SarcomaPhase 1NCT02107963
A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors
A Phase 1 study testing Anti-GD2-CAR engineered T cells, AP1903 and Cyclophosphamide in people with Sarcoma and Osteosarcoma, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 1 year to 35 years
- Conditions the study is for
- Sarcoma, Osteosarcoma, Neuroblastoma
- What is being tested?
- Anti-GD2-CAR engineered T cells, AP1903 and Cyclophosphamide
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 15 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Feb 2014to 31 Jan 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 35 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Diagnosis
- Osteosarcoma, neuroblastoma and melanoma that have been treated with standard frontline therapy and are judged to be incurable with standard therapy, based upon the fact that they are unresectable, metastatic, progressive/persistent or recurrent.
- Evaluable disease must be present.
- For all histologies except osteosarcoma and neuroblastoma, pathologic review of frozen tissue must document GD2+ expression. Positive expression is defined as at least 2+ expression (0-4+ scale) in >50 percent of the tumor cells using anti-GD2 mAb 14G2a. If adequate archived frozen tissue is available, this may be utilized, or if not, patients may undergo biopsy following enrollment to obtain tissue to assess GD2 expression, with the following restrictions.
- Patients with histologies other than osteosarcoma or neuroblastoma must have adequate accessible tumor for biopsy (at least 1 cm diameter).
- Procedures employed to acquire biopsies for tumor lysates will be limited to percutaneous needle or core biopsies, thoracoscopic excision or open biopsies of readily accessible lesions. Pulmonary lesions may be biopsied but extensive surgery such as thoracotomy or laparotomy should not be employed.
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- Patients who will require biopsy should not be enrolled if in the opinion of the principal investigator, the tumor site places the patient at substantial risk from the biopsy procedure.
- Weight greater than or equal to 15 kg
- Age less than or equal to 35 years old at the time of enrollment.
- Prior Therapy:
- The patient s malignancy must have relapsed after or failed to respond to frontline curative therapy and/or there must not be any curative treatment options available at the time of study entry.
- There is no limit to the number of prior treatment regimens. However, patients must have fully recovered from the acute toxic effects of prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less.
- Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea).
- Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim.
- At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinease inhibitor or a metronomic nonmyelosuppressive regimen.
- Monoclonal antibodies: At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody.
- Radiotherapy: 3 weeks must have elapsed since XRT
- Performance status:
- ECOG 0, 1 or 2, or for children less than or equal to 10 years of age, Lansky greater than or equal to 60.
- Cardiac function:
- Left ventricular ejection fraction greater than or equal to 40 percent or fractional shortening greater than or equal to 28 percent.
- Liver function:
- Serum total bilirubin < 2 mg/dl, serum AST and ALT less than or equal to 3 x upper limit of normal. Patients with Gilbert s syndrome are excluded from the requirement of a normal bilirubin and patients will not be excluded if liver enzyme elevation is due to tumor involvement. (Gilbert s syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). NOTE: Adult values will be used for calculating hepatic toxicity and determining eligibility, as is standard on POB phase I trials.
- Renal function:
- Age-adjusted normal serum creatinine according to the following table or a creatinine clearance greater than or equal to 60 ml/min/1.73 m(2).
- Age less than or equal to 5 Maximum serum creatinine (mg/dl) 0.8
- Age greater than 5 and less than or equal to 10 Maximum serum creatinine (mg/dl) 1.0
- Age greater than 10 and less than or equal to 15 Maximum serum creatinine (mg/dl) 1.2
- Age greater than 15 Maximum serum creatinine (mg/dl) 1.5
- Marrow function:
- ANC must be > 750/mm(3), platelet count must be greater than or equal to 75,000/mm(3) (not achieved by transfusion).
- Ability to give informed consent.
- For patients <18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in age-appropriate discussion in order to obtain verbal assent.
- Durable power of attorney form offered (patients (Bullet)18 years of age only).
- Birth Control
- Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential.
- Both men and women of all races and ethnic groups are eligible for this trial.
Who cannot join
- Concurrent Illnesses
- Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would compromise the patient s ability to tolerate protocol therapy or significantly increase the risk of complications.
- Peripheral nerve symptoms from prior therapies or from tumor compression > grade 1.
- Untreated CNS metastasis
- Extradural masses that have not invaded the brain parenchyma or parameningeal tumors without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
- Prior Therapy
Show all 11Show fewer
- Previous treatment with genetically engineered GD2-CAR T cells. Previous vaccine therapy, anti-GD2 mAb therapy or therapy with other genetically engineered T cells is not an exclusion criteria.
- Lactating or pregnant females (due to risk to fetus or newborn).
- Active HIV, HBV or HCV infection.
