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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT02042391




Registration number
NCT02042391
Ethics application status
Date submitted
20/01/2014
Date registered
22/01/2014
Date last updated
25/08/2022

Titles & IDs
Public title
Risk-stratified Sequential Treatment of Post-transplant Lymphoproliferative Disease (PTLD) With Rituximab SC and Immunochemotherapy
Scientific 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
Secondary ID [1] 0 0
DPTLDSG-IIT-PTLD-2
Universal Trial Number (UTN)
Trial acronym
PTLD-2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Posttransplant Lymphoproliferative Disorder 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Diseases of the vasculature and circulation including the lymphatic system
Inflammatory and Immune System 0 0 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Rituximab sc
Treatment: Drugs - Rituximab sc consolidation
Treatment: Drugs - Rituximab sc combined with CHOP chemotherapy
Treatment: Drugs - Rituximab sc combined with alternating chemotherapy with CHOP and DHAOx

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.

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.

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:
Timepoint [1] 0 0
two years
Secondary outcome [1] 0 0
Overall survival
Timepoint [1] 0 0
Two years
Secondary outcome [2] 0 0
Time to progression
Timepoint [2] 0 0
two years
Secondary outcome [3] 0 0
Progression-free survival
Timepoint [3] 0 0
two years
Secondary outcome [4] 0 0
Response at interim staging
Timepoint [4] 0 0
day 50
Secondary outcome [5] 0 0
Response after full treatment
Timepoint [5] 0 0
three months
Secondary outcome [6] 0 0
Duration of response
Timepoint [6] 0 0
two years
Secondary outcome [7] 0 0
Treatment-related mortality
Timepoint [7] 0 0
three months

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
3/02/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
13/07/2022
Sample size
Target
Accrual to date
Final
60
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Aachen
Country [2] 0 0
Germany
State/province [2] 0 0
Berlin
Country [3] 0 0
Germany
State/province [3] 0 0
Bonn
Country [4] 0 0
Germany
State/province [4] 0 0
Bremen
Country [5] 0 0
Germany
State/province [5] 0 0
Erlangen
Country [6] 0 0
Germany
State/province [6] 0 0
Essen
Country [7] 0 0
Germany
State/province [7] 0 0
Flensburg
Country [8] 0 0
Germany
State/province [8] 0 0
Frankfurt/Main
Country [9] 0 0
Germany
State/province [9] 0 0
Gießen
Country [10] 0 0
Germany
State/province [10] 0 0
Hannover
Country [11] 0 0
Germany
State/province [11] 0 0
Kiel
Country [12] 0 0
Germany
State/province [12] 0 0
Mainz
Country [13] 0 0
Germany
State/province [13] 0 0
München
Country [14] 0 0
Germany
State/province [14] 0 0
Oldenburg
Country [15] 0 0
Germany
State/province [15] 0 0
Passau
Country [16] 0 0
Germany
State/province [16] 0 0
Rostock
Country [17] 0 0
Germany
State/province [17] 0 0
Stuttgart

Funding & Sponsors
Primary sponsor type
Other
Name
Diako Ev. Diakonie-Krankenhaus gemeinnützige GmbH
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT02042391
Trial related presentations / 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.
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.
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.
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.
Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed

Contacts
Principal investigator
Name 0 0
Ralf U Trappe, Dr. med.-
Address 0 0
DIAKO Bremen
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT02042391