lch-iv - bspho · lch-iv international collaborative treatment protocol for children and...

LCH-IV

International Collaborative Treatment Protocol for Children and Adolescents

with Langerhans Cell Histiocytosis

Teleconference Study Initiation Belgium 25th of March 2014

Presenter

Presentation Notes

During the past decade Neurodegeneration in LCH has become a topic of major concern. There is a lot of uncertainty regarding the definition , the diagnosis and the treatment of patients with this disorder. In order to better characterize ND in LCH we studied the patients who were registerd on the trials DAL-LCHIII and who were reported to our center with ND disease I would like to start with one of the most crucial points that is the definition of ND Then I would like to describe the clinical presentation and course of the pts. In order to highlight (herausarbeiten) the characteristic features of tiese peculiar patients.

Coordinating Principal Investigators (PIs)

STRATUM I / First-line treatment

M. Minkov / C. Rodriguez-Galindo

STRATUM II / Second-line treatment K. Beutel / R. Jubran STRATUM III / Salvage, Risk-LCH J. Donadieu / K. Stine STRATUM IV / HSCT, Risk LCH S. Matthes / S. Baker STRATUM V / CNS LCH J.-I. Henter / K. McClain STRATUM VI / Natural history of SS-LCH STRATUM VII / Long term follow up

R. Haupt / P. Campbell

V. Nanduri / D. Dix

Chair: M. Minkov Co-Chair: C. Rodriguez-Galindo

International LCH-IV Study Management Group

International LCH-IV Study Management Center

Sponsor representative

Prof. Dr Helmut Gadner ([email protected])

Study Management Milen Minkov

Elfriede Thiem ([email protected]) Ulrike Pötschger (statistician)

Location

St. Anna Kinderkrebsforschung Vienna, Austria

LCH-IV SUBCENTER

NATIONAL PRINCIPAL INVESTIGATOR

ASSOCIATE

Argentina Rosso, Diego Braier, Jorge

Austria Minkov, Milen

Australia Stewart, J. Kellie Wilson, Peter Super, Leanne

Belarus Aleinkova, Olga Efremova, Viktoria

Belgium Van Gool, Stefaan Phillipet, Pierre

Canada Abla, Oussama Weitzman, Sheila

Czech Republic Mottl, Hubert

Denmark Nysom, Karsten

France Donadieu, Jean Thomas, Caroline

Germany Lehrnbecher, Thomas Sörensen, Jan

India Thavaraj, Vasantha Seth, Thulika

LCH-IV National Principal Investigators

LCH-IV SUBCENTER

NATIONAL PRINCIPAL INVESTIGATOR

ASSOCIATE

Israel Attias, Dina Weintraub, Michael

Italy Arico, Maurizio Sieni, Elena

New Zealand Macfarlane, Scott Teague, Lochie R.

Russia Bronin, Gleb Maschan, Michael

Kovaliova, Olga Solopova, Galina

Serbia Krstovski, Nada Janic, Dragana

Spain Astigarraga, Itziar

Sweden Henter, Jan-Inge

Switzerland Leibundgut, Kurt

Turkey Devecioglu, Ömer

The Netherlands van den Bos, Cor van Noesel, Max

UK Visser, Johann Nanduri, Vasantha

USA Rodriguez-Galindo, Carlos Campbell, Patrick K.

LCH-IV National Principal Investigators

LCH IV coordination Belgium

• Prof. Stefaan Van Gool [email protected]

• Dr. Pierre Philippet [email protected]

• National datamanager [email protected]

mailto:[email protected]



LCH-IV STUDY

• International, multicenter, prospective clinical

study for paediatric LCH (age < 18y)

• Patient enrollment through a „Registry &

Stratification“ step

• Assigning of patients to one of the 7 strata,

depending on organ involvement and treatment

indication

LCH-IV Clinical Classification of LCH

DISEASE CATEGORIES

DEFINITIONS

Singlesystem LCH (ss-LCH)

One organ/system involved (uni-or multifocal)