- Immune Therapies
- Patients who require systemic corticosteroid or other immunosuppressive therapy. Immunosuppressive therapy must be stopped at least 14 days prior to cell infusion.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
About this study
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.
Read more
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:
- Determine if administration anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors;
- Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects;
- Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults;
- 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
- 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.
Read the 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.
- Conditions
- Sarcoma, Osteosarcoma, Neuroblastoma, Melanoma
- Being tested
- Anti-GD2-CAR engineered T cells, AP1903, Cyclophosphamide
- Keywords
- GD2-Expressing Tumors, Anti-GD2 Chimeric Antigen Receptor, Osteosarcoma, Adoptive Immunotherapy, Sarcomas
- Medical subject headings
- Sarcoma, Osteosarcoma, Neuroblastoma, Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Anti-GD2-CAR engineered T cellsBiological
Administer anti-GD2 CAR T cells 1 x 105 transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg
AP1903Drug
If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, AP1903, a dimerizing agent, may be administered to mediate clearance of the genetically engineered cells and resolve toxicity
CyclophosphamideDrug
1800mg/m2/d X 2 days as a lymphodepleting regimen
| Study group | Role | What they receive |
|---|---|---|
| Arm 1 | Experimental | Dose escalation of anti-GD2 CAR T cells Receives: Biological: Anti-GD2-CAR engineered T cells; Drug: AP1903; Drug: Cyclophosphamide |
| Arm 2 | Experimental | Dose expansion of anti-GD2 CAR T cells Receives: Biological: Anti-GD2-CAR engineered T cells; Drug: AP1903; Drug: Cyclophosphamide |
What is being measured
The primary outcome is the main question the study is designed to answer.
Feasibility
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.
Measured: 29 days
Secondary outcomes (5)
Determine antitumr effects
Determine antitumr effects
Measured: 60 days
Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects
Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects
Measured: 60 days
Evaluate prevalence of GD2 expression
Evaluate prevalence of GD2 expression
Measured: 3 years
Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells
Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells
Measured: When needed
Safety
Assess toxicity of AP1903
Measured: time of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2014 (estimated)
- Study start28 Feb 2014
- Primary completion15 Aug 2016
- Study completion31 Jan 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for SarcomaStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Rosandra N Kaplan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02107963
- Sponsor's protocol ID
- 140059
- Other IDs
- 14-C-0059
- Status last verified
- May 2024
- First submitted
- 5 Apr 2014
- Last updated
- 16 May 2024
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: .All IPD recorded in the medical record will be shared with intramural investigators upon request
Publications
Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
PubMed 20879881Lee DW, Barrett DM, Mackall C, Orentas R, Grupp SA. The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer. Clin Cancer Res. 2012 May 15;18(10):2780-90. doi: 10.1158/1078-0432.CCR-11-1920.
PubMed 22589486Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152.
PubMed 22047558Kaczanowska S, Murty T, Alimadadi A, Contreras CF, Duault C, Subrahmanyam PB, Reynolds W, Gutierrez NA, Baskar R, Wu CJ, Michor F, Altreuter J, Liu Y, Jhaveri A, Duong V, Anbunathan H, Ong C, Zhang H, Moravec R, Yu J, Biswas R, Van Nostrand S, Lindsay J, Pichavant M, Sotillo E, Bernstein D, Carbonell A, Derdak J, Klicka-Skeels J, Segal JE, Dombi E, Harmon SA, Turkbey B, Sahaf B, Bendall S, Maecker H, Highfill SL, Stroncek D, Glod J, Merchant M, Hedrick CC, Mackall CL, Ramakrishna S, Kaplan RN. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell. 2024 Jan 8;42(1):35-51.e8. doi: 10.1016/j.ccell.2023.11.011. Epub 2023 Dec 21.
PubMed 38134936
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors
- ClinicalTrials.gov ID
- NCT02107963
- Acronym / sponsor ID
- 140059
- Conditions
- Sarcoma, Osteosarcoma, Neuroblastoma, Melanoma
- Keywords
- GD2-Expressing Tumors, Anti-GD2 Chimeric Antigen Receptor, Osteosarcoma, Adoptive Immunotherapy, Sarcomas
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 28 Feb 2014 (actual)
- Primary completion
- 15 Aug 2016 (actual)
- Study completion
- 31 Jan 2017 (actual)
- First posted
- 9 Apr 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- Determine if administration anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors;
- Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects;
- Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults;
- 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
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm 1 | Experimental | Biological: Anti-GD2-CAR engineered T cells, Drug: AP1903, Drug: CyclophosphamideDose escalation of anti-GD2 CAR T cells |
| Arm 2 | Experimental | Biological: Anti-GD2-CAR engineered T cells, Drug: AP1903, Drug: CyclophosphamideDose expansion of anti-GD2 CAR T cells |
Who may qualify
- Ages
- 1 year to 35 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (37 listed)
- Evaluable disease must be present.
