PTLD-2: Risk-stratified Sequential Treatment of Post-transplant Lymphoproliferative Disease (PTLD) With Rituximab SC and Immunochemotherapy

Sponsor

Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH (Other)

Overall Status

Completed

CT.gov ID

NCT02042391

Collaborator

(none)

Enrollment

Locations

Arms

89.3

Actual Duration (Months)

3.3

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Post-transplant lymphoproliferative disorders (PTLD) differ clinically from lymphoma in the general (immunocompetent) population due to their higher incidence and their frequent association with Epstein-Barr virus. Previous clinical trials have shown their remarkably good response to rituximab as well as to chemotherapy.

The PTLD-1 trial demonstrated the efficacy and safety of sequential immunochemotherapy with 4 courses of rituximab IV followed by 4 cycles of CHOP chemotherapy. Compared to trials of rituximab monotherapy in PTLD, median overall survival was extended from 2.4 to 6.5 years. Compared to previous trials of chemotherapy, complications were reduced. In addition, we noted that those patients who already had a good response to the first four cycles of rituximab did better overall than those who did not. As a consequence, the PTLD-1/3 trial introduced risk-stratification in sequential treatment according to the response to the first 4 courses of rituximab monotherapy. Those patients with a complete remission went on to receive four further courses of rituximab whereas those who did not received rituximab and CHOP chemotherapy. Interim results have demonstrated that it is safe to restrict chemotherapy treatment in this manner and thus established the concept of treatment stratification based on the response to rituximab.

The PTLD-2 trial is the next step in the development of this strategy. Compared to the PTLD-1/3 trial, the key difference is the use of subcutaneous instead of intravenous rituximab application. Interim results from an ongoing trial of patients with follicular lymphoma (NCT01200758) have shown that subcutaneous administration results in increased blood levels and in non-inferior remission rates. Furthermore, the stratification strategy is refined based on observations from the previous PTLD-1 and PTLD1/3 trials: Risk groups are now defined not only based on response to rituximab therapy but also on the international prognostic index (IPI, a well-established lymphoma risk score) and the transplanted organ. The major advantage of this new stratification is an extended low-risk group that is eligible for subcutaneous rituximab monotherapy: Patients with a low risk of disease progression, defined as those who achieve a complete remission after the first four courses of subcutaneous rituximab monotherapy and those with an IPI of 0 to 2 who achieve a partial remission at interim staging, will go on with rituximab monotherapy. Patients with high IPI who achieve a partial remission, patients with stable disease at interim staging and non-thoracic transplant recipients with progressive disease at interim staging will be considered high risk. These patients will go on with 4 cycles of rituximab plus CHOP chemotherapy similar to the PTLD-1/3 protocol. Thoracic transplant recipients refractory to rituximab will be considered very high risk and will go on with rituximab subcutaneous plus alternating chemotherapy with CHOP and DHAOx.

The trial hypothesis is that the new protocol will improve the event-free survival, a measure integrating unfavorable events such as death, disease progression and treatment complications, particularly infections, in the low risk-group compared to the results of the PTLD-1 trial. In very high-risk patients data from the PTLD-1 and PTLD-1/3 trial have shown that the current treatment is not sufficient to control the disease. Death due to disease progression was observed in more than 80% of patients. Here, rituximab combined with alternating chemotherapy cycles of CHOP and DHAOx (+GCSF) may increase treatment efficacy with an acceptable toxicity profile.

In summary, the PTLD-2 trials tests if the substitution of subcutaneous for intravenous rituximab and an updated stratification strategy that deescalates treatment for those at low risk and escalates treatment for those at very high risk can further improve the overall efficacy and safety of PTLD therapy.

