Cytomegalovirus - Immunoprophylactic Adoptive Cellular Therapy Study (CMV-IMPACT)

• ClinicalTrials.gov Identifier: NCT01077908
• Recruitment Status: Completed
• First Posted: March 1, 2010
• Last Update Posted: January 25, 2018
• Sponsor: Cell Medica Ltd
• Collaborators: Wellcome Trust; EMAS Pharma; Commitum AB; BioAnaLab
• Information provided by (Responsible Party): Cell Medica Ltd

Tracking Information

• First Submitted Date: February 26, 2010
• First Posted Date: March 1, 2010
• Last Update Posted Date: January 25, 2018
• Study Start Date: July 2008
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 26, 2010): CMV reactivations [ Time Frame: Six months ]
• Original Primary Outcome Measures: Same as current
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cytomegalovirus - Immunoprophylactic Adoptive Cellular Therapy Study
• Official Title: A Phase III Randomised Study to Investigate the Use of Adoptive Cellular Therapy (ACT) in Combination With Conventional Antiviral Drug Therapy for the Treatment of CMV Reactivation Episodes in Patients Following Allogeneic Haematopoietic Stem Cell Transplant
• 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)

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Cytomegalovirus Infection

Intervention

• Biological: Adoptive Cellular Therapy
  CMV-specific T-cells, single infusion at 27 days post-HSCT
• Drug: 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

Study Arms

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

  • Biological: Adoptive Cellular Therapy
  • Drug: Best available antiviral drug therapy
• Active Comparator: Best available antiviral drug therapy
  Intervention: Drug: Best available antiviral drug therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 23, 2018): 89
• Original Estimated Enrollment (submitted: February 26, 2010): 110
• Actual Study Completion Date: October 2014
• Actual Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT01077908
• Other Study ID Numbers: CM-2008-01; 08/H0720/15 ( Other Identifier: REC ); 74928896 ( Registry Identifier: ISRCTN )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Cell Medica Ltd
• Original Responsible Party: Karen Hodgkin, Cell Medica Ltd
• Current Study Sponsor: Cell Medica Ltd
• Original Study Sponsor: Same as current

Collaborators

• Wellcome Trust
• EMAS Pharma
• Commitum AB
• BioAnaLab

Investigators

• Study Chair: Karl S Peggs; University College London Hospitals

• PRS Account: Cell Medica Ltd
• Verification Date: January 2018