NCT02107963

A Phase I Trial of T Cells Expressing an Anti-GD2 Chimeric Antigen Receptor in Children and Young Adults With GD2+ Solid Tumors

Completed Phase 1 Last updated 16 May 2024

What this trial tests

Phase 1 trial testing Anti-GD2-CAR engineered T cells in Sarcoma in 15 participants. Completed in 31 January 2017.

Timeline

28 February 2014

Primary endpoint
15 August 2016

31 January 2017

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 1
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	sequential
Masking	none
Primary purpose	treatment
Enrollment	15
Start date	28 February 2014
Primary completion	15 August 2016
Estimated completion	31 January 2017
Sites	1 location across United States

Drugs / interventions tested

• Anti-GD2-CAR engineered T cells — full drug profile →
• AP1903 — full drug profile →
• Cyclophosphamide (cyclophosphamide) — full drug profile →

Conditions studied

• Sarcoma — all drugs for Sarcoma →
• Osteosarcoma — all drugs for Osteosarcoma →
• Neuroblastoma — all drugs for Neuroblastoma →
• Melanoma — all drugs for Melanoma →

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 1 to 35, any sex, with Sarcoma or Osteosarcoma. Patients with the condition only — healthy volunteers not accepted.

Sponsor's own 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.

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Engineered T cells: the promise and challenges of cancer immunotherapy.
   Fesnak AD, June CH, Levine BL. · · 2016 · cited 812× · PMID 27550819 · DOI 10.1038/nrc.2016.97
2. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment.
   Martinez M, Moon EK. · · 2019 · cited 653× · PMID 30804938 · DOI 10.3389/fimmu.2019.00128
3. Driving CAR T-cells forward.
   Jackson HJ, Rafiq S, Brentjens RJ. · · 2016 · cited 457× · PMID 27000958 · DOI 10.1038/nrclinonc.2016.36
4. Melanoma treatment in review.
   Domingues B, Lopes JM, Soares P, Pópulo H. · · 2018 · cited 432× · PMID 29922629 · DOI 10.2147/itt.s134842
5. CAR-cell therapy in the era of solid tumor treatment: current challenges and emerging therapeutic advances.
   Maalej KM, Merhi M, Inchakalody VP, Mestiri S, et al · · 2023 · cited 421× · PMID 36717905 · DOI 10.1186/s12943-023-01723-z
6. The inducible caspase-9 suicide gene system as a "safety switch" to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells.
   Gargett T, Brown MP. · · 2014 · cited 299× · PMID 25389405 · DOI 10.3389/fphar.2014.00235
7. Molecular targeting therapies for neuroblastoma: Progress and challenges.
   Zafar A, Wang W, Liu G, Wang X, et al · · 2021 · cited 291× · PMID 33155698 · DOI 10.1002/med.21750
8. Prospects for gene-engineered T cell immunotherapy for solid cancers.
   Klebanoff CA, Rosenberg SA, Restifo NP. · · 2016 · cited 277× · PMID 26735408 · DOI 10.1038/nm.4015