Treatment of chemo-refractory viral infections after allogeneic stem cell transplantation with multispecific T cells against CMV, EBV and AdV: A phase III, prospective, multicentre clinical trial (TRACE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medical Center - University Of Freiburg

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Virus Diseases [C02]

Trial duration

2 Oct 2019 → ongoing

Decision date (initial)

2024-07-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-512321-84-00

EudraCT number

2018-000853-29

ClinicalTrials.gov

NCT04832607

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluation of efficacy of multispecific T-cell transfer in patients with chemo-refractory viral infections after allogeneic stem cell transplantation

Secondary objectives 15

1. Incidence and severity of newly occurring GvHD
2. Incidence and severity of acute toxicity
3. Effect on viral load of underlying viral infection
4. Clinical response/resolution of symptoms of underlying viral infection
5. Overall survival
6. Necessity and duration of antiviral chemotherapy
7. Incidence of viral infections other than underlying viral infection: evaluation of putative prophylactic effect of treatment
8. Days of hospitalization
9. Quality of life
10. Effect on the patients’ T-cell immunity in vivo
11. Quality of the IMP and performance of the CliniMACS® Prodigy
12. Evaluation of the drop-out rate
13. Evaluation of time from inclusion to administration of the IMP
14. Overall safety evaluation
15. Concomitant medication

Conditions and MedDRA coding

Patients after HSCT suffering from new or reactivated CMV or EBV or AdV infection, refractory to standard antiviral treatment

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Adult or paediatric patients (>2 months of age) after HSCT (no time restrictions apply) suffering from new or reactivated CMV or EBV or AdV infection, refractory to standard antiviral treatment for two weeks (defined as ≤1 log decrease in viral load over two weeks) as confirmed by quantitative blood PCR analysis
2. Original HSCT-donor available with an immune response at least to the virus causing the therapy-refractory (=underlying) infection
3. Written informed consent given (patient or legal representative)

Exclusion criteria 12

1. Acute GvHD > grade II or extensive chronic GvHD at time of IMP transfer
2. Treatment with steroids (>1 mg/kg Prednisone equivalent) at Screening
3. Therapeutic donor lymphocyte infusion (DLI) from 4 weeks prior to IMP infusion until 8 weeks post IMP infusion. In case of T-cell depleted HSCT, a prescheduled prophylactic DLI ≤3 x 10^5 T cells/kg BW is not considered an exclusion criteria.
4. Organ dysfunction or failure as determined by Karnofsky (age >16 years) or Lansky (age ≤16 years) score ≤30%
5. Concomitant enrolment in another clinical trial interfering with the endpoints of this study
6. Any medical condition which could compromise participation in the study according to the investigator’s assessment
7. Progression of underlying disease (disease that has led to the indication of HSCT, e.g. leukaemia) that will limit the life expectance below the duration of the study
8. Second line or experimental antiviral treatment other than Ganciclovir/Valganciclovir, Foscarnet, Cidofovir and Rituximab from Screening until 8 weeks after IMP infusion or prophylactic treatment other than Aciclovir or Letermovir throughout the study except approved by sponsor
9. Known HIV infection. In case patients do not have a negative HIV test performed within 6 months before enrolment in the study, HIV negativity has to be confirmed by a negative laboratory test
10. Female patient who is pregnant or breast-feeding, or adult of reproductive potential not willing to use an effective method of birth control from Screening until the last follow-up visit (FU6, Visit 8) Note: women of childbearing potential must have a negative serum pregnancy test at study entry
11. Known hypersensitivity to iron dextran
12. Patients unwilling or unable to comply with the protocol or unable to give informed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Percentage of patients with viral clearance (defined as two consecutive negative PCRs)
2. Percentage of patients with progression between Day 7 and Week 8 after IMP transfer

Secondary endpoints 28

1. Incidence/severity of acute GvHD ≥ grade II until Week 8 and Week 15.
2. Incidence of newly occurring acute GvHD grade I from Day 0 to Week 8 and Week 15.
3. Incidence of chronic GvHD from Day 7 to Week 8 and to Week 15 after IMP transfer.
4. Time to newly occurring acute and chronic GvHD.
5. Acute toxicity: maximum toxicity on the day of IMP transfer evaluated by measuring vital signs prior to and at different times after the IMP transfer and monitoring of specific adverse events (chills, nausea, vomiting, diarrhoea, abdominal pain, allergic reactions, respiratory dysfunction or headache from 1 hour prior to IMP transfer to 4 hours post infusion).
6. Change in viral load of underlying viral infection as assessed by quantitative PCR analysis of peripheral blood; samples taken weekly from Day 7 to Week 8 after IMP transfer as compared to samples taken at Day 0.
7. Time to 1 log change in viral load.
8. Percentage of patients with ≥1 log decrease in CMV, EBV or AdV viral load at Week 8.
9. Number of reactivations of the underlying viral infection following initial viral clearance until end of follow-up.
10. Number of patients with reduction or clearance of clinical symptoms of underlying viral infection from Day 7 to Week 8 after IMP transfer as compared to Day 0.
11. Overall survival rate (OS): From Day 0 to end of follow-up.
12. Number of days requiring antiviral chemotherapy after IMP transfer from Day 7 to Week 8 after IMP transfer.
13. Time to last administration of defined antiviral medication or switch to prophylactic treatment from Day 0 to Week 8 after IMP transfer.
14. Number of new viral reactivations (CMV, AdV or EBV) other than the underlying viral infection per patient as assessed by PCR analysis and clinical symptoms throughout the study.
15. Number of days hospitalized after IMP transfer from Day 7 to Week 8.
16. EQ-5D and FACT-BMT for adult patients (≥18 years), and PEDS-QL for paediatric patients (<18 years) at Screening and Week 8.
17. T-cell phenotyping, samples taken at Screening, Day 0 and each visit from Day 7 to Week 15 after IMP transfer.
18. Analysis of virus-specific T cells: frequencies of in vivo expanded virusspecific T cells in peripheral blood samples taken at Screening, Day 0, Day 7 to Week 15 after IMP transfer.
19. Assessment of the number and viability of CD3+ cells and percentage of IFNgamma+ cells and cellular composition in the IMP.
20. Drop-out rate at Day 0 and reasons for drop-out.
21. Number of days from Screening to Day 0 (day of IMP transfer).
22. Documentation of incidence, severity and type of adverse events from Day 0 to Week 8 and serious adverse events throughout the study.
23. Physical examination and vital signs from Screening to Week 8; Karnofsky/Lansky index will be assessed at Screening and at Week 8.
24. Laboratory values for clinical chemistry and haematology from Screening to Week 8.
25. Documentation of all concomitant medication from Screening to Week 8.
26. During follow-up Week 15, only antiviral therapy, immunosuppression and SAErelated concomitant medication as well as chemotherapy will be documented.
27. Non-therapeutic DLI has to be documented as concomitant medication (definition see exclusion criteria).
28. Treatment with T cells after Week 8 will also be documented as concomitant medication.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medical Center - University Of Freiburg

Sponsor organisation

Medical Center - University Of Freiburg

Address

Breisacher Strasse 153, Mooswald Mooswald

City

Freiburg Im Breisgau

Postcode

79110

Country

Germany

Scientific contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Prof. Dr. med. Tobias Feuchtinger

Public contact point

Organisation

Medical Center - University Of Freiburg

Contact name

Prof. Dr. med. Tobias Feuchtinger

Locations

5 EU/EEA countries · 18 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 151 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications