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

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ClinicalTrials.gov Identifier: NCT02042391
Recruitment Status : Recruiting
First Posted : January 22, 2014
Last Update Posted : July 24, 2018
Sponsor:
Information provided by (Responsible Party):
Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH

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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : February 3, 2015
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine

Drug Information available for: Rituximab

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 Name: 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 Name: 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 Name: 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




Primary Outcome Measures :
  1. 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 ]

    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


Secondary Outcome Measures :
  1. Overall survival [ Time Frame: Two years ]
  2. Time to progression [ Time Frame: two years ]
  3. Progression-free survival [ Time Frame: two years ]
  4. Response at interim staging [ Time Frame: day 50 ]
  5. Response after full treatment [ Time Frame: three months ]
  6. Duration of response [ Time Frame: two years ]
  7. Treatment-related mortality [ Time Frame: three months ]

Other Outcome Measures:
  1. Frequency of grade III and IV leucocytopenia and grade III and IV infections by treatment group [ Time Frame: Two years ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02042391


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

Locations
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Germany
Uniklinik RWTH Aaachen Klinik für Onkologie, Hämatologie und Stammzell-transplantation Med. Klinik IV Recruiting
Aachen, Germany, 52074
Charite Universitätsmedizin Berlin Campus Mitte, Medizinische Klinik mit Schwerpunkt Hämatologie und Onkologie Recruiting
Berlin, Germany, 10117
Charité - Universitätsmedizin Berlin CCM Medizinische Klinik m. S. Nephrologie Recruiting
Berlin, Germany, 10117
Universitätsklinikum Bonn Med. Klinik III/ZIM Hämatologie/Onkologie Recruiting
Bonn, Germany, 53105
DIAKO Bremen gGmbH, Klinik für Hämatologie und Onkologie Recruiting
Bremen, Germany, 28239
Universitätsklinikum Erlangen Med. Klinik 5 Hämatologie und Intern. Onkologie Recruiting
Erlangen, Germany, 91054
Universitätsklinikum Essen Klinik für Hämatologie Recruiting
Essen, Germany, 45147
Malteser Krankenhaus St. Franziskus-Hospital Med. Klinik 1 Recruiting
Flensburg, Germany, 24939
Universitätsklinikum Frankfurt Med. Klinik III, Nephrologie Recruiting
Frankfurt/Main, Germany, 60590
Universitätsklinikum Gießen Med. Klinik IV Recruiting
Gießen, Germany, 35385
Universitätsmedizin Göttingen, Klinik für Hämatologie und medizinische Onkologie Not yet recruiting
Göttingen, Germany, 37075
Nephrologisches Zenrtum Niedersachsen Not yet recruiting
Hann-Münden, Germany, 34346
Medizinische Hochschule Hannover Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation Recruiting
Hannover, Germany, 30625
Medizinische Universitätsklinik Heidelberg Abteilung Innere Medizin V Recruiting
Heidelberg, Germany, 69120
II. Medizinische Klinik, Universitätsklinikum Schleswig-Holstein Campus Kiel Recruiting
Kiel, Germany, 24105
Universitätsmedizin der Johannes-Gutenberg-Universität III. Medizinische Klinik Recruiting
Mainz, Germany, 55101
Klinikum der Universität München-Großhadern Med. Klinik III Recruiting
München, Germany, 81377
Klinikum Oldenburg gGmbH Klinik für Innere Medizin II Recruiting
Oldenburg, Germany, 26133
Klinikum Passau II. Med. Klinik Recruiting
Passau, Germany, 94032
Universitätsmedizin Rostock Klinik für Innere Medizin III Hämatologie, Onkologie, Palliativmedizin Not yet recruiting
Rostock, Germany, 18057
Klinikum Stuttgart Klinik für Hämatologie und int. Onkologie Recruiting
Stuttgart, Germany, 70174
Sponsors and Collaborators
Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH
Investigators
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Principal Investigator: Ralf U Trappe, Dr. med.- DIAKO Bremen

Publications:
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Responsible Party: Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH
ClinicalTrials.gov Identifier: NCT02042391     History of Changes
Other Study ID Numbers: DPTLDSG-IIT-PTLD-2
First Posted: January 22, 2014    Key Record Dates
Last Update Posted: July 24, 2018
Last Verified: July 2018

Keywords provided by Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH:
PTLD
CD20-positive
solid organ transplantation

Additional relevant MeSH terms:
Layout table for MeSH terms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Cytarabine
Rituximab
Oxaliplatin
Prednisone
Doxorubicin
Liposomal doxorubicin
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents