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

NCT02107963 | Completed Phase 1 FDA Drug

• 2 other identifiers: 14005914-C-0059
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

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. 1.Determine if administration anti-GD2-CAR engineered T cells mediate antitumor effects in children and young adults with GD2+ solid tumors;
2. 2.Measure persistence of adoptively transferred anti-GD2-CAR T cells and correlate this with antitumor effects;
3. 3.Extend information regarding the prevalence and intensity of GD2 expression in non-neuroblastoma, non-osteosarcoma solid tumors in children and young adults;
4. 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. 5.Assess toxicity of AP1903 if administered to mediate clearance of anti-GD2-CAR T cells.

Conditions

Sarcoma; Osteosarcoma; Neuroblastoma; Melanoma

Keywords

GD2-Expressing Tumors; Anti-GD2 Chimeric Antigen Receptor; Osteosarcoma; Adoptive Immunotherapy; Sarcomas

Outcome Measures

Primary Outcomes (1)

• 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.

  29 days

Secondary Outcomes (5)

• Determine antitumr effects

  60 days

• Persistence of anti-GD2 CAR T cells and correlate with anti-tumor effects

  60 days

• Evaluate prevalence of GD2 expression

  3 years

• Evaluate effectiveness of AP1903 to mediate clearance of anti-GD2 CAR T cells

  When needed

• Safety

  time of treatment

Study Arms (2)

Arm 1

EXPERIMENTAL

Dose escalation of anti-GD2 CAR T cells

Biological: Anti-GD2-CAR engineered T cells; Drug: AP1903; Drug: Cyclophosphamide

Arm 2

EXPERIMENTAL

Dose expansion of anti-GD2 CAR T cells

Biological: Anti-GD2-CAR engineered T cells; Drug: AP1903; Drug: Cyclophosphamide

Interventions

Anti-GD2-CAR engineered T cells BIOLOGICAL

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

Arm 1; Arm 2

AP1903 DRUG

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

Arm 1; Arm 2

Cyclophosphamide DRUG

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

Arm 1; Arm 2

Eligibility Criteria

• Age: 1 Year - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Diagnosis
• (a) 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.
• i) 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.
• ii) Patients with histologies other than osteosarcoma or neuroblastoma must have adequate accessible tumor for biopsy (at least 1 cm diameter).
• iii) 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.
• iv) 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.

You may not qualify if:

• 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
• 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.
• Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 20879881 BACKGROUND

• Lee 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.

  PMID: 22589486 BACKGROUND

• Di 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.

  PMID: 22047558 BACKGROUND

• Kaczanowska 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.

  PMID: 38134936 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Sarcoma; Osteosarcoma; Neuroblastoma; Melanoma

Interventions

AP 1903 reagent; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Officials

• Rosandra N Kaplan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 5, 2014
• First Posted: April 9, 2014
• Study Start: February 28, 2014
• Primary Completion: August 15, 2016
• Study Completion: January 31, 2017
• Last Updated: May 16, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.

Locations

US (1)