

trol r

ate

mor

bidi

ty, P

rogn

ostic

fact

ors,

plan

qua

lity

(targ

et c

over

age,

sp

arin

g of

org

ans a

t ris

k, in

tegr

al

dose

loca

l con

trol,

dise

ase

free

surv

ival

, to

xici

ty,

and

late

toxi

city

at 3

year

s po

st R

T , t

umou

r res

pons

e:

REC

IST

crite

ria

prog

ress

ion

free

surv

ival

pr

ogre

ssio

n-fre

e su

rviv

al

Tabl

e III

: Ana

lysi

s of

stu

dy p

roto

cols

per

form

ed a

t HIT

, Hei

delb

erg,

Ger

man

y




H

IT H

eide

lber

g

Tri

al r

egis

trat

ion

N

CT

0118

2753

N

CT

0116

6321

: N

CT

0118

2779

: N

CT

0115

4270

N

CT

0116

5671

N

CT0

1166

308:

C

ontr

act p

erio

d of

the

stud

y

accr

ual p

erio

d fo

r the

tria

l 7

year

s, fo

llow

up

of p

atie

nts:

5y

ears

from

rand

omis

atio

n

3 ye

ars f

ollo

w u

p fo

r pa

tient

s ac

crua

l per

iod

for t

he tr

ial 7

yea

rs

accr

ual p

erio

d: a

t abo

ut 2

yea

rs,

parti

cipa

tion

for e

ach

patie

nt e

nds

afte

r 3 y

ears

appr

ox. 4

8 m

onth

s;

recr

uitm

ent:

36m

onth

s re

crui

tmen

t: 36

mon

ths

Stat

istic

al c

onsi

dera

tions

m

entio

ned

m

entio

ned

m

entio

ned

no

t lis

ted

lo

gran

k te

st

GC

P gu

idel

ines

Ref

eren

ces

yes

yes

yes

yes

yes

yes

Sam

ple

cons

ent f

orm

ye

s ye

s ye

s ye

s ye

s ye

s St

udy

para

met

ers

pros

pect

ive

rand

omis

ed a

ctiv

e-co

ntro

lled

clin

ical

pha

se II

I tria

l, m

onoc

entri

c

pros

pect

ive

one

arm

sing

le-

cent

er P

hase

II st

udy

pros

pect

ive

mon

o-ce

ntric

pha

se II

tri

al

over

all s

urvi

val

toxi

city

(Pha

seI)

surv

ival

(Pha

se

II)

Perf

orm

ance

stat

us sc

orin

g

Kar

nofs

ky in

dex

Kar

nofs

ky in

dex

Kar

nofs

ky in

dex

Kar

nofs

ky in

dex

Kar

nofs

ky in

dex

Kar

nofs

ky in

des

Stag

ing

syst

em

no

Sim

pson

gra

de o

f res

ectio

n

no

TNM

no

no

Com

orbi

dity

scor

ing

C

TC 4

.0 /

RTO

G-E

OR

TC la

te

mor

bidi

ty sc

orin

g

CTC

AE

Ver

sion

4.0

C

TC 4

.0 /

RTO

G-E

OR

TC la

te

mor

bidi

ty sc

orin

g

CTC

AE

v.3.

0 no

C

TCA

E G

rade

IV

Spec

imen

col

lect

ion

inst

ruct

ions

no

N

o

no

yes

no

no

Follo

w u

p

C

TC sc

orin

g, n

euro

logi

cal

exam

inat

ion,

imag

ing

(MR

I or

CT)

3

year

s for

eac

h pa

tient

, MR

I, ab

dom

inal

ultr

asou

nd, f

ull E

NT

clin

ical

exa

min

atio

n

ever

y tw

o m

onth

s for

at l

east

12

mon

ths

ever

y 2

mon

ths

Info

rmed

con

sent

ye

s ye

s ye

s ye

s ye

s ye

s

Inde

pend

ent E

thic

s Com

mitt

ee

yes

yes

yes

yes

yes

yes

Ran

dom

isat

ion

in-h

ouse

stud

y of

fice

at H

IT

No

on

-line

rand

omis

atio

n to

ol

(ran

dom

izer

.at),

stra

tific

atio

n pa

ram

eter

s inc

luds

age

(</>

30

year

s, an

d ge

nder

)

