Trial document




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  DRKS00007623

Trial Description

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Title

INFORM Registry
INdividualized Therapy FOr Relapsed Malignancies in Childhood

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Trial Acronym

INFORM

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URL of the Trial

http://www.dkfz.de/en/inform/index.html

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Brief Summary in Lay Language

INFORM REGISTRY STUDY:
Although current treatment of childhood malignancies results in overall cure rates in the order of 75% with modern multi-modal protocols, relapse from high risk disease remains a tremendous clinical problem. This medical need is being addressed with the INFORM registry „INdividualized Therapy FOr Relapsed Malignancies in Childhood“. The INFORM consortium is comprised of leading pediatric oncologists from the study groups of the Society for Pediatric Oncology and Hematology (GPOH) or the respective national coordinator in case of international patients and renowned scientists in the field of high-content genomics research.

SEARCH FOR TARGETS:
The concept of the INFORM registry is to biologically characterize tumor samples (collected through routine standard of care biopsies at the time of the current tumor manifestation) for all pediatric patients with relapsed or refractory high risk diseases for whom no further standard of care therapy is available. State-of-the-art next-generation sequencing technologies will be applied to get a “fingerprint” of each individual tumor. An expert panel of experienced pediatric oncologists, biologists, bioinformaticians and pharmacologists classifies and weighs the aberrations/targets found for each single patient according to clinical relevance.These molecular targets shall be available in less than 4 weeks and will be entered in the central database. No therapy recommendation will be given within this registry study. The treating physician has access to the molecular information/targets of their patients and carries the full responsibility as to whether and in which way they use these data for therapy decision-making.

REGISTRATION:
New patients will be registered via a remote data entry system by their local pediatric oncologist. No analyses can be done without this electronic registration. Only patients living in Germany or living in countries participating in the INFORM registry study can be enrolled. The treating physician will have access to the molecular information/targets of their patients and carries the full responsibility as to whether and in which way they use these data for therapy decision-making.

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Brief Summary in Scientific Language

Due to a protocol amendment (professional legal advice by the Heidelberg IEC dated June 23rd 2016) the following changes were made to the protocol:
- concretion of the in- and exclusion criteria
- adaption of the humangenetic Validation and consultation in case of accidental information on germline variants
- definition of way of request for INFORM data
- collection of native tumor material for in vitro and in vivo tumor models.
Due to a protocol amendment (professional legal advice by the Heidelberg IEC dated April 10th 2019) the following changes were made to the protocol:
- Extension of the in- and exclusion criteria
- analyses of the samples expanded- duration of the study extended and number of study participants increased to approx. 150 Patient per annum
- more extensive cooperation with international pediatric-oncological programs to improve the analyses of the samples.

Although current treatment of childhood malignancies results in overall cure rates in the order of 75% with modern multi-modal treatment protocols, relapses from high risk disease remains a tremendous clinical problem. Only a small proportion of patients with relapses (about 10%) can be cured. This medical need will be addressed with the INFORM project „INdividualized Therapy FOr Relapsed Malignancies in Childhood“. The INFORM consortium constitutes leading pediatric oncologists of study groups of the Society for Pediatric Oncology und Hematology (GPOH) or the respective national coordinator in case of international patients and renowned scientists in the field of high content genomics research.

The concept of the INFORM-program is to biologically characterize tumor samples (collected through routine standard of care biopsies) for all pediatric patients with relapsed or refractory high risk disease for which no further standard of care therapy is available, independently of histological diagnosis. State-of-the art next-generation sequencing technologies will be applied to get a “fingerprint” of each individual tumor. An expert panel of experienced pediatric oncologists, bioinformaticians, biologists and pharmacologists classifies and weighs the aberrations/targets found for each single patient according to clinical relevance. These molecular targets shall be available in less than 4 weeks after sample receipt and will be entered in the central database. No therapy recommendation will be given within this registry study. The treating physician has access to the molecular information/targets of his patients and carries the full responsibility as to whether and in which way he uses these data for his therapy decision making.