Bone unifocal (single bone) or multifocal (>1 bone) Skin Lymphnode (not the drining lymph node of another LCH- lesion) Lungs Central nervous system Other (e.g. thyroid gland)

Multisystem LCH (ms-LCH)

Two or more organs/systems involved

+/- involvement of „Risk organ“ (hematopoetic system, liver, spleen)

LCH-IV Definition of Risk Organ involvement

HEMATOPOETIC

INVOLVEMENT: (with or without bone

marrow involvement)

At least 2 of the following:

• anemia: hemoglobin <100 g/L (<10 g/dl), infants <90 g/L

(<9.0 g/dl), not due to other causes e.g. iron deficiency

• leukocytopenia: leukocytes <4,0 x109/l (4,000/µL)

• thrombocytopenia: platelets <100 x109/l (100.000/µL)

SPLEEN

INVOLVEMENT:

• enlargement >2 cm below costal margin in the

midclavicular line

LIVER

INVOLVEMENT:

• enlargement >3 cm below costal margin in the

midclavicular line

and/or

• dysfunction (i.e. hypoproteinemia <55 g/L,

hypoalbuminemia <25 g/L, not due to other causes

and/or

• histopathological findings of active disease

LCH-IV OVERALL TREATMENT CONCEPT

STRATUM I First-line treatment

Study Hypothesis:

• Prolongation and intensification of the continuation

therapy will reduce the cumulative incidence of

reactivations in children with LCH


STRATUM I

First-line treatment for patients with • ms-LCH (GROUP 1)

• ss-LCH (Group 2) as isolated „CNS-risk“ or multifocal

bone lesions: isolated CNS-risk lesions are lesions in one of the craniofacial bones (i.e. orbit, temporal bone, mastoid, sphenoid, zygomatic, ethmoid, maxilla, paranasal sinuses or cranial fossa) +/- intracranial soft tissue extension


STRATUM I Eligibility criteria • Age less than 18 years at time of diagnosis • Verified diagnosis • No prior systemic therapy for LCH • Signed informed consent Exclusion criteria • Pregnancy • LCH related permannent consequences (e.g. vertebra plana,

sclerosing cholangitis, lung fibrosis, ...) in the abscence of active LCH • Prior systemic therapy

RO-: no disease activity in Risk Organs RO+: disease activity in Risk Organs Rx= Randomization time point, refer to Section 8.9.2

•NAD

Initial Course 1 (IC-1)


STRATUM II

Patients who fulfill organ dysfunction criteria go to STRATUM III or STRATUM IV

•AD better (RO-) •AD intermed. (RO-) •AD better (RO+)

•AD worse (RO-)

•AD intermed.(RO+) •AD worse (RO+)

•NAD •AD better (RO-)

•AD intermed./ worse (RO-) •AD better (RO+)

•AD intermediate (RO+) •AD worse (RO+)

CT-Arm A (12 months PRED/VBL)

CT-Arm B (12 months PRED/VBL + 6-MP)

CT-Arm D (24 months PRED/VBL + 6-MP)

CT-Arm C (24 months PRED/VBL)

Rx

STRATUM II

STRATUM I: Group 1

Initial Course 1 (IC-1) VBL 6 mg/m2 i.v.bolus

PRED 40 mg/m2/day

orally; weekly; reduction after week 4

Week 1 2 3 4 5 6 7

Day 1 8 15 22 29 36 42

For dose modification, refer to Section 8.6


PRED 40mg/m2/day orally on day 1-3 of Week 8, 9, 10, 11, 12, 13

Week 8 9 10

Day 49 56 63 70 77 84 91

11 12 13

STRATUM I: Group 1

Continuation Therapy Arm A (CT-A)

VBL 6 mg/m2 i.v.bolus

PRED 40 mg/m2/day

day 1-5 q 3 week

Patients who receive initial therapy course 1 and 2 start with continuation therapy after week 13

8 7 50 Week 51 52 9 10 11 12 49 13


STRATUM I: Group 1

Continuation Therapy Arm B (CT-B)