- ECOG 0, 1 or 2, or for children less than or equal to 10 years of age, Lansky greater than or equal to 60.
- Left ventricular ejection fraction greater than or equal to 40 percent or fractional shortening greater than or equal to 28 percent.
- Serum total bilirubin < 2 mg/dl, serum AST and ALT less than or equal to 3 x upper limit of normal. Patients with Gilbert s syndrome are excluded from the requirement of a normal bilirubin and patients will not be excluded if liver enzyme elevation is due to tumor involvement. (Gilbert s syndrome is found in 3-10% of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis). NOTE: Adult values will be used for calculating hepatic toxicity and determining eligibility, as is standard on POB phase I trials.
- Age-adjusted normal serum creatinine according to the following table or a creatinine clearance greater than or equal to 60 ml/min/1.73 m(2).
Key exclusion criteria (11 listed)
- Concurrent Illnesses
- Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would compromise the patient s ability to tolerate protocol therapy or significantly increase the risk of complications.
- Peripheral nerve symptoms from prior therapies or from tumor compression > grade 1.
- Untreated CNS metastasis
- Extradural masses that have not invaded the brain parenchyma or parameningeal tumors without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Anti-GD2-CAR engineered T cellsAdminister anti-GD2 CAR T cells 1 x 105 transduced T cells/kg; 1 x 106 transduced T cells/kg; 3 x 106 transduced T cells/kg; and 1 x 107 transduced T cells/kg | Biological | Arm 1, Arm 2 |
| AP1903If unacceptable toxicity occurs that is possibly, probably or likely related to anti-GD2-CAR T cells, AP1903, a dimerizing agent, may be administered to mediate clearance of the genetically engineered cells and resolve toxicity | Drug | Arm 1, Arm 2 |
| Cyclophosphamide1800mg/m2/d X 2 days as a lymphodepleting regimen | Drug | Arm 1, Arm 2 |
Primary outcome
Feasibility
Time frame: 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.
5 secondary outcomes
Determine antitumr effects
Time frame: 60 days
Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects
Time frame: 60 days
Evaluate prevalence of GD2 expression
Time frame: 3 years
Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells
Time frame: When needed
Safety
Time frame: time of treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2024.
- Background: PubMed 20879881Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, Smith M, Anderson B, Villablanca JG, Matthay KK, Shimada H, Grupp SA, Seeger R, Reynolds CP, Buxton A, Reisfeld RA, Gillies SD, Cohn SL, Maris JM, Sondel PM; Children's Oncology Group. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010 Sep 30;363(14):1324-34. doi: 10.1056/NEJMoa0911123.
- Background: PubMed 22589486Lee DW, Barrett DM, Mackall C, Orentas R, Grupp SA. The future is now: chimeric antigen receptors as new targeted therapies for childhood cancer. Clin Cancer Res. 2012 May 15;18(10):2780-90. doi: 10.1158/1078-0432.CCR-11-1920.
- Background: PubMed 22047558Di Stasi A, Tey SK, Dotti G, Fujita Y, Kennedy-Nasser A, Martinez C, Straathof K, Liu E, Durett AG, Grilley B, Liu H, Cruz CR, Savoldo B, Gee AP, Schindler J, Krance RA, Heslop HE, Spencer DM, Rooney CM, Brenner MK. Inducible apoptosis as a safety switch for adoptive cell therapy. N Engl J Med. 2011 Nov 3;365(18):1673-83. doi: 10.1056/NEJMoa1106152.
- Derived from this study: PubMed 38134936Kaczanowska S, Murty T, Alimadadi A, Contreras CF, Duault C, Subrahmanyam PB, Reynolds W, Gutierrez NA, Baskar R, Wu CJ, Michor F, Altreuter J, Liu Y, Jhaveri A, Duong V, Anbunathan H, Ong C, Zhang H, Moravec R, Yu J, Biswas R, Van Nostrand S, Lindsay J, Pichavant M, Sotillo E, Bernstein D, Carbonell A, Derdak J, Klicka-Skeels J, Segal JE, Dombi E, Harmon SA, Turkbey B, Sahaf B, Bendall S, Maecker H, Highfill SL, Stroncek D, Glod J, Merchant M, Hedrick CC, Mackall CL, Ramakrishna S, Kaplan RN. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell. 2024 Jan 8;42(1):35-51.e8. doi: 10.1016/j.ccell.2023.11.011. Epub 2023 Dec 21.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. .All IPD recorded in the medical record will be shared with intramural investigators upon request
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rosandra N Kaplan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Anti-GD2-CAR engineered T cells, AP1903 and Cyclophosphamide in people with Sarcoma and Osteosarcoma, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 37 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Feasibility (time frame: 29 days). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02107963, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2024.