PTLD-1/3: Risk Stratified Sequential Treatment for CD20-positive PTLD

Sponsor

Charite University, Berlin, Germany (Other)

Overall Status

Completed

CT.gov ID

NCT00590447

Collaborator

(none)

152

Enrollment

Locations

Arms

103

Duration (Months)

21.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
PTLD Posttransplant Lymphoproliferative Disorder	Drug: rituximab monotherapy Drug: sequential R-CHOP	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

152 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Dec 1, 2006

Actual Primary Completion Date :

Dec 1, 2014

Actual Study Completion Date :

Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Patients achieving a CR after the first 4 applications of single agent rituximab (evaluated between day 40 to 50) will go on with 4 further courses of single agent rituximab on days 50, 72, 94 and 116.	Drug: rituximab monotherapy 375 mg/m2, IV on days 1, 8, 15, 22, 50, 72, 94 and 116. In case of disease progression during the first 4 administration of rituximab antibody or the 4 weeks interval between course 4 and 5 the patients directly enter R-CHOP chemotherapy (Arm B).
Experimental: B All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Patients who do not achieve a CR after the first 4 applications of single agent rituximab (evaluated between day 40 to 50) will go on with 4 courses of R-CHOP on days 50, 72, 94 and 116.	Drug: sequential R-CHOP 375 mg/m2 rituximab, IV on days 1, 8, 15, 22, 50, 72, 94 and 116. Cyclophosphamid 750 mg/m2, adriamycine 50 mg/m2 and vincristine 1.4mg/m2, IV and prednisone 50mg/m2, PO every 3 weeks at days 50, 72, 94 and 116. In case of disease progression during the first 4 administration of rituximab antibody or the 4 weeks interval between antibody and R-CHOP administration the patients directly enter R-CHOP chemotherapy.

Arm

Intervention/Treatment

Experimental: A

All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Patients achieving a CR after the first 4 applications of single agent rituximab (evaluated between day 40 to 50) will go on with 4 further courses of single agent rituximab on days 50, 72, 94 and 116.

Drug: rituximab monotherapy

375 mg/m2, IV on days 1, 8, 15, 22, 50, 72, 94 and 116. In case of disease progression during the first 4 administration of rituximab antibody or the 4 weeks interval between course 4 and 5 the patients directly enter R-CHOP chemotherapy (Arm B).

Experimental: B

All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Patients who do not achieve a CR after the first 4 applications of single agent rituximab (evaluated between day 40 to 50) will go on with 4 courses of R-CHOP on days 50, 72, 94 and 116.

Drug: sequential R-CHOP

375 mg/m2 rituximab, IV on days 1, 8, 15, 22, 50, 72, 94 and 116. Cyclophosphamid 750 mg/m2, adriamycine 50 mg/m2 and vincristine 1.4mg/m2, IV and prednisone 50mg/m2, PO every 3 weeks at days 50, 72, 94 and 116. In case of disease progression during the first 4 administration of rituximab antibody or the 4 weeks interval between antibody and R-CHOP administration the patients directly enter R-CHOP chemotherapy.

Outcome Measures

Primary Outcome Measures

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. [evaluated 4 weeks after comleting therapy]

Secondary Outcome Measures

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. [within 2 years of follow up]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld 4102	Brisbane	Australia
2	Catholic University of Leuven, Department of Hematology	Leuven	Belgium
3	Hôpital Pitié-Salpétrière, Department of Hematology, 47-83 Boulevard de l'Hopital	Paris	France	75651
4	Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Hematology and Oncology, Augustenburger Platz 1	Berlin	Germany	13353
5	Div. Universitaria Ematologia e Terapie Cellulari, University of Torino	Torino	Italy	10128
6	Zakład Propedeutyki Onkologii, Gdańskiego Uniwersytetu Medycznego	Gdynia	Poland	81519
7	Sahlgrens hospital, Department of Hematology	Göteborg	Sweden	41345

Sponsors and Collaborators

Charite University, Berlin, Germany

Investigators

Principal Investigator: Hanno Riess, MD, Charité, Campus Virchow-Klinikum Berlin, Germany
Study Chair: Ralf U Trappe, MD, Charité, Campus Virchow-Klinkum, Berlin, Germany