8 7 50 Week 51 52 9 10 11 12 49

VBL 6 mg/m2 i.v. bolus

PRED 40 mg/m2/day

day 1-5 q 3 week

6-MP 50 mg/m2/day orally;daily

13



STRATUM I: Group 1

Continuation Therapy Arm C (CT-C)


PRED 40 mg/m2/day

day 1-5 q 3 week

8 7 102 Week 103 104 9 10 11 12 101 13



STRATUM I: Group 1

Continuation Therapy Arm D (CT-D)

8 7 102 Week 103 104 9 10 11 12 101


PRED 40 mg/m2/day

day 1-5 q 3 week


13


For dose modification, refer to protoclSection 8.6

STRATUM I: Group 1

•NAD



STRATUM II

•AD better •AD intermed.

• AD worse (RO-)

•NAD •AD better (RO-)

•AD intermed. (RO-) •AD worse (RO-)

CT-Arm E (6 months PRED/VBL)

CT-Arm A (12 months PRED/VBL)

Rx

RO-: no disease activity in Risk Organs Rx: Randomization time point, refer to Section 8.9.2

STRATUM I: Group 2


PRED 40 mg/m2/day

orally; weekly; reduction after week 4

Week 1 2 3 4 5 6 7

Day 1 8 15 22 29 36 42

For dose modification, refer to protocol Section 8.6


PRED 40mg/m2/day orally on day 1-3 of Week 8, 9, 10, 11, 12, 13

Week 8 9 10

Day 49 56 63 70 77 84 91

11 12 13

STRATUM I: Group 2

Continuation Therapy Arm A (CT-A)


PRED 40 mg/m2/day

day 1-5 q 3 week


8 7 50 Week 51 52 9 10 11 12 49 13


STRATUM I: Group 2

Continuation Therapy Arm E (CT-E)


PRED 40 mg/m2/day

day 1-5 q 3 week

8 7 23 Week 24 9 10 11 12 22 13



STRATUM I: Group 2


STRATUM II Second Line treatment for non-Risk LCH

Aim: • for patients without risk organ involvement, who fail First-line treatment have reactivation after completion of First-line treatment


STRATUM II Eligibility criteria: Patients of STRATUM I with • progressive disease (AD* worse) in non-risk organs after 6 wks

(Initial course 1) • AD intermediate or worse in non-risk organs or AD better in risk

organse after 12 wks (Initial course 2) • disease progression (AD worse) in non-risk organs at any time

during continuation treatment • AD at the end of STRATUM I treatment • disease reactivation in non-risk organs at any time after

completion of STRATUM I treatment

*AD: Active disease


STRATUM II Exclusion criteria: • Patients with progressive disease in risk organs • Permanent consequences (e.g. sclerosing cholangitis, lung

fibrosis, ...) without evidence of active LCH • No written consent of the patient or his/her parents or legal

guardian

2nd-line Initial Therapy (SL-IT)

NAD AD better

CT-Arm Indomethacin

CT-Arm 6-MP/MTX

Rx

NAD = Non-Active Disease AD better = Active Disease better Rx = Randomization time point, refer to Section 9.7.2

2 1 Week 24 25 26 104 103 102 27

STRATUM II

Belgium : no Randomization (no participation indomethacine treatment arm)

1 2 3 4 5 6 7 10 Week

PRED

ARA-C

VCR

8 9 11 12

14 13 22 Week 23 24 15 16 17 18 19 20 21

PRED: 40 mg/m2/d for 2 weeks, 20 mg/m2/d for 2 weeks, 10 mg/m2/d for 2 weeks, 5 mg/m2/d for 2 weeks ARA-C: 100 mg/m2/dose as an i.v. push or s.c. for 4 days on weeks 1, 4, 7, 10, 13, 16, 19, 22 VCR: 1.5 mg/m2/d (max 2.0 mg) as an i.v. push on day 1 of weeks 1, 4, 7, 10, 13, 16, 19, 22

