| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse large B-cell lymphoma |
| diffus storcellet B-celle lymfekræft |
|
| E.1.1.1 | Medical condition in easily understood language |
| B-cell lymphoma |
| B-celle lymfekræft |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Failure free survival rate (FFS) of the patients with biological risk factors compared to similar patients from the historical CRY-04 and CHIC studies, with spesific focus on three years survival. |
| Overlevelsesrate uden svigt af behandling for patienter med biologisek risikofaktorer, sammenlignet med patienter fra CRY-04 og CHIC studie, mend speciel fokus på 3 års overlevelse |
|
| E.2.2 | Secondary objectives of the trial |
Failure free survival rate (FFS) at 3 years from date of registration of all patients and the patients in the low risk group
Toxicy
Clinical response rate of all patients and the patients with biological rik factors
CNS relapse rate (1,5 year)
Progression free survival rate (PFS) at 3 years of all patients and the patients with biological risk factors
Overall survival rate (OS) at 3 years of all patients and the patients with biological risk factors
Molecular correlates for survival |
Overlevelsesrate uden behandlingssvigt for alel patienter
Toksicitet
Responsrate for alle patienter og patienter med biologiske risikofaktorer
CNS relapsrate'
Progressionsfir overlevelse ved 3 år, både for alle patienter og patienter med biologiske risikofaktorer
Overall overlevelsesrate, både for alle patienter og patienter med biologiske risikofaktorer
Moleculære faktorer, som korrelerer med overlevelse |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age 18 - < 65 years
• Histologically confirmed CD20+ DLBCL based on revised WHO 2008 Lymphoma Classification [51]. The following subgroups and variants can be included:
o ALK-positive large B-cell lymphoma
o Intravascular large B-cell lymphoma
o T-cell rich B-cell lymphoma
o Myc/BCL-2 double hit lymphoma
o Follicular lymphomas grade 3b
o DLBCL with previously undiagnosed concurrent small cell infiltration in bone marrow, lymph node, or extranodal site and lymphomas intermediate between DLBCL and Burkitt’s lymphoma are allowed
o Posttransplantation lymphoma (PTLD), discordant or transformed lymphoma are NOT allowed
• Patients in at least stage II with age adjusted IPI score of 2 or 3:
o Stage III /IV and elevated LDH
o Stage III/IV and WHO performance status 2 - 3
o Stage II and elevated LDH and WHO performance status 2 – 3
• And/or patients with site specific risk factors for CNS recurrence defined as follows
o More than one extranodal site
o Testicular lymphoma, stage IIE and higher
o Paranasal sinus and orbital lymphoma with destruction of bone
o Large cell lymphoma infiltration of the bone marrow
• Previously untreated, except steroids allowed
• WHO performance status 0-3
• Written informed consent
Biologically high risk group consists of patients with at least one of the following factor
• Myc translocation (FISH)
• Myc/Bcl2 double hits (FISH)
• P53 deletion (FISH)
• Myc+/Bcl2+ (IHC)
• P53+ (ICH)
• CD5+ (IHC)
The biologically low risk group consists of patients without the above listed factors.
Paraffin-embedded tumor tissue must be sent to the central laboratory for determination of biological risk factors
|
-alder 18-65 år,
-Patienter med nydiagnosticeret lymfekræft af diffust storcellet B-celle typen, der ikke tidligere er behandlet. Følgende undertyper er tilladt:
o ALK-positive storceller B-celle lymfom
o Intravasculært storcellet B-celle lymfom
o T-cell rich B-cell lymfom
o Myc/BCL-2 double hit lymfom
o Follikulært lymfom grade 3b
o DLBCL med samtidig småcellet infiltration iknoglemarven, lymfeknude elelr ekstranodal organ, som ikke er diagnosticeret tidligere, og lymfomer intermediate mellem DLBCL and Burkitt lymfom er tilladt
o Posttransplantation lymfom (PTLD), discordant or transformret lymfomer er ikke tilladt allowed
-patienter med minimum stadium II sygdom og aldersjusteret IPI score 2 eller 3:
• Stadium III eller IV og forhøjet LDH
• Stadium III eller IV og WHO performance score 2 eller 3
• Stadium II og forhøjet LDH og WHO performance score 2 eller 3
- og eller patienter, med en særlig høj risiko for spredning af lymfekræft til CNS:
• Mere end et sygdomssted udenfor lymfesystemet og forhøjet LDH-enzym i blodet
• Lymfekræft i testiklerne
• Lymfekræft i bihuler eller øjenhulen
• Indvækst af lymfekræftceller i knoglemarven
-skal have læst deltagerinformationen samt underskrevet fuldmagt og samtykkeerklæring
-WHO performance score 0-3
|
|
| E.4 | Principal exclusion criteria |
• Severe cardiac disease: cardiac function grade 3-4, left ventricular ejection fraction <45%
Impaired bone marrow liver, renal or other organ function not caused by lymphoma, which will interfere with the treatment schedule (Hemoglobin < 9 g/dL, ANC < 1.5 × 109/L, Platelet count < 75 × 109/L, creatinine clearance < 40 mL/min, ALT/AST > 2.5 x ULN, bilirubin >= 1.5 x ULN, INR > 1.5)
• Pregnancy/lactation
• Men and women of reproductive potential not agreeing to use effective contraception during treatment and for 18 months after completion of treatment
• Patients with other severe medical problems, including active infections, cardiac or pulmonary disease, history of PML and with an expected short survival for non-lymphoma reasons
• Known HIV positivity
• Active or chronic hepatitis B virus (HBV) infection (defined as positive HBsAg serology), or active hepatitis C virus (HCV) infection (defined by antibody serology testing). HBsAg, HBcAb, and HCVAb must be tested during screening. Patients who have protective titers of HBsAb along negative HBsAg after vaccination or prior but cured hepatitis B are eligible.