The intention of the INFORM Registry is to establish the technical, structural and information basis for a future clinical trial (AMG) for personalized pediatric oncology. The primary objectives of the INFORM Registry are: To establish the logistics (tissue sample submission, analysis and classification), to establish an individualized risk management support (working group with experts in drug interaction) and access modes for targeted compounds and to establish a database for the documentation of the sequencing results, of identified clinically relevant targets, of clinical courses, and of therapies, including single experimental treatments (Einzelheilversuche). Secondary objectives of the INFORM Registry are the descriptive and exploratory analyses of registered patients regarding response rates, progression free and overall survival.
In addition, a standardized high-throughput drug sensitivity screening platform will be set up to directly test efficacy of drugs on viable tumor cells of the individual patient, liquid biopsy specimens, plasma and cerebrospinal fluid (for brain tumors only) will be collected and analysed and additional protein profiles (proteomics) will be generated for selected samples.
Inclusion criteria for the registry population are relapsed/progressive or refractory diagnoses of ALL-HR, ALL Post-SCT, AML, rhabdoid tumor, ependymoma, medulloblastoma, ewing sarcoma, high grade glioma, high risk neuroblastoma, non-hodgkin lymphoma, osteosarcoma, soft tissue sarcoma, nephroblastoma, hepatoblastoma, retinoblastoma, malignant endocrine tumors and germ cell tumors. Exceptionally, patients with primary diagnosis high-grade glioma (incl. DIPG), primary diagnosis soft tissue sarcoma, ETMR and rare tumor diseases, for which no curative treatment is established, may also be enrolled.
The patients are 0 to 40 years old and were treated according to a protocol of the Society for Pediatric Oncology und Hematology (GPOH) or an equivalent protocol as their first-line protocol, except in case of specific primary soft tissue sarcoma or diffuse intrinsic pontine glioma indications. Patients can be included up until the age of 40 years, but they must have had their primary diagnosis below the age of 21 years. Given the duration of the analyses only patients with a life expectancy of more than 3 months and sufficient general condition can be included. The collection of tumor samples is carried out as part of routine standard of care of the patients. Patients can be enrolled from GPOH centers in Germany and international partners of the INFORM consortium. It is planned to continue the register study openended, about 150 patients are to be included per year.

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Organizational Data

  •   DRKS00007623
  •   2014/12/18
  •   [---]*
  •   yes
  •   Approved
  •   S-502/2013, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   Refractory/relapsed/progressive
    -ALL-HR
    -ALL post-SCT
    -AML
    -rhabdoid tumor
    -ependymoma
    -medulloblastoma
    -Ewing's sarcoma
    -high grade glioma
    -high risk neuroblastoma
    -non-Hodgkin lymphoma
    -osteosarcoma
    -soft tissue sarcoma
    -nephroblastoma
    -hepatoblastoma
    -retinoblastoma
    -malignant endocrine tumor
    -germ cell Tumor
    -Patients with primary diagnosis high-grade glioma (incl. DIPG), primary diagnosis soft tissue sarcoma or ETMR, for which no curative treatment is established
    -rare tumor diseases in case of no established curative treatment
  •   C91.0 -  Acute lymphoblastic leukaemia [ALL]
  •   C92.0 -  Acute myeloblastic leukaemia [AML]
  •   C49 -  Malignant neoplasm of other connective and soft tissue
  •   C71 -  Malignant neoplasm of brain
  •   C72 -  Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system
  •   C40 -  Malignant neoplasm of bone and articular cartilage of limbs
  •   C41 -  Malignant neoplasm of bone and articular cartilage of other and unspecified sites
  •   C74 -  Malignant neoplasm of adrenal gland
  •   C48 -  Malignant neoplasm of retroperitoneum and peritoneum
  •   C47 -  Malignant neoplasm of peripheral nerves and autonomic nervous system
  •   C85.9 -  Non-Hodgkin lymphoma, unspecified
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Interventions/Observational Groups

  •   The concept of the INFORM-program is to biologically characterize tumor samples (collected through routine standard of care biopsies), independently of histological diagnosis. State-of-the art next-generation sequencing technologies will be applied to get a “fingerprint” of each individual tumor. An expert panel of experienced pediatric oncologists, bioinformaticians, biologists and pharmacologists classifies and weighs the aberrations/targets found for each single patient according to clinical relevance. These molecular targets shall be available in less than 4 weeks after sample receipt and will be entered in the central database. No therapy recommendation will be given within this registry study.
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Characteristics

  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Other
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

ESTABLISHMENT OF LOGISTICS FOR PERSONALIZED TREATMENT:
Tissue sample submission, molecular analysis and target identification within 4 weeks after receipt of all required samples in the Central Pathology Laboratory in Heidelberg.
Individualized risk management support including collection of pharmaco-genomic data.
Establishment of access mode for off-label application of targeted compounds.

ESTABLISHMENT OF A COMPREHENSIVE DATABASE:
Collecting and providing information about individual druggable targets.
Collecting and providing information about targeted therapy options.
Documentation of individualized treatments (“Einzelheilversuche”) and follow-up.
Collecting toxicity data.