STRATUM II: Initial Therapy Course

For dose modification, refer to protocol Section 9.4.3

®

26 25 102 Week 103 104 27 28 29 30 100 101

INDOMETHACIN

6-MP

MTX

INDO (Indomethacin): 2mg/kg/d daily orally with gastric protection 6-MP (Mercaptopurine) : 50mg/m2/d daily orally MTX (Methotrexat): 20mg/m2/d weekly orally

R= Randomization time point, refer to protocol Section 9.7.2

STRATUM II: Continuation Therapy Course

For dose modification, refer to protocol Section 9.4.3

Belgium : no participation indomethacine treatment arm


STRATUM III Salvage treatment for RISK LCH

Aim: • to assess the efficacy of the combination 2-CdA/Ara-C in ms-

LCH patients with risk organ involvement, who fail to respond to

First-line treatment (STRATUM I)


STRATUM III

Eligibility criteria Patients from STRATUM I with

• AD worse in risk organs after wk 6 (after Initial course 1)

• AD worse or AD intermediate in risk organs after wk 12 (after Initial

course 2)

• Presence of unequivocally severe organ dysfunction at the above

mentioned evaluation points (hematological dysfunction, liver

dysfunction or both of them)


STRATUM III

Organ dysfunction eligibility criteria for enrollment in STRATUM III (table XI):

• Hematologic dysfunction – Hb <70 g/L (<7.0 g/dl) and/or transfusion dependency – PLT <20 x109/L (20,000/µL) and/or transfusion dependency

(both criteria have to be fulfilled) AND/OR • Liver dysfunction (or digestive involvement with protein loss)

– Total protein <55 g/L or substitution dependency – Albumin <25 g/L or substitution dependency

(at least one of the two criteria to be fulfilled)

Continuation Therapy (Part 1, 2, 3)

RIC-HSCT

Contact PI 2-CdA

+ Ara-C

Evaluation

2-CdA +

Ara-C

NAD = Non-active disease

AD B = AD Better

AD I = AD Intermediate

AD W = AD Worse

2-CdA +

Ara-C

2-CdA +

Ara-C

1 2 3 4

NAD

AD B

AD W

AD I

Part 1

Evaluation

NAD

AD B

AD W

AD I

Part 1 Part 2,3

Part 2,3

Part 2,3

Part 2,3

Initial Therapy

STRATUM III

Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Ara-C

2-CdA

Ara-C 500 mg/m2 q12 h (2-hr infusion) 2-CdA 9 mg/m2 qday (2-hr infusion) The course has to be repeated after an interval of 4 weeks

STRATUM III: Initial Therapy Block Ara-C / 2-CdA


Part 1

Part 3 6-MP 50 mg/m2/d MTX 20 mg/m2/week

2 CdA 5 mg/m2/d x 3 d, for 2 courses VBL 6 mg/m2 x 1 day,

PRD 40 mg/m2/d x 5 days, every 2 weeks for 6 months

Part 2

for 12 months

STRATUM III: Continuation Therapy


Day 1 Day 2 Day 3

2-CdA

2-CdA: 5 mg/m2/day, 2-hr infusion, 2 courses

STRATUM III: Continuation Therapy Part 1

Day 1 Day 2 Day 3 3 weeks break


2 1 23 Week 24 3 4 5 6 22

VBL 6 mg/m2 i.v. bolus day 1 q 2 week

PRED 40 mg/m2/day day 1-5 q 2 week


7

MTX 20 mg/m2/day orally, weekly

21

Part 2 STRATUM III: Continuation Therapy


26 25 75 Week 76 27 28 29 30 74

6-MP 50 mg/m2/day orally, daily

31

MTX 20 mg/m2/day orally, weekly

73

STRATUM III: Continuation Therapy

Part 3



STRATUM IV

Hematopoetic stem cell transplantation for Risk LCH (HSCT)

Aim: • to establish an effective salvage treatment option for ms-LCH

patients with risk organ involvement, who fail to respond to First-

line treatment (STRATUM I) OR to the salvage 2-CdA/Ara-C

regimen (STRATUM III)