Condition or Disease	Intervention/Treatment	Phase
Posttransplant Lymphoproliferative Disorder	Drug: Rituximab sc Drug: Rituximab sc consolidation Drug: Rituximab sc combined with CHOP chemotherapy Drug: Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

60 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Risk-stratified Sequential Treatment of Post-transplant Lymphoproliferative Disease (PTLD) With 4 Courses of Rituximab SC Followed by 4 Courses of Rituximab SC, 4 Courses of Rituximab SC Combined With CHOP-21 or 6 Courses of Rituximab SC Combined With Alternating CHOP-21 and DHAOx: The PTLD-2 Trial

Actual Study Start Date :

Feb 3, 2015

Actual Primary Completion Date :

Jul 13, 2021

Actual Study Completion Date :

Jul 13, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low-risk All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered low-risk if they reached a complete remission with the first 4 applications of rituximab monotherapy or if they reached a partial remission and had a baseline IPI of 0, 1 or 2. Patients considered low-risk will receive rituximab sc consolidation.	Drug: Rituximab sc All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Rituximab will be administered as a single therapeutic agent at a standard dosage of 375 mg/m2 infused intravenously at day 1. Three subsequent single therapeutic agent applications of rituximab will be administered subcutaneously at a fixed dose of 1400 mg once a week for 3 weeks at days 8, 15 and 22. Other Names: Mabthera sc Drug: Rituximab sc consolidation Patients considered low-risk will receive four more single therapeutic agent applications of rituximab administered subcutaneously at a fixed dose of 1400 mg once every three weeks at days 50, 71, 92 and 113. Other Names: Rituximab sc Mabthera sc
Experimental: High risk All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered high-risk, if the reached a partial remission and were IPI 3, 4 or 5 at time of diagnosis of PTLD, if they show stable disease or if they had progressive disease but are not recipients of heart or lung transplants. Patients considered high-risk will receive four more applications of rituximab sc combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113.	Drug: Rituximab sc All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Rituximab will be administered as a single therapeutic agent at a standard dosage of 375 mg/m2 infused intravenously at day 1. Three subsequent single therapeutic agent applications of rituximab will be administered subcutaneously at a fixed dose of 1400 mg once a week for 3 weeks at days 8, 15 and 22. Other Names: Mabthera sc Drug: Rituximab sc combined with CHOP chemotherapy Patients considered high-risk will receive four more applications of rituximab administered subcutaneously at a fixed dose of 1400 mg combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113. CHOP chemotherapy will be administered at standard doses: cyclophosphamide 750 mg/m2, adriamycine 50 mg/m2, vincristine 1.4mg/m2 (maximum total dose: 2mg) and prednisone 100mg (at day 1 to 5 of each cycle). Cyclophosphamid, adriamycine and vincristine will be infused intravenously. Prednison will be administered orally in a single dose. At day 3-4 of each treatment cycle either a single dose of 6 mg Peg-GCSF or repetitive doses of 5 µg/kg GCSF until recovery of WBC will be applied subcutaneously, as per institutional practice. Other Names: Mabthera sc Cyclophosphamide Adriamycine Vincristin Prednisone
Experimental: Very high-risk All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, heart and lung transplant recipients and patients with a combination of organs transplanted including a heart or lung transplant who show disease progression during rituximab monotherapy or at interim staging will be considered very high-risk. Patients considered very high-risk will receive six more applications of rituximab sc combined with alternating chemotherapy with CHOP and DHAOx.	Drug: Rituximab sc All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Rituximab will be administered as a single therapeutic agent at a standard dosage of 375 mg/m2 infused intravenously at day 1. Three subsequent single therapeutic agent applications of rituximab will be administered subcutaneously at a fixed dose of 1400 mg once a week for 3 weeks at days 8, 15 and 22. Other Names: Mabthera sc Drug: Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx Patients considered very high-risk will receive six more applications of rituximab sc at a fixed dose of 1400 mg combined with chemotherapy every 3 weeks. Chemotherapy is CHOP at days 50, 92 and 134 (cyclophosphamide IV 750 mg/m2, adriamycine IV 50 mg/m2, vincristine IV 1.4mg/m2 (maximum total dose: 2mg) and prednisone PO 100mg (at day 1 to 5 of each cycles). Chemotherapy is DHAOx at days 71, 113 and 155 (oxaliplatin (130 mg/m2, day 1) and cytarabine (ARA-C, 2x 1000 mg/m2 at day 2) dexamethasone PO (40 mg/m2, day 1)), as per institutional practice. At day 3-4 of each treatment cycle either a single dose of 6 mg Peg-GCSF or repetitive doses of 5 µg/kg GCSF until recovery of WBC will be applied subcutaneously, as per institutional practice. Other Names: Mabthera sc Cyclophosphamide Adriamycine Vincristin Prednisone Oxaliplatin Cytarabine Ara-C Dexamthasone

