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.
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
| Drug | Synonyms | Arms |
|---|
| Rituximab sc | Mabthera sc | High risk |
| Rituximab sc consolidation | Rituximab sc, Mabthera sc | Low-risk |
| Rituximab sc combined with CHOP chemotherapy | Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin, Prednisone | High risk |
| Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx | Mabthera sc, Cyclophosphamide, Adriamycine, Vincristin, Prednisone, Oxaliplatin, Cytarabine, Ara-C, Dexamthasone | Very 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
| Name | Type | Description | Interventions |
|---|
| 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. | - Rituximab sc
- 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. | - Rituximab sc
- 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. | - 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: | Active, not recruiting |
| Lead Sponsor: | Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH |
Trial Keywords
- PTLD
- CD20-positive
- solid organ transplantation
Last Updated
July 21, 2020