LCH-IV OVERALL TREATMENT CONCEPT STRATUM IV

Eligibility criteria: Patients from STRATUM I or STRATUM III with

• AD worse in risk organs after wk 6 (after Initial course 1), or AD worse or AD intermediate in risk organs after wk 12 (after Initial course 2) of STRATUM I

OR • AD worse after the 2nd and 3rd 2-CdA/Ara-C course, and those AD worse or

AD intermediate after the 4th 2-CdA/Ara-C course of STRATUM III

AND

• Presence of unequivocally severe organ dysfunction at the above mentioned evaluation points (hematological/liver dysfunction or both of them) as defined

in table XI • Informed consent • Adequate hepatic, renal, cardiac, pulmonary function to undergo HSCT


STRATUM IV

Exclusion criteria:

• Pulmonary failure (requiring mechanical ventilation) AD worse in risk organs after wk 6 (after Initial course 1)

• Isolated liver sclerosis or pulmonary fibrosis, without active LCH

• Uncontrolled active life-threatening infection

• Decreased renal function with a GFR or less than 50ml/1.73m2/min

• Pregnancy or breast feeding

• Failure to provide signed informed consent

-8 Fludarabin 5 x 30 mg/m2

Melphalan 1 x 140 mg/m2

MabCampath 5 x 0.2 mg/kg

CSA

MMF

-7 -6 -5 -4 -3 -2 -1 0

Prophylaxis of GvHD/ Rejection from day -3 if indicated

Conditioning regimen

STRATUM IV: RIC-HSCT therapy for Risk-LCH

Presenter

Presentation Notes

Here you can see the basic protocol for this reduced intensity conditioning concept: It includes fludarabine, melphalan, ATG and a TLI with 2 Gray.

STRATUM IV: RIC-HSCT therapy for Risk-LCH

Class I: A,BC – high resolution Class II: DR, DQ: high resolution CMV status, ABO If sibling/parent HLA-identical SCT with MSD/MRD (or 1 MMRD/SD) If no identical sibling Start search for MUD

Compatible donor SCT with

MUD (or MMUD ) No compatible donor SCT with UCB


STRATUM V Monitoring and treatment of isolated tumorous and

neurodegenerative CNS-LCH

Aim:

• to better understand CNS-LCH (presentation, risk factors, course), in

particular neurodegenerative CNS-LCH (ND-CNS-LCH)

and

• to prospectively study the effectiveness of

2-CdA in tumorous CNS-LCH

intravenous immunoglobulin (IVIG) or Ara-C in ND-CNS-LCH


STRATUM V Monitoring and treatment of isolated tumorous and

neurodegenerative CNS-LCH

Eligibility criteria: • Patients with verified diagnosis of LCH and MRI findings consistent with

ND-CNS-LCH, irrespective of previous treatments (also those not registered to other LCH-IV Strata)

• Patients with isolated tumorous CNS-LCH (including isolated DI with

mass lesion in the hypothalamus-pituitary axis). In patients with already established diagnosis of LCH and radiologic finding of CNS lesions compatible with LCH, a biopsy of the lesion is not obligatory. In all other cases a biopsy of the lesion is needed for inclusion into the study.

Day 1 Day 2 Day 3 Day 4 Day 5

2-CdA

2-CdA: 5 mg/m2/day (2-hr infusion), 6 courses maximum

STRATUM V

Treatment of isolated tumorous CNS-LCH

Day 1 Day 2 Day 3 Day 4 Day 5

4 weeks break

For dose modification refer to Section 12.8

Ara-C

ARA-C: 150 mg/m2/day, daily for 5 days, every 4 weeks for 12 months

STRATUM V

Treatment of neurodegenerative (ND)-CNS LCH

For dose modification refer to Section 12.8

Day 1 Day 2 Day 3 Day 4 Day 5 Day 1 Day 2 Day 3 Day 4 Day 5

OR

IVIG

Intravenous Immunoglobulin (IVIG): 0,5 g/kg /dose, every 4 weeks for 12 months

Week 1 2 3 4 5 6 48 49 50 51 52

4 weeks break


STRATUM VI

Natural history and management of „other“ ss-LCH

Aim:

