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

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.

Conditions

• Sarcoma
• Osteosarcoma
• Neuroblastoma
• Melanoma

Interventions

BIOLOGICAL

Anti-GD2-CAR engineered T cells

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

DRUG

AP1903

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

DRUG

Cyclophosphamide

1800mg/m2/d X 2 days as a lymphodepleting regimen

Sponsors & Collaborators

• National Cancer Institute (NCI)

  lead NIH

Principal Investigators

• Rosandra N Kaplan, M.D. · National Cancer Institute (NCI)

Study Design

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Model

SEQUENTIAL

Eligibility

Min Age

1 Year

Max Age

35 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2014-02-28

Primary Completion

2016-08-15

Completion

2017-01-31

FDA Drug

Yes

Countries

• United States

Study Locations