Trial Outcomes & Findings for Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma (NCT NCT01460901)

Results Overview

Immediate: Patients were monitored following infusion to assess for toxicity related to infusion. Potential toxicities related to cellular therapy infusions, such as allergic reaction to the cellular product or cryopreservation media, hemolytic reactions, volume overload, and hemodynamic instability, were monitored. Short Term: Patients were monitored for 8 weeks for short term toxicity related to infusion. Such adverse reactions monitored were acute graft versus host disease and cytokine release syndrome.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

5 participants

Primary outcome timeframe

Post infusion week 8

Results posted on

2019-07-23

Participant Flow

Patients were consented and screened in the outpatient clinic. First consent was 10/2012 and last consent was signed 2/2014.

Patients could withdraw at their discretion or were withdrawn for rapid disease progression.

Participant milestones

Participant milestones
Measure	Treatment Single arm study - GD2-CAR modified Tri-virus specific cytotoxic T-cell Infusion
Overall Study STARTED	5
Overall Study tV-CTL Infusion	3
Overall Study COMPLETED	3
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Treatment Single arm study - GD2-CAR modified Tri-virus specific cytotoxic T-cell Infusion
Overall Study Withdrawal by Subject	2

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GD2 CAR Modified Tri-virus CTL n=5 Participants This is a feasibility study to assess safety of an infusion of chimeric-antigen receptor gene modified allogeneic virus specific T lymphocytes after reduced intensity allogeneic stem cell transplant. The intent is to treat three patients and evaluate safety. A single infusion of 2 million cells per meter squared was dosed. Tri-virus specific cytotoxic t-cells: Infusion of donor derived tri-virus specific cytotoxic t-cell post allogeneic stem cell transplantation
Age, Categorical <=18 years	5 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	7.7 years STANDARD_DEVIATION 1.9 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants
Region of Enrollment United States	5 participants n=5 Participants

PRIMARY outcome

Timeframe: Post infusion week 8

Immediate: Patients were monitored following infusion to assess for toxicity related to infusion. Potential toxicities related to cellular therapy infusions, such as allergic reaction to the cellular product or cryopreservation media, hemolytic reactions, volume overload, and hemodynamic instability, were monitored. Short Term: Patients were monitored for 8 weeks for short term toxicity related to infusion. Such adverse reactions monitored were acute graft versus host disease and cytokine release syndrome.

Outcome measures

Outcome measures
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 Participants Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks Immediate Infusion Toxicity	0 Participants
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks Short Term Toxicity (Week 8)	0 Participants
Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks No Toxicity	3 Participants

PRIMARY outcome

Timeframe: 1 year

Population: Evaluable patients

Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.

Outcome measures

Outcome measures
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 Participants Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Peak Transgene Copy Number Per 1000ng PBMC DNA Participant 1	10562 Transgene Copy per 1000ng PBMC DNA
Peak Transgene Copy Number Per 1000ng PBMC DNA Participant 3	44 Transgene Copy per 1000ng PBMC DNA
Peak Transgene Copy Number Per 1000ng PBMC DNA Participant 5	1464 Transgene Copy per 1000ng PBMC DNA

PRIMARY outcome

Timeframe: 8 weeks

Outcome measures

Outcome measures
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 Participants Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Death Within 8 Weeks of Infusion	1 participants

SECONDARY outcome

Timeframe: up to 1 year

The following analyses were performed on peripheral blood samples from patients at protocol assigned time points (pre-infusion, post-infusion at 4 hrs, weeks 1,2,4,6 and 8, month 3, 6 and 12: ELISPOT assay for CMV, Adenovirus and EBV specific CTL reported as SFU (spot forming unit) per 2x10e5 mononuclear cells

Outcome measures

Outcome measures
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 Participants Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well Participant 1	180 SFU/2x10e5 Mononuclear Cells
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well Participant 3	175 SFU/2x10e5 Mononuclear Cells
Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well Participant 5	150 SFU/2x10e5 Mononuclear Cells

SECONDARY outcome

Timeframe: 1 year

Pre and post-therapy evaluation by modalities consistent with prior disease evaluation in each patient. When possible, tumors were assessed per Response Evaluation Criteria In Solid Tumors (RECIST v1.0): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>/=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD) neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Bone marrow aspirations and biopsies were evaluated by histopathology and appropriate immunohistochemistry; Modified Curie score was used for MIBG evaluation.

Outcome measures

Outcome measures
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 Participants Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Maximum Tumor Response (RECIST 1.1) Complete Response	0 Response
Maximum Tumor Response (RECIST 1.1) Non-complete Response	3 Response
Maximum Tumor Response (RECIST 1.1) Progressive Disease	0 Response

Adverse Events

GD2 CAR Modified Tri-virus CTL Infusion

Serious events: 3 serious events

Other events: 2 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 participants at risk This was a single-center, investigator-initiated, single-arm, pilot study of post-allogeneic transplant, adoptive immunotherapy for the treatment of patients with relapsed/refractory neuroblastoma expressing the mesenchymal tumor marker GD2. Three patients were treated. Patients received infusion of tri-virus cytotoxic T-lymphocytes, transduced with a first generation GD2 targeted chimeric antigen receptor (tvs-CTL). Infusion of the tvs-CTL was performed 30 to 120 days after reduced intensity, mismatched related donor, CD34 selected peripheral blood stem cell transplant on a separate clinical trial. The tvs-CTL were derived from the stem cell transplant donor. Patients were monitored for safety of the allogeneic tvs-CTL at infusion and for adverse events such as graft vs host disease and insertional mutagenesis/carcinogenesis related to the gene transduction.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Death	100.0% 3/3 • Number of events 3 • Adverse event data was collected over 1 year. 3 patients were treated. All 3 patients died of disease with the last patient dying 324 days after infusion

Other adverse events

Other adverse events
Measure	GD2 CAR Modified Tri-virus CTL Infusion n=3 participants at risk This was a single-center, investigator-initiated, single-arm, pilot study of post-allogeneic transplant, adoptive immunotherapy for the treatment of patients with relapsed/refractory neuroblastoma expressing the mesenchymal tumor marker GD2. Three patients were treated. Patients received infusion of tri-virus cytotoxic T-lymphocytes, transduced with a first generation GD2 targeted chimeric antigen receptor (tvs-CTL). Infusion of the tvs-CTL was performed 30 to 120 days after reduced intensity, mismatched related donor, CD34 selected peripheral blood stem cell transplant on a separate clinical trial. The tvs-CTL were derived from the stem cell transplant donor. Patients were monitored for safety of the allogeneic tvs-CTL at infusion and for adverse events such as graft vs host disease and insertional mutagenesis/carcinogenesis related to the gene transduction.
Infections and infestations Fever	66.7% 2/3 • Number of events 2 • Adverse event data was collected over 1 year. 3 patients were treated. All 3 patients died of disease with the last patient dying 324 days after infusion

Additional Information

Dr. Gary Douglas Myers

Children's Mercy Hospitals and Clinics

Phone: 8163026817

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place