no

yes p

roto

ns v

s. Ca

rbon

ions

ye

s Pha

se II

exam

inat

ion

of th

e do

cum

ents

no

no

no

no

in

terim

ana

lysi

s afte

r 50%

of

the

expe

cted

eve

nts h

ave

occu

rred

part

icip

atin

g de

part

men

ts

in-h

ouse

stud

y

in-h

ouse

stud

y

in h

ouse

stud

y

in h

ouse

stud

y

in h

ouse

stud

y

in h

ouse

stud

y

Mon

itori

ng

Dat

a m

onito

ring

com

mitt

ee

Dat

a m

onito

ring

com

mitt

ee

Dat

a m

onito

ring

com

mitt

ee

yes i

n ho

use

ye

s in

hous

e

yes i

n ho

use

A

udit

qual

ity a

ssur

ance

no

(in

hous

e)

no (i

n ho

use)

no

(in

hous

e)

no (i

n ho

use)

no

(in

hous

e)

no (i

n ho

use)

H

ypot

hesi

s ze

ro h

ypot

hesi

s, pr

imar

y +

secu

ndar

y en

dpoi

nts,

clin

ical

re

leva

nt d

iffer

ence

s

zero

hyp

othe

sis,

prim

ary

+ se

cund

ary

endp

oint

s, cl

inic

al

rele

vant

diff

eren

ces

zero

hyp

othe

sis,

prim

ary

+ se

cund

ary

endp

oint

s, cl

inic

al

rele

vant

diff

eren

ces

eval

uatio

n of

the

toxi

city

of

com

bine

d IM

RT/

carb

on io

ns in

m

alig

nant

saliv

ary

glan

d tu

mou

rs

the

effe

ct o

f car

bon

ions

ra

diot

hera

py fo

r the

trea

tmen

t of

glio

blas

tom

a is

exp

ecte

d to

be

subs

tant

ially

hig

her t

han

with

con

vent

iona

l pro

ton

radi

othe

rapy

Phas

e I:

to c

hoos

e re

com

men

ded

dose

, Pha

se II

: is

desi

gned

to d

emon

stra

te

supe

riorit

y of

surv

ival

of c

arbo

n io

n ra

diot

hera

py (e

xper

imen

tal)

vs. F

SRT(

stan

dard

)

Tabl

e III

: Ana

lysi

s of

stu

dy p

roto

cols

per

form

ed a

t HIT

, Hei

delb

erg,

Ger

man

y




H

IT H

eide

lber

g

Tri

al r

egis

trat

ion

N

CT

0118

2753

N

CT

0116

6321

: N

CT

0118

2779

: N

CT

0115

4270

N

CT

0116

5671

N

CT0

1166

308:

D

rop

out r

ate

appr

ocim

atel

y 10

%

ap

prox

imat

ely

10%

ye

s

not m

entio

ned

Stat

istic

al a

naly

sis

K

apla

n M

eyer

Cur

ves

stat

istic

al m

etho

ds a

re

subj

ect t

o G

CP

guid

elin

es

no

t spe

cifie

d

desc

ribed

in d

etai

l

desc

ribed

in d

etai

l

Inte

rim a

naly

sis

no

no

afte

r 5.5

yea

rs

not s

peci

fied

ye

s afte

r occ

urre

nce

of 5

0%

of th

e ex

pect

ed e

vent

s ye

s in

Phas

e II,

whe

n 40

% o

f th

e ex

pect

ed e

vent

s und

er th

e nu

ll-hy

poth

eses

hav

e oc

curre

d

Aba

ndon

men

t of t

he st

udy

no

t lis

ted

no

t lis

ted

st

udy

term

inat

ed e

arlie

r in

case

of

the

inte

rim a

naly

sis s

how

ing

5%

smal

ler r

ate

of th

e LP

FS ra

te o

f st

anda

rd tr

eatm

ent.

