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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/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]

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

Condition category

Condition code

Cardiovascular

Diseases of the vasculature and circulation including the lymphatic system

Inflammatory and Immune System

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]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

Event free survival (EFS) of low-risk patients in the intention to treat population with following definitions for low-risk and event:

Timepoint [1]

two years

Secondary outcome [1]

Overall survival

Timepoint [1]

Two years

Secondary outcome [2]

Time to progression

Timepoint [2]

two years

Secondary outcome [3]

Progression-free survival

Timepoint [3]

two years

Secondary outcome [4]

Response at interim staging

Timepoint [4]

day 50

Secondary outcome [5]

Response after full treatment

Timepoint [5]

three months

Secondary outcome [6]

Duration of response

Timepoint [6]

two years

Secondary outcome [7]

Treatment-related mortality

Timepoint [7]

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?

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

Recruitment in Australia

Recruitment state(s)

Recruitment outside Australia

Country [1]

United Kingdom

State/province [1]

England

Country [2]

Germany

State/province [2]

Aachen

Country [3]

Germany

State/province [3]

Berlin

Country [4]

Germany

State/province [4]

Bonn

Country [5]

Germany

State/province [5]

Bremen

Country [6]

Germany

State/province [6]

Erlangen

Country [7]

Germany

State/province [7]

Essen

Country [8]

Germany

State/province [8]

Flensburg

Country [9]

Germany

State/province [9]

Frankfurt/Main

Country [10]

Germany

State/province [10]

Gießen

Country [11]

Germany

State/province [11]

Hannover

Country [12]

Germany

State/province [12]

Kiel

Country [13]

Germany

State/province [13]

Mainz

Country [14]

Germany

State/province [14]

München

Country [15]

Germany

State/province [15]

Oldenburg

Country [16]

Germany

State/province [16]

Passau

Country [17]

Germany

State/province [17]

Rostock

Country [18]

Germany

State/province [18]

Stuttgart

Country [19]

United Kingdom

State/province [19]

Scotland

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/study/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.
Zimmermann H, Koenecke C, Dreyling MH, Pott C, Duhrsen U, Hahn D, Meidenbauer N, Hauser IA, Rummel MJ, Wolf D, Heuser M, Schmidt C, Schlattmann P, Ritgen M, Siebert R, Oschlies I, Anagnostopoulos I, Trappe RU. Modified risk-stratified sequential treatment (subcutaneous rituximab with or without chemotherapy) in B-cell Post-transplant lymphoproliferative disorder (PTLD) after Solid organ transplantation (SOT): the prospective multicentre phase II PTLD-2 trial. Leukemia. 2022 Oct;36(10):2468-2478. doi: 10.1038/s41375-022-01667-1. Epub 2022 Aug 16.

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

Ralf U Trappe, Dr. med.-

Address

DIAKO Bremen

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

No information has been provided regarding IPD availability

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Type	Citations or Other Details
Journal	Zimmermann H, Koenecke C, Dreyling MH, Pott C, Duh... [More Details]

Results not provided in https://clinicaltrials.gov/study/NCT02042391

Trial Review

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