Clinical trial NCT00590447: Risk Stratified Sequential Treatment for CD20-positive PTLD
Official title: Treatment of Patients With Posttransplant Lymphoproliferative Disorder (PTLD) With a Sequential Treatment Consisting of Anti-CD20 Antibody Rituximab and CHOP+GCSF Chemotherapy (PTLD-1/3)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: PTLD
Posttransplant Lymphoproliferative Disorder
Keywords: 1st-line therapy
single agent rituximab
CHOP
risk stratification
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2008-01-10
Enrollment: 152
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase-II trial will investigate the efficacy, safety and the tolerability of a sequential therapy consisting of 4 courses of single agent rituximab followed by 4 courses of R-CHOP chemotherapy in patients with CD20+ posttransplant lymphoproliferative disorders (PTLD). However, responders to rituximab achieving a CR after the first 4 applications of rituximab will go on with rituximab monotherapy and will not receive chemotherapy.

Detailed description: The rationale for performing the present study is to combine two highly active treatment modalities in first line therapy of solid organ recipients with B-cell PTLD. The monoclonal antibody CD20 represents an effective therapeutic approach in the treatment of PTLD. Unfortunately this effect seems to be of limited duration in some patients, who benefited from monotherapy with rituximab. The advantage of this therapeutic approach in PTLD is due to the low incidence of third to fourth degree adverse events. At diagnosis of PTLD a relevant proportion of these patients is not suitable for first line cytotoxic chemotherapy due to widespread disease, organ dysfunction or reduced performance state. Insufficiencies of kidney or bone marrow function are frequent in organ recipients due the toxic side effects of the immunosuppressive drugs. After pre-phase treatment with the monoclonal antibody rituximab the CHOP chemotherapy is suggested to be less toxic due to the lower tumor burden. Thereby treatment related severe or even lethal toxicities, frequently reported in patients with PTLD who underwent cytotoxic chemotherapy, may be prevented. Furthermore the total number of cytotoxic cycles of CHOP-therapy is reduced from 6 for 8 to 4 cycles and thus may result in an additional reduction of toxicity in the single patient. Because immunochemotherapy (R-CHOP) is clearly superior to CHOP with respect to progression free survival and relapse rates in patients with classical NHL and rituximab is very unlikely to add any further toxicity to CHOP the majority of patients will go on with four courses of R-CHOP. However, patients with a complete remission after 4 courses of single agent rituximab may have a very favourable risk profile and therefore will go on with rituximab single agent instead of R-CHOP.

Eligibility criteria: Inclusion Criteria:

* PTLD with or without EBV association, confirmed after biopsy or resection of tumor
* Measurable disease of \> 2 cm in diameter and/or bone marrow involvement
* Patients having undergone heart, lung, liver, kidney, pancreas, small intestine transplantation or other or a combination of the organ transplantations mentioned
* Karnofsky scale \>50% or ECOG ≤ 3
* Reduction of immunosuppression with or without antiviral therapy
* A complete surgical extirpation of tumor was not performed
* A radiation therapy was not performed
* Effective contraception for women in childbearing age
* Patient's written informed consent and written consent for data collection
* Patients are \> 18 years (or ≥ 15 years with parental agreement )

Exclusion Criteria:

* Life expectancy less than 6 weeks
* Karnofsky-scale \<50% or ECOG ≥ 3
* Treatment with rituximab before
* Known allergic reactions against foreign proteins
* Concomitant diseases, which exclude the administration of therapy as outlined by the study protocol
* non-compensated heart failure
* Dilatative cardiomyopathy
* Myocardial infarction during the last 6 months
* Severe non-compensated hypertension
* Severe non-compensated diabetes mellitus
* Renal insufficiency (creatinine more than 3-fold of the upper normal value), not related to lymphoma
* Hepatic insufficiency with transaminase values greater than 3-fold of the normal values and/or bilirubin levels \>3.0 mg/dl, not related to lymphoma
* Clinical signs of cerebral dysfunction
* Women during the lactation period, pregnant or of childbearing potential not using a reliable contraceptive method
* Involvement of the central nervous system by the disease
* Severe psychiatric disease
* Known to be HIV positive
* Missing written informed consent of the patient

Primary outcomes:
measure: The primary objective is the evaluation of the efficacy.For this aim the overall objective response rates after therapy = complete and partial response and the duration of the response will be measured.
timeFrame: evaluated 4 weeks after comleting therapy
Secondary outcomes:
measure: The secondary objective is to determine the adverse events and tolerability of rituximab and/or chemotherapy. Furthermore, the long-term safety will be determined, especially the frequency of complicating infections and the overall survival.
timeFrame: within 2 years of follow up
Other outcomes:
Locations:
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld 4102
city: Leuven
country: Belgium
facility: Catholic University of Leuven, Department of Hematology
city: Paris
country: France
facility: Hôpital Pitié-Salpétrière, Department of Hematology, 47-83 Boulevard de l'Hopital
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Hematology and Oncology, Augustenburger Platz 1
city: Torino
country: Italy
facility: Div. Universitaria Ematologia e Terapie Cellulari, University of Torino
city: Gdynia
country: Poland
facility: Zakład Propedeutyki Onkologii, Gdańskiego Uniwersytetu Medycznego
city: Göteborg
country: Sweden
facility: Sahlgrens hospital, Department of Hematology
Study officials:
affiliation: Charité, Campus Virchow-Klinikum Berlin, Germany
name: Hanno Riess, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charité, Campus Virchow-Klinkum, Berlin, Germany
name: Ralf U Trappe, MD
role: STUDY_CHAIR
References:
citation: Trappe RU, Dierickx D, Zimmermann H, Morschhauser F, Mollee P, Zaucha JM, Dreyling MH, Duhrsen U, Reinke P, Verhoef G, Subklewe M, Huttmann A, Tousseyn T, Salles G, Kliem V, Hauser IA, Tarella C, Van Den Neste E, Gheysens O, Anagnostopoulos I, Leblond V, Riess H, Choquet S. Response to Rituximab Induction Is a Predictive Marker in B-Cell Post-Transplant Lymphoproliferative Disorder and Allows Successful Stratification Into Rituximab or R-CHOP Consolidation in an International, Prospective, Multicenter Phase II Trial. J Clin Oncol. 2017 Feb 10;35(5):536-543. doi: 10.1200/JCO.2016.69.3564. Epub 2016 Dec 19.