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

NCT02042391 | Completed Phase 2 DMC

• 1 other identifier: DPTLDSG-IIT-PTLD-2
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 18

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.

Conditions

Posttransplant Lymphoproliferative Disorder

Keywords

PTLD; CD20-positive; solid organ transplantation

Outcome Measures

Primary Outcomes (1)

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

  Time from start of treatment to event with following definitions for low-risk and event: 1. 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 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

  two years

Secondary Outcomes (7)

• 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

Other Outcomes (1)

• Frequency of grade III and IV leucocytopenia and grade III and IV infections by treatment group

  Two years

Study Arms (3)

Low-risk

EXPERIMENTAL

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; Drug: Rituximab sc consolidation

High risk

EXPERIMENTAL

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; Drug: Rituximab sc combined with CHOP chemotherapy

Very high-risk

EXPERIMENTAL

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

Interventions

Rituximab sc DRUG

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.

Also known as: Mabthera sc

High risk; Low-risk; Very high-risk

Rituximab sc consolidation DRUG

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.

Also known as: Rituximab sc, Mabthera sc

Low-risk

Rituximab sc combined with CHOP chemotherapy DRUG

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.

Also known as: Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin, Prednisone

High risk

Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx DRUG

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.

Also known as: Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin, Prednisone, Oxaliplatin, Cytarabine, Ara-C, Dexamthasone

Very high-risk

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH: lead

Study Sites (18)

Uniklinik RWTH Aaachen Klinik für Onkologie, Hämatologie und Stammzell-transplantation Med. Klinik IV

Aachen, 52074, Germany

Location

Charite Universitätsmedizin Berlin Campus Mitte, Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie

Berlin, 10117, Germany

Location

Charité - Universitätsmedizin Berlin CCM Medizinische Klinik m. S. Nephrologie

Berlin, 10117, Germany

Location

Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie

Bonn, 53105, Germany

Location

DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie

Bremen, 28239, Germany

Location

Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie

Erlangen, 91054, Germany

Location

Universitätsklinikum Essen Klinik für Hämatologie

Essen, 45147, Germany

Location

Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1

Flensburg, 24939, Germany

Location

Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie

Frankfurt am Main, 60590, Germany

Location

Universitätsklinikum Gießen Med. Klinik IV

Giessen, 35385, Germany

Location

Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

Hanover, 30625, Germany

Location

II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel

Kiel, 24105, Germany

Location

Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik

Mainz, 55101, Germany

Location

Klinikum der Universität München-Großhadern Med. Klinik III

München, 81377, Germany

Location

Klinikum Oldenburg gGmbH Klinik für Innere Medizin II

Oldenburg, 26133, Germany

Location

Klinikum Passau II. Med. Klinik

Passau, 94032, Germany

Location

Universitätsmedizin Rostock Klinik für Innere Medizin III Hämatologie, Onkologie, Palliativmedizin

Rostock, 18057, Germany

Location

Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie

Stuttgart, 70174, Germany

Location

Related Publications (5)

• 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.

  PMID: 22173060 BACKGROUND

• 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.

  PMID: 17522862 BACKGROUND

• 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.

  PMID: 17296588 BACKGROUND

• 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.

  PMID: 16303003 BACKGROUND

• 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.

  PMID: 35974101 RESULT

Related Links

• PTLD-2 trial full text article including supplements (open access)

MeSH Terms

Interventions

Cyclophosphamide; Doxorubicin; Vincristine; Prednisone; Oxaliplatin; Cytarabine

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Coordination Complexes; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Ralf U Trappe, Dr. med.-

  DIAKO Bremen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 20, 2014
• First Posted: January 22, 2014
• Study Start: February 3, 2015
• Primary Completion: July 13, 2021
• Study Completion: July 13, 2022
• Last Updated: August 25, 2022

Record last verified: 2022-08

Locations

DE (18)