Clinical Trials Logo

Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT01570283
Other study ID # H-29966 ARMS
Secondary ID
Status Completed
Phase Phase 1/Phase 2
First received
Last updated
Start date September 2012
Est. completion date September 2017

Study information

Verified date April 2019
Source ViraCyte
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

The subjects eligible for this trial have a type of blood cell cancer, other blood disease or a genetic disease for which they will receive a stem cell transplant. The donor of the stem cells will be either the subject's brother or sister, or another relative, or a closely matched unrelated donor. The Investigators are asking subjects to participate in this study which tests if blood cells from the subject's donor that have been grown in a special way, can prevent or be a effective treatment for early infection by five viruses - Epstein Barr virus (EBV), cytomegalovirus (CMV), adenovirus, BK virus (BKV) and human herpes virus 6 (HHV6).

The Investigators have grown T cells from the subject's stem cell donor in the laboratory in a way that will train them to recognize the viruses and control them when the T cells are given after a transplant. This treatment with specially trained T cells (also called cytotoxic T cells or "CTLs") has had activity against three of these viruses (CMV, EBV and Adenovirus) in previous studies. In this study the Investigators want to see if they increase the number of viruses that can be targeted to include BKV and HHV6 using a simple and fast approach to make the cells.

The Investigators want to see if they can use a kind of white blood cell called T lymphocytes (or T cells) to prevent and treat adenovirus, CMV, EBV, BKV and HHV6 in the early stages of reactivation or infection.


Description:

To make the CTLs, subject's donors' cells were mixed with small pieces of proteins, called peptides that come from adenovirus, CMV, EBV, BKV and HHV6. These peptides stimulate donor T cells that react against the viruses to grow and train the donor T cells to kill cells that are infected with CMV, EBV, adenovirus, BKV and HHV6. Once sufficient numbers of T cells were made, they were tested to make sure they would target the cells infected with these viruses but not the normal cells. Then the cells were frozen.

When the Investigators think the subject needs them, the subject's donor's CTL cells will be thawed and injected into the intravenous line. To prevent an allergic reaction, prior to receiving the CTLs the subject may be given diphenhydramine (Benadryl) and acetaminophen (Tylenol). After the subject receives the cells, Investigators will monitor the levels of these five viruses in the blood. They will also take blood to see how long the T cells they gave the subject are lasting in the body.

If the CTL infusion has helped the subjects infection or if they have had a treatment, for example with steroid drugs that might have destroyed the T cells the subject was given, then they are allowed to receive up to 2 more doses of the cells.

The first part of this study was a dose escalation study. That means that at the beginning, patients were started on the lowest dose (1 of 3 different levels) of T cells. The next group of patients were started at a higher dose. This process continued until all 3 dose levels were studied. They would now like to enroll more patients at the highest dose level to get more information about how the T cells work.

Subjects will continue to be followed by their transplant doctors after the injection. The subject will either be seen in the clinic or they will be contacted by a research nurse to follow up for this study every week for 6 weeks then at 8 week and 3, 6 and 12 months. The subject may have other visits for their standard care. Subjects will also have regular blood tests done to follow their counts and the viral infection. To learn more about the way the T cells are working in the body, up to an extra 30-40 ml (6-8 teaspoons) of blood will be taken before the infusion and then at 1, 2, 4, 5, 6 and 8 weeks and 3 months. Blood should come from the central intravenous line, and should not require extra needle sticks.

If subjects experience a positive response or are taking medicines (such as steroids) that may affect how long T cells stay in the body, they may be able to receive up to two additional doses of the T cells at the same initial dose level from 28 days after their initial dose. After each T-cell infusion, they will be monitored as described above.

Study Duration: Subjects will be on study for approximately one year. If they receive additional doses of the T cells as described above, they will be followed until 1 year after their last dose of T-cells.


Recruitment information / eligibility

Status Completed
Enrollment 21
Est. completion date September 2017
Est. primary completion date August 2016
Accepts healthy volunteers No
Gender All
Age group N/A and older
Eligibility Inclusion Criteria:

Patients will be eligible following any type of allogeneic transplant to receive CTLs as prevention or for early reactivations as defined below.

1. Prior myeloablative or non-myeloablative allogeneic hematopoietic stem cell transplant using either bone marrow or peripheral blood stem cells within 12 months.