• Vaccination with a live vaccine within one month prior to randomization
• Patients with a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to enrollment
• Earlier treatment containing anthracyclins
• Psychiatric or mental disorder which make the patient unable to give an informed consent and/or adhere to the protocol
• CNS disease as diagnosed by MRI or CSF cytology. Positive CSF flow cytometry below diagnostic threshold level by cytology is allowed
• Transformed lymphoma
• Primary mediastinal B-cell lymphoma
• Pleural or peritoneal fluid that cannot be drained safely
• Hypersensitity to the active substance or any of the other ingredients
• History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products
• Patients participating in other clinical studies, unless followed for survival
• Lower urinary tract constriction, which cannot be treated adequately
• Degenerative and toxic encephalopathy
• Neuromuscular disease
|
-alvorlig hjertesygdom med ejection fraction <45%
Påvirkede funktion af knogemarv, lever, nre og andre organer, som ikke er forårsaget af lymfom, som vil have indflygelse på behandlignen (Hemoglobin < 9 g/dL, ANC < 1.5 × 109/L, thrombocyttal < 75 × 109/L, creatinine clearance < 40 mL/min, ALT/AST > 2.5 x ULN, bilirubin >= 1.5 x ULN, INR > 1.5)
• Graviditet/amning
• Man og kvinde i i fødedygtig alder, som ikke samtykke til at bruge effektiv svangerskabsforebyggelse under behandling og 18 mdr efter afsluttet behandling
• Patients med andre alvorlige medicisnke problemer, herunder aktive infektioner, hjrete og lungesygdommer, anamnese med PML og forventet kort levetid af ikke lymfomrelateret årsag
• Kendt HIV positivitet
• Aktiv eller kronisk hepatitis B virus (HBV) infektion (definret udfra positive HBsAg serology), eller aktiv hepatitis C virus (HCV) infektion (udfra antibody serology test). HBsAg, HBcAb, and HCVAb skal testes under screening. Patients who have protective titers of HBsAb along negative HBsAg efter vaccination eller tidligere hepatitis B are eligible.
• Vaccination med eivende vaccine indenfor en måned før inklusion
• Patienter med malignitet, sombelv behandlet men ikke med kurativ sigte, medmindre malignaniteten har været i remission uden behandling ≥ 5 år før inklusion
• Tidligere behandling med anthracyclin-holdig kemoterapi
• Psychiatrisk eller mental sygdom, som gøre at patienten ikke jkan afgive informeret samtykke og /eller følger protokollen
• CNS involvering diagnosticeret med billeddiagnostik eller CSF cytology. Positive CSF flow cytometry under diagnostisk niveau for cytology er tilladt
• Transformeret lymfom
• Primært mediastinalt B-celle lymfom
• Pleura eller peritoneal væske som ikke udtømmes
• Hypersensititet til de stoffer, der indgår i behandling
• Alvorlig allergisk og anaphylactisk reaktion til humanized eller muse monoklonale antistoffer eller museprodukter
• Patienter, som deltager i andre kliniske protokoller, medmindre de er kun fulgt for overlevelse
• nedre urinvejs forsnævring som ikke kan behandles sufficient
• Degenerative and toksisk encephalopathy
• Neuromusculær sygdom |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1.Time to treatment failure
|
| Tid til behandlingsvigt |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.Time to treatment failure
Interval between the registration date and the date of documented progression or lack of response, first relapse, death for any reason or discontinuation/change of therapy because of toxicity, whichever occurs first.
|
| Interval mellem registrering af patienten til dokumenteret progression eller manglende respons, første relaps, død af hvilken som helst årsag eller afbrydelse/ændring af behandling pga bivirknigner. |
|
| E.5.2 | Secondary end point(s) |
1. Progression free survival
2. Overall survival (all causes of death)
3. Disease free survival
4. Cause of death |
2.Progression free survival
The time from the registration date to the date of progression or death from any cause.
3.Overall survival (all causes of death)
The time from the registration date to the date of death.
4.Disease free survival
The time from the first assessment within 2 months of completion of therapy that documents response to the date of disease progression.
5.Cause of death
During the study and after its completion the cause of death will be registered.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression fri overlevelse:
Overall overlevelse
Disease fri overlevelse
Dødsårsag |
Progression fri overlevelse: fra registrationsdato til progression eller død
Overall overlevelse: fra registration til død af any årsag
Disease fri overlevelse: fra dato af dokumenteret response efter afsluttet behandling til sygdomsprogression
Dødsårsag: Tidspunktet af død af any årsag |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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