• to describe the natural history of ss-LCH treated by conservative

methods, „wait & watch“ approach or local therapy


STRATUM VI


Eligibility criteria:

• Patients with newly diagnosed ss-LCH and localisation other than

„multifocal bone“, isolated tumorous CNS lesion, or isolated „CNS-risk“

lesion


STRATUM VI


Exclusion criteria:

• Patients with ss-LCH with an isolated tumorous CNS lesion (they are

eligible for STRATUM V)

• Patients with isolated „CNS-risk“ or multifocal bone lesions, isolated

tumorous CNS lesion, or isolated „CNS-risk“ lesion


STRATUM VII

Long-term follow-up

Aim:

• to collect data on long term-outcome and the incidence and prevalence

of sequelae/permanent consequences (PC) in all patients registered

on LCH-IV


STRATUM VII

Long-term follow-up

Eligibility criteria:

• Patients registered in LCH-IV (regardless of treatment) as long as

consent for long-term follow-up has not been withheld.

Flowchart LCH-IV

Roadmap example Stratum I

For All Roadmaps see appendices protocol (A_IV)

Follow –up LCH-IV

Shipping of samples (ONLY for Stratum V)

LCH-IV Database

• Web-based system

• Patient registration, enrolment and randomisation

• Completion CRF

• Queries

• SAE reporting

For back-up paper CRF forms see Appendices protocol

LCH-IV Database

• Link to training system: https://histio-ehealth-systems.at The training system is basically identical to the productive system, but it is only intended for training purpose. Data in the training system might be deleted or altered at any time without warning.

• Link to productive system: https://histio-ehealth-systems.at Good study documentation is important for reconstruction of the clinical trial process (scientific requirement)! • User account management: Any user can get access to the system according to his/her specific

role (e.g. National Principal Investigators, site investigator, CRA, etc.) helpdesk: [email protected]

https://histio-ehealth-systems.at/









SAE Reporting

• LCH IV Database: https://histio-ehealth-systems.at (login, complete, sign

and send SAE) • If database not available paper SAE Form should be sent

within 24 hours to: -National Principal Investigator: [email protected] -Coordinating Principal Investigator (Stratum chair): Fax Number see protocol p5-6 for Stratum Specific Coordinating investigators for Europe -International LCH-IV Study Management Center in Vienna +43 1 40470 7430

For paper SAE form see Appendices protocol (CRF pages)



Participating sites

Investigator Site File

• Table of Content ISF: provided by sponsor

• Necessary documents ISF: dropbox link will be sent / BSPHO site

Monitoring

• When?

After inclusion of the first patient

Each year

At study completion

• What?

Investigator site file

Signed Informed Consent

Inclusion / Exclusion Criteria

Stratum enrolment

Stratum therapy

Follow up evaluations

Conclusions

• LCH IV is open for inclusion: EC approval 19/3/2014

(CHR Citadelle No EC Approval)

• Intersite contract signed: UZ Gent, UZ Brussel, CHC

• Intersite contract pending: UZA, UCL, HUDERF

• Slides initiation, final approved documents, relevant documents and

content investigator site file : dropbox link will be sent / BSPHO site

• Acces to LCH IV database: list will be sent to datamanagment, you

will receive a login and password soon

Thank you and good luck!

Participants teleconference 25/3

UZ Gent • G. Laureys • Maaike Van Hoecke • Adelheid Hollebosch UZ Brussel • J. Van der Werrf Ten Bosch • Ingrid Van Limbergen UCL • S. Dupont CHC • P. Philippet • Catherine Sondag CHR Citadelle • C. Hoyoux HUDERF • D. Sauvage • Hakima Ouled UZ Leuven • S. Van Gool • Goedele Stegen • An Michiels

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