Arm

Intervention/Treatment

Experimental: Low-risk

All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered low-risk if they reached a complete remission with the first 4 applications of rituximab monotherapy or if they reached a partial remission and had a baseline IPI of 0, 1 or 2. Patients considered low-risk will receive rituximab sc consolidation.

Drug: Rituximab sc

All patients will receive 4 courses of rituximab on days 1, 8, 15 and 22. Rituximab will be administered as a single therapeutic agent at a standard dosage of 375 mg/m2 infused intravenously at day 1. Three subsequent single therapeutic agent applications of rituximab will be administered subcutaneously at a fixed dose of 1400 mg once a week for 3 weeks at days 8, 15 and 22.

Other Names:

Mabthera sc

Drug: Rituximab sc consolidation

Patients considered low-risk will receive four more single therapeutic agent applications of rituximab administered subcutaneously at a fixed dose of 1400 mg once every three weeks at days 50, 71, 92 and 113.

Other Names:

Rituximab sc

Mabthera sc

Experimental: High risk

All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, patients will be considered high-risk, if the reached a partial remission and were IPI 3, 4 or 5 at time of diagnosis of PTLD, if they show stable disease or if they had progressive disease but are not recipients of heart or lung transplants. Patients considered high-risk will receive four more applications of rituximab sc combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113.

Drug: Rituximab sc

Other Names:

Mabthera sc

Drug: Rituximab sc combined with CHOP chemotherapy

Patients considered high-risk will receive four more applications of rituximab administered subcutaneously at a fixed dose of 1400 mg combined with CHOP chemotherapy every 3 weeks at days 50, 71, 92 and 113. CHOP chemotherapy will be administered at standard doses: cyclophosphamide 750 mg/m2, adriamycine 50 mg/m2, vincristine 1.4mg/m2 (maximum total dose: 2mg) and prednisone 100mg (at day 1 to 5 of each cycle). Cyclophosphamid, adriamycine and vincristine will be infused intravenously. Prednison will be administered orally in a single dose. At day 3-4 of each treatment cycle either a single dose of 6 mg Peg-GCSF or repetitive doses of 5 µg/kg GCSF until recovery of WBC will be applied subcutaneously, as per institutional practice.

Other Names:

Mabthera sc

Cyclophosphamide

Adriamycine

Vincristin

Prednisone

Experimental: Very high-risk

All patients will receive rituximab sc on days 1, 8, 15 and 22. Interim staging will be performed around day 50. After interim staging, heart and lung transplant recipients and patients with a combination of organs transplanted including a heart or lung transplant who show disease progression during rituximab monotherapy or at interim staging will be considered very high-risk. Patients considered very high-risk will receive six more applications of rituximab sc combined with alternating chemotherapy with CHOP and DHAOx.

