STALLONe: Study of Donor Derived, Multi-virus-specific, Cytotoxic T-Lymphocytes for Relapsed/Refractory Neuroblastoma

• Sponsor: Children's Mercy Hospital Kansas City (Other)
• Overall Status: Completed
• CT.gov ID: NCT01460901
• Collaborator: Center for Cell and Gene Therapy, Baylor College of Medicine (Other)
• Enrollment: 5
• Location: 1
• Arm: 1
• Duration (Months): 27
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is 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 will be treated. The study will focus on the safety and efficacy of allogeneic, donor derived viral specific cytotoxic T-lymphocytes, retrovirally transduced to express a chimeric antigen receptor specific for disialoganglioside, GD2, expressed on neuroblastoma.

Condition or Disease	Intervention/Treatment	Phase
Neuroblastoma	Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells	Phase 1

Detailed Description

Neuroblastoma (NB) is the most common extracranial tumor of childhood and prognosis for patients with relapsed or refractory disease is < 10% and there is no standard therapy for these patients. Research toward immunotherapeutic agents has intensified as monoclonal antibody targeting GD2, when incorporated into upfront NB therapy, prolongs survival. Allogeneic Hematopoietic stem cell transplantation (HSCT) has been utilized in patients with NB with evidence of a graft versus tumor (GVT) effect but transplant related mortality (TRM) has nullified the survival benefit. In an effort to harness the GVT effect of allogeneic transplant and lower TRM, harvested viral specific cytotoxic T-cells from the donor will be infused early post-HSCT to the HSCT recipient to shorten the recovery of immunity toward the most significant viral infections. The investigators will also retrovirally transduce the viral specific CTL with a chimeric antigen receptor (CAR) gene complex such that the tV-CTL can expand, via their native T-cell receptors in response to viral infections post-HSCT and carry the capability of killing tumor cells through their transduced receptor which, on the extracellular component of the CAR, has specificity for GD2 expressed on the surface of NB. In essence, the investigators intend to take the specificity of the monoclonal antibody to GD2, already utilized in therapy for NB, and combine this specificity with the cytotoxicity of T-cells to target NB. The investigators hypothesize that the infusion will be safe and viral specificity of the tV-CTL will provide long term immunity to both viral infections and the investigators will see anti-tumor effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 5 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I Study of Donor Derived,Gene Modified, Multi-virus-specific, Cytotoxic T-Lymphocytes Redirected to GD2 for Relapsed/Refractory Neuroblastoma Post-allo Stem Cell Transplantation With Submyeloblative Conditioning
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Jan 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: GD2 CAR modified Tri-virus CTL infusion A single infusion of 2x10e6 cells per meter squared was performed 30 to 120 days following allogeneic stem cell transplant.

Biological: GD2 CAR modified Tri-virus specific cytotoxic t-cells; 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. Three patients were treated and safety was evaluated. Patients received a single infusion of 2x10e6/m2 donor derived, GD2 CAR modified, tri-virus specific CTL performed 30-120 days after allogeneic stem cell transplantation

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks [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.

2. Peak Transgene Copy Number Per 1000ng PBMC DNA [1 year]

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

3. Death Within 8 Weeks of Infusion [8 weeks]

Secondary Outcome Measures

1. Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well [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

2. Maximum Tumor Response (RECIST 1.1) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Months to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Allogeneic transduced tV-CTLs with >15% expression of 14g2a.zeta chimeric antigen receptor

• Patient or responsible person must be able to understand and sign a permission/assent or consent form for infusion

• Age 18 months through 17 years at time of relapse/progression

• Life expectancy >8weeks

• Karnofsky score 60% or greater if 10 yrs old or older. Lansky score 60% or greater if under 10 yrs old

• Patient must be HIV negative

• ANC >500

• Pulse ox>90% on room air

• AST/ALT/direct bili <5x upper limit of normal

• Recovered from toxic effects of all prior chemotherapy

• Absence of human/anti-mouse antibody (HAMA) (patients who have received prior therapy with murine antibodies)

• 50% donor engraftment

Exclusion Criteria:

• Patient pregnant or lactating or refuses birth control methods

• HIV positive

• Uncontrolled intercurrent infection

• Renal failure (creatinine clearance <40ml/min/1.73m2)

• Active hepatitis or cirrhosis with bilirubin, AST, ALT >5xnormal

• Rapidly progressive disease

• Currently receiving any investigational drugs

• Tumor potentially causing airway obstruction

• Cardiomegaly or bilateral pulmonary infiltrates on CXR

• Receiving >0.25mg/kg/day methylprednisolone or equivalent systemic steroid. Topical steroid therapy is acceptable

