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Posttransplant Lymphoproliferative DisorderPhase 2PTLD-2NCT02042391

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

A Phase 2 study testing Rituximab sc, Rituximab sc consolidation and Rituximab sc combined with CHOP chemotherapy in people with Posttransplant Lymphoproliferative Disorder, run by Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH at 18 sites in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Rituximab sc, Rituximab sc consolidation and Rituximab sc combined with CHOP chemotherapy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
60 participants
Where
18 sitesGermany
Study dates
3 Feb 2015to 13 Jul 2022
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • 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
Show all 11Show fewer
  • 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

Trial locations and contacts

18 sites in 1 country.

18 sites in 1 country

Germany18 sites

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

    Aachen, 52074

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

    Berlin, 10117

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

    Berlin, 10117

  • Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie

    Bonn, 53105

  • DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie

    Bremen, 28239

  • Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie

    Erlangen, 91054

  • Universitätsklinikum Essen Klinik für Hämatologie

    Essen, 45147

  • Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1

    Flensburg, 24939

  • Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie

    Frankfurt am Main, 60590

  • Universitätsklinikum Gießen Med. Klinik IV

    Giessen, 35385

  • Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

    Hanover, 30625

  • II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel

    Kiel, 24105

  • Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik

    Mainz, 55101

  • Klinikum der Universität München-Großhadern Med. Klinik III

    München, 81377

  • Klinikum Oldenburg gGmbH Klinik für Innere Medizin II

    Oldenburg, 26133

  • Klinikum Passau II. Med. Klinik

    Passau, 94032

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

    Rostock, 18057

  • Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie

    Stuttgart, 70174

Other trials in Germany

About this study

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

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.

Read more

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.

Being tested
Rituximab sc, Rituximab sc consolidation, Rituximab sc combined with CHOP chemotherapy, Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx
Keywords
PTLD, CD20-positive, solid organ transplantation

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Rituximab scDrug

    Also called Mabthera 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.

  • Rituximab sc consolidationDrug

    Also called Rituximab sc, Mabthera sc

    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.

  • Rituximab sc combined with CHOP chemotherapyDrug

    Also called Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin

    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.

  • Rituximab sc combined with alternating chemotherapy with CHOP and DHAOxDrug

    Also called Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin

    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.

Study groups in NCT02042391
Study groupRoleWhat they receive
Low-riskExperimentalAll 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.
Receives: Drug: Rituximab sc; Drug: Rituximab sc consolidation
High riskExperimentalAll 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.
Receives: Drug: Rituximab sc; Drug: Rituximab sc combined with CHOP chemotherapy
Very high-riskExperimentalAll 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.
Receives: Drug: Rituximab sc; Drug: Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx

What is being measured

The primary outcome is the main question the study is designed to answer.

  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
    1. 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

    Measured: two years

Secondary outcomes (7)

  1. Overall survival

    Measured: Two years

  2. Time to progression

    Measured: two years

  3. Progression-free survival

    Measured: two years

  4. Response at interim staging

    Measured: day 50

  5. Response after full treatment

    Measured: three months

  6. Duration of response

    Measured: two years

  7. Treatment-related mortality

    Measured: three months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jan 2014 (estimated)
  2. Study start3 Feb 2015
  3. Primary completion13 Jul 2021
  4. Study completion13 Jul 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
60 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02042391
Sponsor's protocol ID
DPTLDSG-IIT-PTLD-2
Acronym
PTLD-2
Status last verified
Aug 2022
First submitted
20 Jan 2014
Last updated
25 Aug 2022
Results posted
No
Data monitoring committee
Yes

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, 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.

    PubMed 22173060

  • 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.

    PubMed 17522862

  • 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.

    PubMed 17296588

  • 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.

    PubMed 16303003

  • 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.

    PubMed 35974101

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Rituximab sc, Rituximab sc consolidation and Rituximab sc combined with CHOP chemotherapy in people with Posttransplant Lymphoproliferative Disorder, run by Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH at 18 sites in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Aug 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event: (time frame: two years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02042391, which also lists 5 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2022.

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