Drug: Rituximab sc

Other Names:

Mabthera sc

Drug: Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx

Patients considered very high-risk will receive six more applications of rituximab sc at a fixed dose of 1400 mg combined with chemotherapy every 3 weeks. Chemotherapy is CHOP at days 50, 92 and 134 (cyclophosphamide IV 750 mg/m2, adriamycine IV 50 mg/m2, vincristine IV 1.4mg/m2 (maximum total dose: 2mg) and prednisone PO 100mg (at day 1 to 5 of each cycles). Chemotherapy is DHAOx at days 71, 113 and 155 (oxaliplatin (130 mg/m2, day 1) and cytarabine (ARA-C, 2x 1000 mg/m2 at day 2) dexamethasone PO (40 mg/m2, day 1)), as per institutional practice. At day 3-4 of each treatment cycle either a single dose of 6 mg Peg-GCSF or repetitive doses of 5 µg/kg GCSF until recovery of WBC will be applied subcutaneously, as per institutional practice.

Other Names:

Mabthera sc

Cyclophosphamide

Adriamycine

Vincristin

Prednisone

Oxaliplatin

Cytarabine

Ara-C

Dexamthasone

Outcome Measures

Primary Outcome Measures

Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event: [two years]
Time from start of treatment to event with following definitions for low-risk and event: Low-risk: all patients in complete remission at interim staging, i.e. 4 weeks after the four weekly courses of rituximab SC monotherapy all patients in partial remission at interim staging with an initial international prognostic index (IPI) of 0,1 or 2 Events: any grade III or IV infection during the treatment period treatment discontinuation from any reason disease progression at any time death from any reason

Secondary Outcome Measures

Overall survival [Two years]
Time to progression [two years]
Progression-free survival [two years]
Response at interim staging [day 50]
Response after full treatment [three months]
Duration of response [two years]
Treatment-related mortality [three months]

Other Outcome Measures

Frequency of grade III and IV leucocytopenia and grade III and IV infections by treatment group [Two years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

CD20-positive 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 a combination of the organ transplantations mentioned
ECOG ≤ 2
Clinically insufficient response to an upfront reduction of immunosuppression with or without antiviral therapy
Age at least 18 years
Not legally incapacitated
Written informed consent from the trial subject has been obtained

Exclusion Criteria:

Complete surgical extirpation of the tumor or irradiation of residual tumor masses
Upfront treatment with rituximab or chemotherapy
Known allergic reactions against foreign proteins
Concomitant diseases, which exclude the administration of therapy as outlined by the study protocol
Meningeal and CNS involvement
Known to be HIV-positive
Pregnant women and nursing mothers
Failure to use highly-effective contraceptive methods
Persons held in an institution by legal or official order
Persons with any kind of dependency on the investigator or employed by the sponsor or investigator
Life expectancy less than 6 weeks

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Uniklinik RWTH Aaachen Klinik für Onkologie, Hämatologie und Stammzell-transplantation Med. Klinik IV	Aachen	Germany	52074
2	Charite Universitätsmedizin Berlin Campus Mitte, Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie	Berlin	Germany	10117
3	Charité - Universitätsmedizin Berlin CCM Medizinische Klinik m. S. Nephrologie	Berlin	Germany	10117
4	Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie	Bonn	Germany	53105
5	DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie	Bremen	Germany	28239
6	Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie	Erlangen	Germany	91054
7	Universitätsklinikum Essen Klinik für Hämatologie	Essen	Germany	45147
8	Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1	Flensburg	Germany	24939
9	Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie	Frankfurt/Main	Germany	60590
10	Universitätsklinikum Gießen Med. Klinik IV	Gießen	Germany	35385
11	Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation	Hannover	Germany	30625
12	II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel	Kiel	Germany	24105
13	Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik	Mainz	Germany	55101
14	Klinikum der Universität München-Großhadern Med. Klinik III	München	Germany	81377
15	Klinikum Oldenburg gGmbH Klinik für Innere Medizin II	Oldenburg	Germany	26133
16	Klinikum Passau II. Med. Klinik	Passau	Germany	94032
17	Universitätsmedizin Rostock Klinik für Innere Medizin III Hämatologie, Onkologie, Palliativmedizin	Rostock	Germany	18057
18	Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie	Stuttgart	Germany	70174