• Receiving more than one lymphocyte inhibiting agent (ex. Tacrolimus/CSA and MMF or other similar agent

• Patients relapsing or progressing before the age of 18 months from Stage I/II disease, and/or those who, in the opinion of their oncologist, may benefit from further conventional therapy

• Donor lymphocyte infusion in last 28 days

• Evidence of GvHD greater than or equal to grade 2

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Mercy Hospital	Kansas City	Missouri	United States	64108

Sponsors and Collaborators

• Children's Mercy Hospital Kansas City
• Center for Cell and Gene Therapy, Baylor College of Medicine

Investigators

• Principal Investigator: Doug Myers, MD, Children's Mercy Hospital Kansas City

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Children's Mercy Hospitals and Clinics

Publications

None provided.

• Responsible Party: Doug Myers, Principal Investigator, Children's Mercy Hospital Kansas City
• ClinicalTrials.gov Identifier: NCT01460901
• Other Study ID Numbers: STALLONe; 00038
• First Posted: Oct 27, 2011
• Last Update Posted: Jul 23, 2019
• Last Verified: Jul 1, 2019

• Keywords provided by Doug Myers, Principal Investigator, Children's Mercy Hospital Kansas City: Neuroblastoma; Relapsed; Refractory
• Additional relevant MeSH terms: Neuroblastoma

Study Results

Participant Flow

Recruitment Details	Patients were consented and screened in the outpatient clinic. First consent was 10/2012 and last consent was signed 2/2014.
Pre-assignment Detail	Patients could withdraw at their discretion or were withdrawn for rapid disease progression.

Arm/Group Title	Treatment
Arm/Group Description	Single arm study - GD2-CAR modified Tri-virus specific cytotoxic T-cell Infusion
Period Title: Overall Study
STARTED	5
tV-CTL Infusion	3
COMPLETED	3
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	GD2 CAR Modified Tri-virus CTL
Arm/Group Description	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
Overall Participants	5
Age (Count of Participants)
<=18 years	5 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.7 (1.9)
Sex: Female, Male (Count of Participants)
Female	2 40%
Male	3 60%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United States	5 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Immediate and Short Term Toxicity of Infusion Over 8 Weeks
Description	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.
Time Frame	Post infusion week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GD2 CAR Modified Tri-virus CTL Infusion
Arm/Group Description	Single arm study - Single infusion of 2x10e6 GD2 CAR modified tri-virus CTL following allogeneic stem cell transplant
Measure Participants	3
Immediate Infusion Toxicity	0 0%
Short Term Toxicity (Week 8)	0 0%
No Toxicity	3 60%

2. Primary Outcome

Title	Peak Transgene Copy Number Per 1000ng PBMC DNA
Description	Peak Transgene Copy Number per 1000ng PBMC DNA from peripheral blood samples measured during study participation.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Evaluable patients

Arm/Group Title	Treatment
Arm/Group Description	Single arm study - GD2 CAR Tri-virus CTL infusion
Measure Participants	3
Participant 1	10562
Participant 3	44
Participant 5	1464

3. Primary Outcome

Title	Death Within 8 Weeks of Infusion
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Single arm study - GD2 CAR Tri-virus CTL infusion
Measure Participants	3
Number [participants]	1 20%

4. Secondary Outcome

Title	Peak Viral Specific SFU/2x10e5 Mononuclear Cells Per Well
Description	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
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Single arm study - GD2 CAR modified tri-virus specific CTL infusion
Measure Participants	3
Participant 1	180
Participant 3	175
Participant 5	150

5. Secondary Outcome

Title	Maximum Tumor Response (RECIST 1.1)
Description	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.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment
Arm/Group Description	Single arm study - treatment
Measure Participants	3
Complete Response	0
Non-complete Response	3
Progressive Disease	0

Adverse Events

Time Frame	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
Arm/Group Title	GD2 CAR Modified Tri-virus CTL Infusion
Arm/Group Description	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.
All Cause Mortality
	GD2 CAR Modified Tri-virus CTL Infusion
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Serious Adverse Events
	GD2 CAR Modified Tri-virus CTL Infusion
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death	3/3 (100%)	3
Other (Not Including Serious) Adverse Events
	GD2 CAR Modified Tri-virus CTL Infusion
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Infections and infestations
Fever	2/3 (66.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.