Clinical Trials /

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

NCT02042391

Description:

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.

Related Conditions:
  • Post-Transplant Lymphoproliferative Disorder
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: DPTLDSG-IIT-PTLD-2
  • NCT ID: NCT02042391

Conditions

  • Posttransplant Lymphoproliferative Disorder

Interventions

DrugSynonymsArms
Rituximab scMabthera scLow-risk
Rituximab sc consolidationRituximab sc, Mabthera scLow-risk
Rituximab sc combined with CHOP chemotherapyMabthera sc, Cyclophosphamide, Adriamycine, Vincristin, PrednisoneHigh risk
Rituximab sc combined with alternating chemotherapy with CHOP and DHAOxMabthera sc, Cyclophosphamide, Adriamycine, Vincristin, Prednisone, Oxaliplatin, Cytarabine, Ara-C, DexamthasoneVery high-risk

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
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.
  • Rituximab sc
  • 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.
  • Rituximab sc
  • 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.
  • Rituximab sc
  • Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
Description:Time from start of treatment to event with following definitions for low-risk and event: 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 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

Measure:Overall survival
Time Frame:Two years
Safety Issue:
Description:
Measure:Time to progression
Time Frame:two years
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:two years
Safety Issue:
Description:
Measure:Response at interim staging
Time Frame:day 50
Safety Issue:
Description:
Measure:Response after full treatment
Time Frame:three months
Safety Issue:
Description:
Measure:Duration of response
Time Frame:two years
Safety Issue:
Description:
Measure:Treatment-related mortality
Time Frame:three months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH

Trial Keywords

  • PTLD
  • CD20-positive
  • solid organ transplantation

Last Updated

February 26, 2017