2. Prevention for patients at risk of CMV, adenovirus, EBV, BK virus, or HHV6 infection

3. Treatment of reactivation or infection which is defined for each virus as below

- CMV- CMV antigenemia is monitored at least weekly post transplant. Reactivation is defined at CMV antigenemia with <10 leukocytes positive or elevated PCR. If any patient develops CMV antigenemia with >10 leukocytes positive or clinical evidence of CMV infection (defined as the demonstration of CMV by biopsy specimen from visceral sites (by culture or histology) either pre or after CTL infusions, standard treatment with Ganciclovir, and/or Foscarnet and Immunoglobulins will be initiated. Patients may receive CTLs for antigenemia or elevated PCR without visceral infection.

- Adenovirus- Adenovirus infection will be defined as the presence of adenoviral positivity as detected by PCR or culture from ONE site such as stool or blood or urine or nasopharynx.

Adenovirus disease will be defined as the presence of adenoviral positivity as detected by culture from more than two sites such as stool or blood or urine or nasopharynx.

In patients who meet the criteria for disease Cidofovir may be added unless the subject could not tolerate this agent due to nephrotoxicity. Patients may receive CTLs for elevated PCR in blood or stool.

- EBV- EBV-LPD is defined according to recent guidelines as proven EBV-LPD defined by biopsy or probable EBV-LPD defined as an elevated EBV DNA level associated with clinical symptoms (adenopathy or fever or masses on imaging) but without biopsy confirmation. Patients with EBV DNA reactivation only may receive CTLs on study. Patients with proven or probable EBV-LPD should also receive Rituxan

- BK virus- Patients post transplant may develop asymptomatic BKV viruria or viremia. BK reactivation will be defined as detection of elevated BK levels by PCR in blood or urine while disease will be defined as detection in multiple sites or in one site with symptoms. Cidofovir has been administered intravenously in a low dose (i.e. up to 1 mg/kg 3 times weekly, without probenecid) or a high dose (ie, 5 mg/kg per week with probenecid) to HSCT patients with BK infections but no randomized trials are available proving its clinical efficacy. In patients who meet the criteria for disease Cidofovir may be added unless the subject could not tolerate this agent due to nephrotoxicity.

- HHV6- HHV6 reactivation will be defined as detection of elevated HHV6 levels by PCR in blood while disease will be defined as detection in multiple sites or in one site with symptoms. Ganciclovir, Cidofovir, and foscarnet have variable in vitro activity against HHV-6, and may have a role in treating HHV-6-associated disease - hence one or more of these agents will be added in patients with disease.

4. Treatment may be given to eligible patients with a single or multiple infections. Patients with multiple infections with one or more reactivation and one or more controlled infection are eligible to enroll.

5. Clinical status at enrollment to allow tapering of steroids to less than 0.5 mg/kg/day prednisone.

6. Karnofsky/Lansky score of = 50

7. ANC greater than 500/µL.

8. Bilirubin </= 2x upper limit normal

9. AST </= 3 x upper limit normal

10. Serum creatinine </= 2 x upper limit normal

11. HgB > 8.0

12. Pulse oximetry of > 90% on room air

13. Available multivirus-specific CTLs

14. Negative pregnancy test in female patients if applicable (childbearing potential who have received a reduced intensity conditioning regimen).

15. Written informed consent and/or signed assent line from patient, parent or guardian.

Exclusion Criteria:

1. Patients receiving ATG, or Campath or other immunosuppressive T cell monoclonal antibodies within 28 days of screening for enrollment.

2. Patients with other uncontrolled infections. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to enrollment. For fungal infections patients must be receiving definitive systemic anti-fungal therapy and have no signs of progressing infection for 1 week prior to enrollment.

Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.

3. Patients who have received donor lymphocyte infusion (DLI) within 28 days.

4. Patients with active acute GVHD grades II-IV.

5. Active and uncontrolled relapse of malignancy

Study Design


Intervention

Biological:
Multivirus-specific T cells Dose Level 1
The feasibility and safety of 3 different dose levels will be evaluated and will determine the maximum tolerated dose (MTD) level. Dose Level One: 5x10^6 mCTLs/m2 There may be an option of administering 2 additional doses (at the same level the patient was receiving), 28 days after the first dose, in subjects that have a partial response after one dose or who receive other therapy that may affect the persistence or function of the infused CTL.
Multivirus-specific T cells Dose Level 2
The feasibility and safety of 3 different dose levels will be evaluated and will determine the maximum tolerated dose (MTD) level. Dose Level Two: 1x10^7 mCTLs/m2 There may be an option of administering 2 additional doses (at the same level the patient was receiving), 28 days after the first dose, in subjects that have a partial response after one dose or who receive other therapy that may affect the persistence or function of the infused CTL
Multivirus-specific T cells Dose Level 3
The feasibility and safety of 3 different dose levels will be evaluated and will determine the maximum tolerated dose (MTD) level. Dose Level Three: 2x10^7 mCTLs/m2 There may be an option of administering 2 additional doses (at the same level the patient was receiving), 28 days after the first dose, in subjects that have a partial response after one dose or who receive other therapy that may affect the persistence or function of the infused CTL

