Cytomegalovirus - Immunoprophylactic Adoptive Cellular Therapy Study

NCT ID: NCT01077908

Last Updated: 2018-01-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 89 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-07-31
• Study Completion Date: 2014-10-31

Brief Summary

The purpose of this study is to evaluate the potential clinical benefit of prophylactic cytomegalovirus (CMV)-specific adoptive cellular therapy following T cell depleted allogeneic hematopoietic stem cell transplantation (HSCT) for reducing recurrent CMV reactivation.

Detailed Description

As with other herpes viruses, CMV infection is thought to result most frequently from reactivation of latent virus. Transmission of the virus can also occur from donor marrow infusion or from allogeneic red cell, leukocyte or platelet transfusions. In an allogeneic haematopoietic stem cell (bone marrow) transplant patient who is CMV seropositive or receiving a transplant from a donor who is CMV seropositive, CMV frequently reactivates and disease resulting from the progression of infection is a major cause of infectious morbidity and mortality. CMV infection is a consequence both of the immunosuppression these patients receive and may also reflect delayed immune reconstitution in these patients following transplant.

Existing evidence suggests that adoptive cellular therapy can be an effective approach for treating viral reactivation following allo HSCT, with a minimal risk of inducing GVHD. The major advantage to the patient is likely to be avoidance of extended periods of therapy with antiviral medications that have significant associated morbidities, and sometimes require inpatient care. A proof of efficacy in the sibling donor setting would strengthen the case for extending the therapy to the unrelated donor setting, where both potential risks and benefits are greater. From a pharmacoeconomic viewpoint, the avoidance of the costs associated with these treatment episodes could offset the costs of adoptive cellular therapy. A number of issues remain unresolved. These include the relative contributions of transferred CD4+ and CD8+ T cell populations (which may have direct relevance to the best approach for selection), the issue of whether adoptive cellular therapy improves outcomes in a randomised setting, and equally importantly, the issue of whether such immunotherapies can be delivered outside of the setting of a few academic institutions on a multicentre basis.

These considerations emphasise the importance of undertaking a randomised phase III study of prophylactic adoptive cellular therapy for CMV following T cell depleted allogeneic HSCT from a sibling donor (CMV~IMPACT). There are multiple methods for T cell depletion available, and differences between them will likely have an effect on immune reconstitution. In order to avoid this confounding influence the study will be restricted to patients receiving alemtuzumab-containing conditioning protocols.

In summary, this study is a multicentre, prospective, controlled, open-label 3 arm randomized study comparing 'best-available' standard anti-viral monitoring and therapy alone, with 'best available'anti-viral monitoring and therapy plus prophylactic adoptive cellular therapy (ACT) with cells selected by either the Gamma Catch or Multimer Selection techniques. Patients will be randomised to:

A. Standard best available antiviral drug therapy alone B. Immunoprophylactic (Day 27) ACT prepared using Gamma Catch Selection in combination with standard best available antiviral drug therapy C. Immunoprophylactic (Day 27) ACT prepared using Multimer Selection in combination with standard best available antiviral drug therapy

The study will test the hypothesis that CMV-specific ACT based upon a prescribed T-cell dose/kg recipient body weight, can augment the impaired CMV immune function post-transplant and reduce the number of recurrent reactivations in patients following a primary reactivation event (and thereby reduce the requirement for antiviral drug therapy) without causing an increase in GVHD.

Individual groups will be compared for duration of antiviral therapy and number of reactivation episodes, plus GVHD incidence. Similar analyses will be performed for adoptive cellular therapy versus no therapy (i.e. (B+C) versus A)

Conditions

Cytomegalovirus Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

ACT plus standard therapy

Adoptive Cellular Therapy (ACT) prepared using Multimer or Gamma Catch Selection in combination with standard best available antiviral drug therapy

Group Type: EXPERIMENTAL

Adoptive Cellular Therapy

Intervention Type: BIOLOGICAL

CMV-specific T-cells, single infusion at 27 days post-HSCT

Best available antiviral drug therapy

Intervention Type: DRUG

1. Intravenous ganciclovir 5mg/kg twice daily

2. Oral valganciclovir 900mg twice daily

3. Intravenous foscarnet 90 mg/kg twice daily

Best available antiviral drug therapy

Group Type: ACTIVE_COMPARATOR

Best available antiviral drug therapy

Intervention Type: DRUG

1. Intravenous ganciclovir 5mg/kg twice daily

2. Oral valganciclovir 900mg twice daily

3. Intravenous foscarnet 90 mg/kg twice daily

Interventions

Adoptive Cellular Therapy

CMV-specific T-cells, single infusion at 27 days post-HSCT

Intervention Type: BIOLOGICAL

Best available antiviral drug therapy

1. Intravenous ganciclovir 5mg/kg twice daily

2. Oral valganciclovir 900mg twice daily

3. Intravenous foscarnet 90 mg/kg twice daily

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Suitable participants will be selected from patients already scheduled to undergo a T cell depleted sibling donor HSCT. The criteria will include:
• Age 18 years or older
• Negative markers of Infectious Disease screen
• Recipient of allogeneic HSCT (that incorporates T cell depletion with alemtuzumab) who is CMV seropositive with a CMV seropositive sibling donor
• Informed consent from both donor and patient and to be assessed prior to CMV-specific T cell infusion (confirmed prior to product release):
• Donor engraftment (neutrophils > 0.5x109/l)

Exclusion Criteria

• Pregnant or lactating women
• Co-existing medical problems that would place the patient at significant risk of death due to GVHD or its sequelae
• HIV infection and to be assessed prior to CMV-specific T cell infusion (confirmed prior to product release):
• Active acute GVHD > Grade I
• Concurrent use of systemic corticosteroids
• Organ dysfunction as measured by

1. creatinine > 200 uM/l

2. bilirubin > 50 uM/l

3. ALT > 3x upper limit of normal

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Wellcome Trust

OTHER

Sponsor Role: collaborator

EMAS Pharma

INDUSTRY

Sponsor Role: collaborator

Commitum AB

INDUSTRY

Sponsor Role: collaborator

BioAnaLab

UNKNOWN

Sponsor Role: collaborator

Cell Medica Ltd

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karl S Peggs

Role: STUDY_CHAIR

University College London Hospitals

Locations

Birmingham Heartlands Hospital

Birmingham, West Midlands, United Kingdom

St James's University Hospital

Leeds, West Yorkshire, United Kingdom

Queen Elizabeth Hospital

Birmingham, , United Kingdom

Bristol Royal Hospital for Children

Bristol, , United Kingdom

Addenbrookes Hospital

Cambridge, , United Kingdom

Beatson West of Scotland Cancer Centre

Glasgow, , United Kingdom

Royal Liverpool Hospital

Liverpool, , United Kingdom

University College Hospital

London, , United Kingdom

Kings College Hospital

London, , United Kingdom

Royal Free Hospital

London, , United Kingdom

Christie Hospital

Manchester, , United Kingdom

Manchester Royal Infirmary

Manchester, , United Kingdom

City Hospital

Nottingham, , United Kingdom

Southampton General Hospital

Southampton, , United Kingdom

Countries

United Kingdom

Other Identifiers

08/H0720/15

Identifier Type: OTHER

Identifier Source: secondary_id

74928896

Identifier Type: REGISTRY

Identifier Source: secondary_id

CM-2008-01

Identifier Type: -

Identifier Source: org_study_id

NCT01115816

Identifier Type: -

Identifier Source: nct_alias