yes,

desc

ribed

ov

erw

helm

ing

treat

men

t ef

fect

, sto

ppin

g ru

le sp

ecifi

ed

acco

rdin

g to

O`B

rien

and

Flem

ing,

obj

ectiv

es o

f the

st

udy

cann

ot b

e re

ache

d,

bene

fit/ri

sk ra

tio h

as

wor

sene

d m

arke

dly

yes,

desc

ribed

Aba

ndon

men

t cri

teri

a no

t lis

ted

no

t lis

ted

s.o

. m

edic

al o

r eth

ical

reas

ons a

ffect

ing

the

risk-

bene

fit re

latio

nshi

p,

diffi

culti

es in

recr

uitm

ent o

f su

bjec

ts su

gges

t unj

ustif

iabl

e pr

olon

gatio

n of

the

stud

y,

prev

ieou

sly

unex

pect

ed a

dver

se

even

ts, u

nexp

ecte

dly

high

in

cide

nce

of e

xpec

ted

adve

rse

even

ts, r

elev

ant s

uper

iorit

y of

pa

tient

s in

one

treat

men

t arm

of a

co

mpa

rabl

e st

udy,

lega

l aut

horit

ies

deci

sion

over

whe

lmin

g tre

atm

ent

effe

ct, s

topp

ing

rule

spec

ified

ac

cord

ing

to O

`Brie

n an

d Fl

emin

g, o

bjec

tives

of t

he

stud

y ca

nnot

be

reac

hed,

be

nefit

/risk

ratio

has

w

orse

ned

mar

kedl

y

yes,

desc

ribed

Dat

a an

alys

is, D

ocum

enta

tion

biom

etri

c co

ntro

l st

udy

offic

e

stud

y of

fice

st

udy

offic

e

in h

ouse

stud

y

in h

ouse

stud

y

in h

ouse

stud

y

Qua

lity

cont

rol

not l

iste

d

not l

iste

d

not l

iste

d

in h

ouse

no

furth

er sp

ecifi

catio

n

no

in h

ouse

no

furth

er sp

ecifi

catio

n

Adv

erse

eff

ect r

epor

ting

crite

ria

CTC

AE

4.0

CTC

AE

4.0

CTC

AE

4.0/

EOR

TC/R

TOG

C

TC A

E v.

3.0

not m

entio

ned

CTC

AE

Gra

de IV

Stor

age

of st

udy

docu

men

ts

in h

ouse

stud

y of

fice

in

hou

se st

udy

offic

e

in h

ouse

stud

y of

fice

in

hou

se

in h

ouse

stud

y

in h

ouse

no

furth

er sp

ecifi

catio

n

Dec

lara

tion

of H

elsi

nki

not l

iste

d

not l

iste

d

not l

iste

d

yes

yes

yes

Eth

ics c

omm

issio

n ye

s ye

s ye

s ye

s ye

s ye

s In

sura

nce

polic

y

not l

iste

d

not l

iste

d

not l

iste

d

not l

iste

d

not m

entio

ned

not m

entio

ned

Fin

anci

ng o

f the

stud

y no

t lis

ted

no

t lis

ted

no

t lis

ted

no

t lis

ted

no

t men

tione

d no

t men

tione

d Li

tera

ture

ye

s ye

s ye

s ye

s ye

s ye

s

Tabl

e III

: Ana

lysi

s of

stu

dy p

roto

cols

per

form

ed a

t HIT

, Hei

delb

erg,

Ger

man

y




2 Analysis of study protocol guidelines

Analysis of clinical study protocols was followed by a structure analysis of different existing studyprotocol guidelines.

2.1 Analysed study protocol guidelines

Determination referred to the following study protocol guidelines:

• ECCO-AACR-ASCO Methods in Clinical Cancer Research Phase I/II/III studies;

• EORTC guidelines for writing protocols for clinical trials of radiotherapy (1995);

• GCP (good clinical practice) Guidelines for Clinical Trial Protocol development,

States;

• Masterprotokoll (Deutschen Krebsgesellschaft e.V. and Deutsche Krebshilfe).

2.2 Results of study protocol guidelines analyses

Results are shown in the Table 12.

2.3 Conclusion of study protocol guideline analyses

In conclusion it can be stated that the following study protocol guidelines showed an enumeration ofdifferent aspects of clinical studies:

• ECCO-AACR-ASCO;

• EORTC;

• GCP (good clinical practice) Guidelines;

• Masterprotokoll.

The headlines were elaborated more in detail in

• Masterprotokoll.

A detailed description of phase I/II/III studies was given in

• ECCO-AACR-ASCO.