COLLECTION OF DATA ON INDIVIDUAL:
-Genomic,
-Epigenomic,
-Transcriptomic
-Circulating tumor DNA
characteristics of high risk refractory/relapsed/progressive pediatric malignancies

EVALUATION OF COLLECTED DATA:
Identification and prioritization of druggable target patterns across histological entities.
Definition of a set of “targeted compounds of interest” within the registry population.
Documentation of number of patients per year/entity suitable for a future AMG-trial of personalized oncology in terms of:
-re-biopsy, molecular analysis, target definition including turnaround time
-dynamics of disease progression/PFS
-definition of standard of care/best care chemotherapy in registry population

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Secondary Outcome

Response rate, PFS, and OS of all registered patients with individualized targeted treatments (Einzelheilversuche).
Response rate, PFS, and OS of registered patients with individualized targeted treatments separately for each entity of malignancy.
Response rate, PFS, and OS of registered patients without individualized targeted treatments.
Response rate, PFS, and OS of registered patients with individualized targeted treatments stratified by different levels of prioritized target evidence.
Time to progression (TTP) of all registered patients with individualized targeted treatments before individualized targeted treatment.
Time to progression (TTP) of all registered patients with individualized targeted treatments after individualized targeted treatment.
General performance (Lansky/Karnofsky Score) after 3, 6, 9, 12, 18, 24 months.
Safety and toxicity.
Collection of fresh native tumor tissue for establishment of in vitro and in vivo tumor models.
Establishment of a standardized high-throughput screening platform to generate drug sensitivity/resistance profiles of fresh native tumor material and thereof derived in vitro and in vivo tumor models.
Comparison of drug response profiles of patient-derived short term cultures and xenograft (PDX) models with correlated clinical response profiles of the patients.
Evaluation of liquid biopsies as tools for molecular diagnostics and target identification.
Feasibility and timeframe of proteomic analyses as well as information gained through these data when integrated with results from standard INFORM pipelines.

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Countries of Recruitment

  •   Germany
  •   Sweden
  •   Switzerland
  •   Finland
  •   Austria
  •   Greece
  •   Poland
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Locations of Recruitment

  • Medical Center 
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Recruitment

  •   Actual
  •   2015/01/21
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  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   40   Years
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Additional Inclusion Criteria

GENERAL INCLUSION CRITERIA:

Children, adolescents and young adults 0 to 40 years old with refractory/relapsed/progressive oncological disease following first, second or third line treatment protocols (except for high-grade gliomas (incl. DIPG), specific soft tissue sarcomas, ETMR and rare tumor diseases, may be enrolled upon primary diagnosis), including targeted treatment approaches considering entity-specific high risk criteria.

Patients can be included up until the age of 40 years, but they must have had their primary diagnosis below the age of 21 years.

No established curative treatment options

Life expectancy > 3 months and sufficient general condition (Lansky ≥ 50 or Karnofsky ≥ 50)

Residency in Germany or in one of the partner countries.

First-line treatment within one of the therapy optimization/registry trials of the GPOH or an equivalent protocol, except for primary diagnosis high-grade gliomas (incl. DIPG), specific primary soft tissue sarcomas, ETMR and rare tumor diseases included in the STEP-Registry .

Inclusion in INFORM Registry discussed with and agreed by respective GPOH Entity Study group (or with the respective national coordinator).

Histopathological/molecular confirmation of clinically suspected diagnosis.

Routine biopsy/puncture of the current refractory/relapsed/progressive oncological disease as part of standard of care treatment.

Time between biopsy/puncture of the current refractory/relapsed/progressive oncological disease and receipt of all required samples in the Central Pathology Laboratory in Heidelberg < 8 weeks.

For German patients with solid tumors and brain tumors suitable fresh frozen tumor material of the current disease episode and non-malignant material will be sent to INFORM Registry for molecular analysis.

For all international patients (and German patients with non-solid tumors) already extracted tumor DNA and tumor RNA from fresh frozen malignant material (tumor cell content at least 40%) of the current disease episode as well as DNA from non-malignant material will be sent to INFORM Registry for molecular Analysis.

Written informed consent of the patients and/or the legal guardians concerning data and tumor material transfer.


ENTITY SPECIFIC INCLUSION CRITERIA:

ALL-HR:
Refractory disease at first relapse (>40% blasts in bone marrow).
2nd relapse post chemotherapy (>40% blasts in bone marrow).
Bone marrow involvement.

ALL POST-SCT:
Bone marrow relapse of ALL (> 40% blasts in bone marrow)
Post allogeneic hematopoietic stem cell transplantation.

