Trial document




drksid header

  DRKS00005380

Trial Description

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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

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Trial Acronym

DPTLDSG-IIT-PTLD-2

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URL of the Trial

http://www.lymphome.de/Gruppen/DPTLDSG/index.jsp

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Brief Summary in Lay Language

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.

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Brief Summary in Scientific Language

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.
In an amendment in 2017, the planned recruitment was reduced to 60 patients.

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Organizational Data

  •   DRKS00005380
  •   2014/11/12
  •   2014/01/20
  •   yes
  •   Approved
  •   2014-05-015, Ethikkommission des Landes Bremen
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Secondary IDs

  •   2013-004479-11 
  •   NCT02042391  (clinicaltrials.gov)
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Health Condition or Problem studied

  •   Previously untreated CD20-positive lymphoproliferative disorder (PTLD) following solid organ transplantation
  •   ICD10 Version 2014: D47.Z1 Post-transplant lymphoproliferative disorder (PTLD)
  •   D47 -  Other neoplasms of uncertain or unknown behaviour of lymphoid, haematopoietic and related tissue
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Interventions/Observational Groups

  •   All patients will receive rituximab sc 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. 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 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.
  •   All patients will receive rituximab sc 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. 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 progessive disease but are not recipients of heart or lung transplants. 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 d1, adriamycine 50 mg/m2 d1, vincristine 1.4mg/m2 d1 (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.
  •   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 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 d1, adriamycine IV 50 mg/m2 d1, vincristine IV 1.4mg/m2 d1 (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 cytarabin (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.
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Characteristics

  •   Interventional
  •   [---]*
  •   Other
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Treatment
  •   Other
  •   II
  •   Yes
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Primary Outcome

- Event free survival (EFS) of low-risk patients in the intention to treat population defined as 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
- all patients in partial remission at interim staging with an negative PET scan*

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

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Secondary Outcome

- Overall survival, time to progression, progression free survival, response at interim staging, response after full treatment, duration of response, treatment related mortality in the ITT and PP population
- Secondary end points will be analysed in the total trial cohort and by treatment group

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2015/02/03
  •   60
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional 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
• Negative pregnancy test (females with child-bearing potential only; not required in postmenopausal women and permanently sterilised women)
• Use of highly-effective contraceptive methods during treatment and for 12 months following study therapy (this applies to female trial participants as well as female partners of male participants: females with child-bearing potential only)

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Exclusion Criteria

• Complete surgical extirpation of the tumor or irradiation of residual tumor masses
• Missing data for IPI stratification
• Upfront treatment with rituximab or chemotherapy
• Known hypersensitivity to rituximab, murine proteins or to any of the excipients
• Concomitant diseases which exclude the administration of therapy as outlined by the study protocol, in particular:
severe heart failure (New York Heart Association Class IV), severe uncontrolled cardiac disease; HIV infection; other active, severe infections such as tuberculosis or Hepatitis B
• Meningeal and CNS involvement
• Pregnant women and nursing mothers
• 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

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Addresses

  • start of 1:1-Block address primary-sponsor
    • DIAKO Ev. Diakonie-Krankenhaus Bremen gGmbH
    • Mr.  Prof. Dr. med.  Ralf Ulrich  Trappe 
    • Gröpelinger Heerstrasse 406-408
    • 28239  Bremen
    • Germany
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    • DIAKO Ev. Diakoniekrankenhaus Bremen gGMBH
    • Mr.  Prof. Dr. med  Ralf Ulrich  Trappe 
    • Gröpelinger Heerstr. 406-408
    • 28239  Bremen
    • Germany
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    end of 1:1-Block address contact scientific-contact
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    • DIAKO Ev. Diakoniekrankenhaus Bremen gGmbH
    • Mr.  Prof. Dr. med  Ralf Ulrich  Trappe 
    • Gröpelinger Heerstr. 406 - 408
    • 28239  Bremen
    • Germany
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Sources of Monetary or Material Support

  • start of 1:1-Block address materialSupport
    • Roche Pharma AG
    • Emil-Barell-Str. 1
    • 79639  Grenzach-Wyhlen
    • Germany
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    •   [---]*
    •   [---]*
    •   [---]*
    •   [---]*
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    • Deutsche PTLD Studiengruppe c/o DIAKO BremenMedizinische Klinik II
    • Gröperlinger Heerstr. 406-408
    • 28239  Bremen
    • Germany
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    •   [---]*
    •   [---]*
    •   [---]*
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Status

  •   Recruiting ongoing
  •   [---]*
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Trial Publications, Results and other Documents

  • [---]*
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* This entry means the parameter is not applicable or has not been set.