Clinical trial NCT02042391: Risk-stratified Sequential Treatment of Post-transplant Lymphoproliferative Disease (PTLD) With Rituximab SC and Immunochemotherapy
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Posttransplant Lymphoproliferative Disorder
Keywords: PTLD
CD20-positive
solid organ transplantation
Lead sponsor: Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH
Sponsor class: OTHER
First posted: 2014-01-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:
timeFrame: two years
Secondary outcomes:
measure: Overall survival
timeFrame: Two years
measure: Time to progression
timeFrame: two years
measure: Progression-free survival
timeFrame: two years
measure: Response at interim staging
timeFrame: day 50
measure: Response after full treatment
timeFrame: three months
measure: Duration of response
timeFrame: two years
measure: Treatment-related mortality
timeFrame: three months
Other outcomes:
measure: Frequency of grade III and IV leucocytopenia and grade III and IV infections by treatment group
timeFrame: Two years
Locations:
city: Aachen
country: Germany
facility: Uniklinik RWTH Aaachen Klinik für Onkologie, Hämatologie und Stammzell-transplantation Med. Klinik IV
city: Berlin
country: Germany
facility: Charite Universitätsmedizin Berlin Campus Mitte, Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin CCM Medizinische Klinik m. S. Nephrologie
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie
city: Bremen
country: Germany
facility: DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie
city: Essen
country: Germany
facility: Universitätsklinikum Essen Klinik für Hämatologie
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1
city: Frankfurt/Main
country: Germany
facility: Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen Med. Klinik IV
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
city: Kiel
country: Germany
facility: II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik
city: München
country: Germany
facility: Klinikum der Universität München-Großhadern Med. Klinik III
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg gGmbH Klinik für Innere Medizin II
city: Passau
country: Germany
facility: Klinikum Passau II. Med. Klinik
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock Klinik für Innere Medizin III Hämatologie, Onkologie, Palliativmedizin
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie
Study officials:
affiliation: DIAKO Bremen
name: Ralf U Trappe, Dr. med.-
role: PRINCIPAL_INVESTIGATOR
References:
citation: Trappe R, Oertel S, Leblond V, Mollee P, Sender M, Reinke P, Neuhaus R, Lehmkuhl H, Horst HA, Salles G, Morschhauser F, Jaccard A, Lamy T, Leithauser M, Zimmermann H, Anagnostopoulos I, Raphael M, Riess H, Choquet S; German PTLD Study Group; European PTLD Network. Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial. Lancet Oncol. 2012 Feb;13(2):196-206. doi: 10.1016/S1470-2045(11)70300-X. Epub 2011 Dec 13.
citation: Choquet S, Oertel S, LeBlond V, Riess H, Varoqueaux N, Dorken B, Trappe R. Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution. Ann Hematol. 2007 Aug;86(8):599-607. doi: 10.1007/s00277-007-0298-2. Epub 2007 May 24.
citation: Choquet S, Trappe R, Leblond V, Jager U, Davi F, Oertel S. CHOP-21 for the treatment of post-transplant lymphoproliferative disorders (PTLD) following solid organ transplantation. Haematologica. 2007 Feb;92(2):273-4. doi: 10.3324/haematol.10595.
citation: Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Vary M, Babel N, Trappe RU, Jonas S, Hummel M, Anagnostopoulos I, Dorken B, Riess HB. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant. 2005 Dec;5(12):2901-6. doi: 10.1111/j.1600-6143.2005.01098.x.
citation: Zimmermann H, Koenecke C, Dreyling MH, Pott C, Duhrsen U, Hahn D, Meidenbauer N, Hauser IA, Rummel MJ, Wolf D, Heuser M, Schmidt C, Schlattmann P, Ritgen M, Siebert R, Oschlies I, Anagnostopoulos I, Trappe RU. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial. Leukemia. 2022 Oct;36(10):2468-2478. doi: 10.1038/s41375-022-01667-1. Epub 2022 Aug 16.