Locations

Country Name City State
United States Houston Methodist Hospital Houston Texas
United States Texas Children's Hospital Houston Texas

Sponsors (4)

Lead Sponsor Collaborator
ViraCyte Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital System

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Primary Number of Participants With a DLT DLT is defined as acute GvHD grades III-IV within 42 days of the last dose of CTLs, # of patients with Grade 3-5 infusion-related adverse events within 30 days of the last dose of CTLs, and # of patients with Grade 4-5 non-hematological adverse events within 30 days of the last dose of CTLs. GVHD grade III-IV scoring is based on the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) GVHD scoring stamp or equivalent. Grade 3-5 infusion-related adverse events and Grade 4-5 non-hematological adverse events are graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.X. 42 days
Secondary Percentage of Patients Who Have a Response in Anti-viral Activity Percentage of patients who have a response in anti-viral activity that is defined as a viral load reduction to the normal level for at least one of the five virus types 42 days
Secondary Percentage Change of Viral Load From Baseline to Follow-up Percentage change of viral load by PCR from baseline to follow-up. A positive number indicates a percentage decrease and a negative number indicates a percentage increase. 3 months
Secondary Median Peak Frequency of Specific T Cells Post-infusion Median peak frequency of specific T cells as measured by Elispot to assess reconstitution of antiviral immunity. 3 months
See also
  Status Clinical Trial Phase
Recruiting NCT05568953 - An Experimental Medicine Decipher of a Minimum Correlate of Cellular Immunity Phase 2
Not yet recruiting NCT05902702 - Isotonic Saline for Children With Bronchiolitis N/A
Not yet recruiting NCT05953233 - School Inner City Air Study N/A
Not yet recruiting NCT01159470 - The Rate of C-reactive Protein (CRP) Increase as a Marker for Bacterial Infections in Children N/A
Recruiting NCT02532452 - Third Party Viral Specific T-cells (VSTs) Phase 2
Recruiting NCT05246098 - REVIVe: Frailty, Rehabilitation, and Outcomes in Critically Ill Adult and Pediatric Survivors of COVID-19 or ARI
Recruiting NCT05603650 - Effects of Mouthrinses on the Microbiome of the Oral Cavity and GI Tract N/A
Completed NCT04525456 - Immune Responses With Reduxium N/A
Completed NCT04643678 - Anakinra in the Management of COVID-19 Infection Phase 2/Phase 3
Completed NCT03189537 - Study of Post-Exposure Ingavirin® Prophylaxis of Influenza and Acute Respiratory Viral Infections Phase 3
Completed NCT04267809 - Modulate Cellular Stress in the Immune Cells to Reduce Rate of Symptomatic Viral Infection Phase 2
Completed NCT00341081 - Validation of Self-Reported Needle Sharing Among Injection Drug Users N/A
Recruiting NCT04088916 - Proviral DNA as a Target for HIV-1 Resistance Analysis
Terminated NCT04401410 - Anti-SARS Cov-2 T Cell Infusions for COVID 19 Phase 1
Terminated NCT00952185 - Influenza Vaccine in Preventing Flu in Patients Who Have Undergone Stem Cell Transplant and in Healthy Volunteers N/A
Recruiting NCT06149494 - RCT of Vapendavir in Patients With COPD and Human Rhinovirus/Enterovirus Upper Respiratory Infection Phase 2
Active, not recruiting NCT04254991 - A Controlled, Blinded Study to Validate the Diagnostic Accuracy and Assess the Clinical Utility of a Host-response Based Diagnostic Tool for Distinguishing Between Bacterial and Viral Etiologies in Pediatric Patients Presenting to the ED With Suspicion of Acute Infection
Completed NCT05897801 - Distinguishing Bacterial and Viral Infections by MeMed BV® Test to Limit Gut Colonization by MDRO
Terminated NCT02696291 - Safety and Pharmacokinetics of UV-4B Solution Administered Orally as Multiple Ascending Doses to Healthy Subjects Phase 1
Recruiting NCT02456610 - Administration of Virus Specific CTLs for the Prophylaxis and Treatment of EBV/CMV Infections After HSCT in China Phase 1