A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors
- Conditions
- SarcomaOsteosarcomaNeuroblastomaMelanoma
- Interventions
- Registration Number
- NCT02107963
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
Background
GD2 is a well-characterized tumor antigen in neuroblastoma, which is also expressed on osteosarcomas and some other sarcomas. T cells expressing 1st generation anti-GD2 chimeric antigen receptors (CARs) were safe and mediated modest antitumor activity in some patients with refractory neuroblastoma.
A 3rd generation anti-GD2-CAR (GD2-CAR.OX40.28.z.ICD9) has been produced and holds promise for increased activity compared to the 1st generation GD2-CAR already studied in clinical trials. As an added safety measure, the vector includes a suicide switch comprising a caspase dimerization domain (ICD9) that can be activated by a small molecule to induce death of the genetically engineered cells if they were induce untoward toxicity.
Objectives
Primary:Determine the feasibility of producing anti GD2-CAR cells meeting the established release criteria and to assess the safety of administering escalating doses of anti-GD2-CAR engineered T cells in children and young adults with GD2+ solid tumors, including neuroblastoma, following cyclophosphamide-based lymphodepletion.
Secondary:
1. Determine if administration anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors;
2. Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects;
3. Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults;
4. If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity; and
5. Assess toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.
Eligibility
Patients 1-35 years of age, at least 15 kg, with osteosarcoma or a GD2+ solid tumor (including neuroblastoma) that has recurred after or not responded to standard therapy and is deemed incurable by standard therapy.
Design
After apheresis to collect T cells for transduction, patients receive cyclophosphamide 1800mg/m(2)/d as a lymphodepleting regimen. A phase I cell dose escalation scheme will used at 4 dose levels (1 x 10(5) transduced T cells/kg; 1 x 10(6) transduced T cells/kg; 3 x 10(6) transduced T cells/kg; and 1 x 10(7) transduced T cells/kg), using a standard 3 plus 3 dose escalation design. An expanded group of a total of 12 patients will be treated at the highest dose, comprising at least 6 osteosarcoma patients.
Patients will be monitored for toxicity, antitumor effects and persistence of anti-GD2-CAR T cells.
Patients with a PR, SD may receive a 2nd cycle at the next higher dose level a minimum of 60 days following completion of the first cycle if eligibility criteria are met.
A maximum of 36 patients may be treated on this study. Given that there is likelihood that some patients with non-osteosarcoma will not meet the criteria for GD2 expression to be eligible for enrollment, up to 72 subjects will be screened to enroll a maximum of 36 patients for treatment. Up to 2-3 patients will be accrued per month, and therefore this study may require up to 2-3 years to complete enrollment and treatment.
- Detailed Description
Background
GD2 is a well-characterized tumor antigen in neuroblastoma, which is also expressed on osteosarcomas and some other sarcomas. T cells expressing 1st generation anti-GD2 chimeric antigen receptors (CARs) were safe and mediated modest antitumor activity in some patients with refractory neuroblastoma.
A 3rd generation anti-GD2-CAR (GD2-CAR.OX40.28.z.ICD9) has been produced and holds promise for increased activity compared to the 1st generation GD2-CAR already studied in clinical trials. As an added safety measure, the vector includes a suicide switch comprising a caspase dimerization domain (ICD9) that can be activated by a small molecule to induce death of the genetically engineered cells if they were induce untoward toxicity.
Objectives
* Primary:Determine the feasibility of producing anti GD2-CAR cells meeting the established release criteria and to assess the safety of administering escalating doses of anti-GD2-CAR engineered T cells in children and young adults with GD2+ solid tumors, including neuroblastoma, following cyclophosphamide-based lymphodepletion.
* Seconday: 1) Determine if administration of anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors; 2) Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects; 3) Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non- osteosarcoma solid tumors in children and young adults; 4) If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, assess the capacity for AP1903, a dimerizing agent, to mediate clearance of the genetically engineered cells and resolve toxicity; and 5) Assess toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.
Eligibility
Patients 1-35 years of age, at least 15 kg, with osteosarcoma or a GD2+ solid tumor (including neuroblastoma) that has recurred after or not responded to standard therapy and is deemed incurable by standard therapy.
Design
After apheresis to collect T cells for transduction, patients receive cyclophosphamide 1800mg/m(2)/d as a lymphodepleting regimen. A phase I cell dose escalation scheme will used at 4 dose levels (1 x 10(5) transduced T cells/kg; 1 x 10(6) transduced T cells/kg; 3 x 10(6) transduced T cells/kg; and 1 x 10(7) transduced T cells/kg), using a standard 3 plus 3 dose escalation design. An expanded group of a total of 12 patients will be treated at the highest dose, comprising at least 6 osteosarcoma patients.
Patients will be monitored for toxicity, antitumor effects and persistence of anti-GD2-CAR T cells.
Patients with a PR, SD may receive a 2nd cycle at the next higher dose level a minimum of 60 days following completion of the first cycle if eligibility criteria are met.
A maximum of 36 patients may be treated on this study. Given that there is likelihood that some patients with non-osteosarcoma will not meet the criteria for GD2 expression to be eligible for enrollment, up to 72 subjects will be screened to enroll a maximum of 36 patients for treatment. Up to 2-3 patients will be accrued per month, and therefore this study may require up to 2-3 years to complete enrollment and treatment.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm 1 Anti-GD2-CAR engineered T cells Dose escalation of anti-GD2 CAR T cells Arm 2 Anti-GD2-CAR engineered T cells Dose expansion of anti-GD2 CAR T cells Arm 1 AP1903 Dose escalation of anti-GD2 CAR T cells Arm 2 AP1903 Dose expansion of anti-GD2 CAR T cells Arm 1 Cyclophosphamide Dose escalation of anti-GD2 CAR T cells Arm 2 Cyclophosphamide Dose expansion of anti-GD2 CAR T cells
- Primary Outcome Measures
Name Time Method Feasibility 29 days Determine the feasibility of producing anti-GD2-CAR cells meeting the established release criteria and to assess the safety of administering escalating doses of autologous anti-GD2-CAR (anti-GD2.28.z.OX40.ICD9) engineered T cells in children and young adults with osteosarcoma and GD2+ solid tumors (excluding neuroblastoma) following cyclophosphamide based lymphodepletion.
- Secondary Outcome Measures
Name Time Method Determine antitumr effects 60 days Determine antitumr effects
Safety time of treatment Assess toxicity of AP1903
Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects 60 days Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects
Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells When needed Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells
Evaluate prevalence of GD2 expression 3 years Evaluate prevalence of GD2 expression
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States