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

NCT02107963

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.

Related Conditions:
  • Melanoma
  • Neuroblastoma
  • Osteosarcoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

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

Title

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

    NCT ID: NCT02107963

    ORG ID: 140059

    NCI ID: 14-C-0059

    Trial Conditions

    Sarcoma

    Osteosarcoma

    Neuroblastoma

    Melanoma

    Trial Interventions

    Drug Synonyms Arms
    AP1903 1
    Cyclophosphamide 1

    Trial Purpose

    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.

    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.

    Treatment Schema:

    Upon enrollment: Apheresis volume as estimated based upon patient weight and target cell
    dose. PBMC may be cryopreserved if necessary prior to initiation of CAR transduction. CAR

    transduced T cells may be cryopreserved if necessary prior to administration.

    At least 7 and no more than 28 days may elapse between apheresis and initiation of

    chemotherapy.

    Day 3, 2: Cyclophosphamide, 1800 mg/m2 per day IV over 2 hours daily x2, Mesna, 1800

    mg/m2 per day by continuous IV infusion daily x2

    Day 0: 30-60 minutes prior to cell infusion administer diphenhydramine 1 mg/kg/d (max 50 mg)
    IV or po, acetaminophen 15 mg/kg/dose (max 650 mg) po

    Infuse anti-GD2-CAR T cells over 15-30 minutes

    Trial Arms

    Name Type Description Interventions
    1 Experimental Lympodepleting chemotherapy followed by infusion of anti-GD2 CAR T cells AP1903, Cyclophosphamide

    Eligibility Criteria

    - INCLUSION CRITERIA:

    1. 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.

    2. Weight greater than or equal to 15 kg

    3. Age less than or equal to 35 years old at the time of enrollment.

    4. Prior Therapy:

    1. 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.

    2. 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.

    3. Myelosuppressive chemotherapy: Patients must not have received
    myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if
    prior nitrosourea).

    4. 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.

    5. 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.

    6. Monoclonal antibodies: At least 4 weeks must have elapsed since prior
    therapy that included a monoclonal antibody.

    7. Radiotherapy: 3 weeks must have elapsed since XRT

    5. 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.

    6. Cardiac function:

    Left ventricular ejection fraction greater than or equal to 40 percent or
    fractional shortening greater than or equal to 28 percent.

    7. 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.

    8. 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

    9. 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).

    10. 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.

    11. Durable power of attorney form offered (patients (Bullet)18 years of age only).

    12. 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.

    EXCLUSION CRITERIA:

    1. 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.

    2. 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.

    3. Prior Therapy

    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.

    4. Lactating or pregnant females (due to risk to fetus or newborn).

    5. Active HIV, HBV or HCV infection.

    6. Immune Therapies

    Patients who require systemic corticosteroid or other immunosuppressive therapy.
    Immunosuppressive therapy must be stopped at least 14 days prior to cell infusion.

    INCLUSION OF WOMEN AND MINORITIES:

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

    Minimum Eligible Age: 1 Year

    Maximum Eligible Age: 35 Years

    Eligible Gender: Both

    Primary Outcome Measures

    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...

    Secondary Outcome Measures

    Determine antitumr effects

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

    Evaluate prevalencew of GD2 expression

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

    Assess toxicity of AP1903

    Trial Keywords

    GD2-Expressing Tumors

    Anti-GD2 Chimeric Antigen Receptor

    Osteosarcoma

    Adoptive Immunotherapy

    Sarcomas