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

Primary Purpose

PTLD, Posttransplant Lymphoproliferative Disorder

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

rituximab monotherapy

sequential R-CHOP

About this trial

This is an interventional treatment trial for PTLD focused on measuring 1st-line therapy, single agent rituximab, CHOP, risk stratification

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld 4102
Catholic University of Leuven, Department of Hematology
Hôpital Pitié-Salpétrière, Department of Hematology, 47-83 Boulevard de l'Hopital
Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Hematology and Oncology, Augustenburger Platz 1
Div. Universitaria Ematologia e Terapie Cellulari, University of Torino
Zakład Propedeutyki Onkologii, Gdańskiego Uniwersytetu Medycznego
Sahlgrens hospital, Department of Hematology

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Arm Description

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.

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.

Outcomes

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.

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.

Full Information

NCT ID

NCT00590447

First Posted

December 28, 2007

Last Updated

March 6, 2017

Sponsor

Charite University, Berlin, Germany

1. Study Identification

Unique Protocol Identification Number

NCT00590447

Brief Title

Risk Stratified Sequential Treatment for CD20-positive PTLD

Acronym

PTLD-1/3

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

2. Study Status

Record Verification Date

March 2017

Overall Recruitment Status

Completed

Study Start Date

December 2006 (undefined)

Primary Completion Date

December 2014 (Actual)

Study Completion Date

July 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Charite University, Berlin, Germany

4. Oversight

Data Monitoring Committee

5. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

PTLD, Posttransplant Lymphoproliferative Disorder

Keywords

1st-line therapy, single agent rituximab, CHOP, risk stratification

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

152 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Experimental

Arm Description

Arm Title

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

rituximab monotherapy

Intervention Description

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).

Intervention Type

Drug

Intervention Name(s)

sequential R-CHOP

Intervention Description

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.

Primary Outcome Measure Information:

Title

Time Frame

evaluated 4 weeks after comleting therapy

Secondary Outcome Measure Information:

Title

Time Frame

within 2 years of follow up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hanno Riess, MD

Organizational Affiliation

Charité, Campus Virchow-Klinikum Berlin, Germany

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Ralf U Trappe, MD

Organizational Affiliation

Charité, Campus Virchow-Klinkum, Berlin, Germany

Official's Role

Study Chair

Facility Information:

Facility Name

Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, Qld 4102

City

Brisbane

Country

Australia

Facility Name

Catholic University of Leuven, Department of Hematology

City

Leuven

Country

Belgium

Facility Name

Hôpital Pitié-Salpétrière, Department of Hematology, 47-83 Boulevard de l'Hopital

City

Paris

ZIP/Postal Code

75651

Country

France

Facility Name

Charité - Universitätsmedizin Berlin, Campus Virchow Klinikum, Department of Hematology and Oncology, Augustenburger Platz 1

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

Div. Universitaria Ematologia e Terapie Cellulari, University of Torino

City

Torino

ZIP/Postal Code

10128

Country

Italy

Facility Name

Zakład Propedeutyki Onkologii, Gdańskiego Uniwersytetu Medycznego

City

Gdynia

ZIP/Postal Code

81519

Country

Poland

Facility Name

Sahlgrens hospital, Department of Hematology

City

Göteborg

ZIP/Postal Code

41345

Country

Sweden

12. IPD Sharing Statement

Citations:

PubMed Identifier

27992268

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.

Results Reference

result

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Risk Stratified Sequential Treatment for CD20-positive PTLD

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