E

OR

TC

Gui

delin

es fo

r w

ritin

g pr

otoc

ols f

or c

linic

al tr

ials

of

radi

othe

rapy

(199

5) E

OR

TC

Mas

terp

roto

koll

Ger

man

y

G

uide

lines

for

desig

ning

a c

linca

l st

udy

prot

ocol

bas

ed o

n In

tern

. C

onfe

renc

e on

Her

mon

izat

ion

(IC

H),

Goo

d cl

inic

al p

ract

ice

(GC

P)B

ethe

sda

USA

EC

CO

-AA

CR

-ASC

O

met

hods

in c

linic

al

Can

cer

Res

earc

h Ph

ase

I/II

/III s

tudi

es

Gen

eral

Info

rmat

ion

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l

Intr

oduc

tion

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l

Stud

y ob

ject

ives

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l

Stud

y de

sign

(pri

mar

y,

seco

ndar

y en

dpoi

nts)

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l

Part

icip

atin

g ce

nter

s m

entio

ned

in d

etai

l

in d

etai

l Pa

tient

sele

ctio

n cr

iteri

a

men

tione

d in

det

ail

x (in

clus

ion/

excl

usio

n cr

iteria

) in

det

ail

Reg

istr

atio

n, r

ando

mis

atio

n pr

oced

ure

w

here

and

whe

n to

cal

l in

det

ail

men

tione

d in

det

ail

Tre

atm

ent s

trat

egy:

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l D

rugs

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l R

adio

ther

apy

in

det

ail

in d

etai

l m

entio

ned

in d

etai

l Q

ualit

y as

sura

nce

in

det

ail

AK

K -

AR

O P

rüfli

ste

für

Stud

ienp

roto

kolle

mit

stra

hlen

ther

apeu

tsch

. Ant

eil

in

det

ail

Surg

ery

m

entio

ned

(oth

er th

erap

ies)

in

det

ail

men

tione

d in

det

ail

Clin

ical

follo

w u

p

men

tione

d in

det

ail

men

tione

d in

det

ail

Stud

y pa

thol

ogy

no

t men

tione

d in

det

ail

not m

entio

ned

in d

etai

l St

udy

dura

tion

m

entio

ned

in d

etai

l m

entio

ned

in d

etai

l E

valu

atio

n cr

iteri

a

in d

etai

l in

det

ail

not m

entio

ned

in d

etai

l T

oxic

ity e

valu

atio

n

appr

opria

te sc

orin

g sy

stem

WH

O,

EOR

TC, R

TOG

in

det

ail (

WH

O/N

CIC

) m

entio

ned

in d

etai

l (W

HO

/NC

IC)

Stat

istic

al a

naly

sis

men

tione

d in

det

ail

men

tione

d in

det

ail

ICH

E3

in

det

ail

in

det

ail

ICH

E6

in

det

ail

in

det

ail

ICH

E9

in

det

ail

in

det

ail

Dat

a m

anag

emen

t da

ta m

onito

ring

com

mitt

ee

Stud

ienz

entra

le

men

tione

d in

det

ail

Qua

lity

cont

rol

in d

etai

l in

det

ail

men

tione

d in

det

ail

Eht

ical

con

side

ratio

ns

men

tione

d in

det

ail

men

tione

d in

det

ail

Leg

al-

adm

inis

trat

ive

issu

es

men

tione

d in

det

ail (

ICH

-GC

P G

uide

lines

) ac

cord

ing

to S

OP

and

the

fede

ral,

stat

e an

d lo

cal r

egul

atio

ns

in d

etai

l

Lite

ratu

re

men

tione

d in

det

ail

men

tione

d in

det

ail

Att

achm

ents

in

det

ail

in d

etai

l m

entio

ned

in d

etai

l E

cono

mic

eva

luat

ion

po

ssib

ly in

futu

re

not m

entio

ned

in

det

ail

Publ

icat

ion

polic

y

men

tione

d no

t men

tione

d m

entio

ned

in d

etai

l

Table 12: Analysis of study protocol guidelines.



CONCLUSIONSOn the basis of the performed analysis of different clinical protocols it can be concluded that thegeneral structure and/or the main topics of protocols appear to be relatively similar in all protocolsbut – going more in detail – there are several open questions. Methodology of dealing with thesedifferences has to be discussed and worked out within the future activities of the ULICE WP 2.2.Structure analysis of existing study protocol guidelines revealed that all study protocol guidelinesshowed an enumeration of different aspects of clinical studies but the most detailed description ofphase I/II/III studies was given in the ECCO-AACR-ASCO guidelines.


d.jra 2.2- review of the existing protocol structure in large clinical

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