AML:
Early 1st relapse AML/ refractory disease following re-induction,
or at least 2nd relapse AML (>40% blasts in bone marrow or sorted blasts)

SOFT TISSUE SARCOMA:
Combined or metastatic relapsed RMS,
or first-line therapy: Progressive RMS, no option for local therapy,
or primary metastatic RMS in patients age > 10years or bone/bone marrow metastasis,
or non-resectable desmoplastic small round cell tumor (primary diagnosis or refractory/relapsed/progressive DSRCT).
Other sarcomas

EPENDYMOMA AND MEDULLOBLASTOMA AND EMBRYONAL TUMORS:
Medulloblastoma or ependymoma (WHO°II or III)
Refractory or progressive disease following first-line therapy or first or multiple relapse
Newly diagnosed ETMRs

EWING SARCOMA:
Any relapsed and/or therapy refractory ewing sarcoma, including pPNET.
Tumor at biopsy accessible site.

HIGH GRADE GLIOMA (INCL. DIPG):
Primary diagnosis or relapsed/progressive high-grade malignant glioma (WHO grade 3 or 4 or analogous tumors incl. DIPG)


NEUROBLASTOMA:
High risk neuroblastoma patients; Any neuroblastoma relapse after high risk therapy, or intermediate risk neuroblastoma patients: Second relapse after HD chemotherapy and ASCT.
Relapsed tumor accessible to low risk surgery or, in case of bone marrow infiltration and only if tumor tissue not available, aspirate containing at least 40% neuroblast infiltration (% after cytospin, not in bone marrow smear).

NON-HODGKIN LYMPHOMA:
Burkitt lymphoma, mature aggressive B-cell NHL not further classified or LBL with non-response, progression, or relapse.

OSTEOSARCOMA:
Relapsed or first-line therapy refractory Osteosarcoma.

RHABDOID TUMORS:
Relapse or first-line therapy refractory rhabdoid tumors.

“OTHER” REFRACTORY OR PROGRESSIVE/RELAPSED ENTITIES INCLUDING RARE TUMOR DISEASES:
Exceptional cases discussed with and agreed by INFORM Registry Trial Office
In case of rare tumor diseases with the GPOH STEP registry
In case of nephroblastoma, hepatoblastoma, retinoblastoma, malignant endocrine tumors, or germ cell tumors with the respective GPOH study group

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Exclusion Criteria

AML:
Acute promyelocytic leukemia.
Acute myeloid leukemia in patients with Down Syndrome.

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Addresses

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    • Deutsches Krebsforschungszentrum / Universitätsklinikum Heidelberg
    • Mr.  Prof. Dr. med.   Olaf  Witt 
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    • Gesellschaft für Pädiatrische Onkologie und Hämatologie / German So­cie­ty for Pa­ed­ia­tric On­co­lo­gy and Hae­ma­to­lo­gy (GPOH)
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    • German Cancer Research Center (DKFZ)
    • Mr.  Dr. med.  Kristian  Pajtler 
    • Im Neuenheimer Feld 580
    • 69120  Heidelberg
    • Germany
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    • KiTZ Clinical Trial Unit
    • Ms.  Ingrid  Bauer 
    • Im Neuenheimer Feld 130.3
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Krebshilfe e.V.
    • Buschstr. 32
    • 53113  Bonn
    • Germany
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    • Deutsche Kinderkrebsstiftung
    • Adenauerallee 134
    • 53113  Bonn
    • Germany
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    • Deutsches Konsortium für Translationale Krebsforschung / German Cancer Konsortium (DKTK)
    • Im Neuenheimer Feld 280
    • 69120  Heidelberg
    • Germany
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    • Bild hilft e.V. Ein Herz für Kinder
    • Brieffach 3410
    • 20350  Hamburg
    • Germany
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Status

  •   Recruiting ongoing
  •   [---]*
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Trial Publications, Results and other Documents

  •   Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, Boudalil M, Previti C, Wolf S, Schmidt S, Chotewutmontri S, Bewerunge-Hudler M, Schick M, Schlesner M, Hutter B, Taylor L, Borst T, Sutter C, Bartram CR, Milde T, Pfaff E, Kulozik AE, von Stackelberg A, Meisel R, Borkhardt A, Reinhardt D, Klusmann J, Fleischhack G, Tippelt S, Dirksen U, Jürgens H, Kramm CM, Von Bueren AO, Westermann F, Fischer M, Burkhardt B, Wößmann W, Nathrath M, Bielack SS, Frühwald MC, Fulda S, Klingebiel T, Koscielniak E, Schwab M, Tremmel R, Hernaiz Driever P, Schulte JH, Brors B, Von Deimling A, Lichter P, Eggert A, Capper D, Pfister SM*, Jones DTW* and Witt O*. Next-generation personalized medicine for high-risk pediatric cancer patients – the INFORM pilot study. Eur J Cancer 2016 65:91-101 [Epub ahead of print].
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* This entry means the parameter is not applicable or has not been set.