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

Information source: Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Posttransplant Lymphoproliferative Disorder

Intervention: Rituximab sc (Drug); Rituximab sc consolidation (Drug); Rituximab sc combined with CHOP chemotherapy (Drug); Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH

Official(s) and/or principal investigator(s):
Ralf U Trappe, Dr. med.-, Principal Investigator, Affiliation: DIAKO Bremen

Overall contact:
Ralf U Trappe, Dr. med., Phone: +49 (0)421-6102-1481, Email: r.trappe@diako-bremen.de

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.

Clinical Details

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 design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:

Secondary outcome:

Overall survival

Time to progression

Progression-free survival

Response at interim staging

Response after full treatment

Duration of response

Treatment-related mortality

Eligibility

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

Locations and Contacts

Ralf U Trappe, Dr. med., Phone: +49 (0)421-6102-1481, Email: r.trappe@diako-bremen.de

Uniklinik RWTH Aaachen Klinik für Onkologie, Hämatologie und Stammzell-transplantation Med. Klinik IV, Aachen 52074, Germany; Recruiting

Charite Universitätsmedizin Berlin Campus Mitte, Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie, Berlin 10117, Germany; Recruiting

Charité - Universitätsmedizin Berlin CCM Medizinische Klinik m. S. Nephrologie, Berlin 10117, Germany; Not yet recruiting

Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie, Bonn 53105, Germany; Not yet recruiting

DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie, Bremen 28239, Germany; Recruiting

Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie, Erlangen 91054, Germany; Recruiting

Universitätsklinikum Essen Klinik für Hämatologie, Essen 45147, Germany; Recruiting

Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1, Flensburg 24939, Germany; Recruiting

Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie, Frankfurt/Main 60590, Germany; Recruiting

Universitätsklinikum Gießen Med. Klinik IV, Gießen 35385, Germany; Recruiting

Universitätsmedizin Göttingen, Klinik für Hämatologie und medizinische Onkologie, Göttingen 37075, Germany; Not yet recruiting

Nephrologisches Zenrtum Niedersachsen, Hann-Münden 34346, Germany; Not yet recruiting

Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Hannover 30625, Germany; Recruiting

Medizinische Universitätsklinik Heidelberg Abteilung Innere Medizin V, Heidelberg 69120, Germany; Recruiting

II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel, Kiel 24105, Germany; Recruiting

Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz 55101, Germany; Not yet recruiting

Klinikum der Universität München-Großhadern Med. Klinik III, München 81377, Germany; Recruiting

Klinikum Oldenburg gGmbH Klinik für Innere Medizin II, Oldenburg 26133, Germany; Recruiting

Klinikum Passau II. Med. Klinik, Passau 94032, Germany; Not yet recruiting

Universitätsmedizin Rostock Klinik für Innere Medizin III Hämatologie, Onkologie, Palliativmedizin, Rostock 18057, Germany; Not yet recruiting

Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie, Stuttgart 70174, Germany; Not yet recruiting

Additional Information

Related publications:

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, Leithäuser 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.

Choquet S, Oertel S, LeBlond V, Riess H, Varoqueaux N, Dörken 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. Epub 2007 May 24.

Choquet S, Trappe R, Leblond V, Jäger 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.

Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Váry M, Babel N, Trappe RU, Jonas S, Hummel M, Anagnostopoulos I, Dörken 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.

Starting date: December 2014
Last updated: August 3, 2015

Page last updated: August 23, 2015

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