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Trial record 12 of 77 for:    cancer IL-15

Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma

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ClinicalTrials.gov Identifier: NCT03721068
Recruitment Status : Not yet recruiting
First Posted : October 26, 2018
Last Update Posted : February 20, 2019
Sponsor:
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:
Phase I study to determine safety of administering iC9-GD2.CAR.IL-15-T-cells in subjects with refractory or relapsed neuroblastoma.

Condition or disease Intervention/treatment Phase
Neuroblastoma Biological: iC9.GD2.CAR.IL-15 T-cells Drug: Cyclophosphamide Drug: Fludarabine Phase 1

Detailed Description:
This study is a single center, open-label Phase I clinical trial to determine the safety of administration of autologous chimeric antigen receptor (CAR) T cells targeting disialoganglioside (GD2) and co-expressing interleukin (IL)-15 and the inducible caspase 9 safety switch to subjects with relapsed or refractory neuroblastoma. A continual reassessment method (CRM) escalation design will be used for estimating the maximum tolerated dose (MTD) with dose cohorts comprised of a minimum of 2 subjects. The study will enroll a minimum 10 subjects. All subjects will undergo lymphodepletion with cyclophosphamide and fludarabine (Cy/Flu). In addition to the primary goal of establishing a safe dose of iC9.GD2.CAR.IL-15 T-cells, secondary objectives will include measurement of survival of the iC9.GD2.CAR.IL-15 T-cells in vivo, overall survival (OS) and progression free survival (PFS), anti-tumor activity and response rate as measured by the revised International Neuroblastoma Response Criteria (INRC), and cytokine levels after T cell infusion.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study of Autologous Activated T-cells Transduced With a 3rd Generation GD2 Chimeric Antigen Receptor, Co-expression of IL-15, and iCaspase9 Safety Switch Administered To Patients With Relapsed or Refractory Neuroblastoma
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : April 1, 2021
Estimated Study Completion Date : April 1, 2036

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: iC9.GD2.CAR.IL-15 T-cells
The continuous reassessment method (CRM) will be used to estimate the maximum-tolerated dose (MTD) of cells that to be given in dose escalation cohorts comprised of 2-6 subjects. The final MTD will be the dose with estimated probability of dose limiting toxicity (DLT) closest to the target toxicity rate of 20%. Three cell doses will be evaluated: 0.5 x 10^6 cells/kg, 1.0 x 10^6 cells/kg, 1.5 x 10^6 cells/kg. Cohort enrollment will be staggered and each subject must complete at least 2 weeks of the cell treatment without incident of DLT before another subject can be enrolled at that dose level. A minimum of two subjects must complete the 4-week post-infusion DLT period before enrollment at the next higher dose level will be considered. If dose level 1 is determined to be above a tolerable dose, de-escalation would occur to dose level -1 where subjects would receive 0.25 x 10^6 cells/kg.
Biological: iC9.GD2.CAR.IL-15 T-cells
Three dose levels are being evaluated: 0.5 x 10^6, 1.0 x 10^6, 1.5 x 10^6

Drug: Cyclophosphamide
500 mg/m^2 IV dose on days 1-2 for lymphodepletion prior to cell infusion

Drug: Fludarabine
30 mg/m^2 IV dose on days 1-4 for lymphodepletion prior to cell infusion




Primary Outcome Measures :
  1. Number of participants with adverse events as a measure of safety and tolerability of iC9.GD2.CAR.IL-15 T cells administered to pediatric subjects with relapsed or refractory neuroblastoma [ Time Frame: 4 weeks ]
    Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, version 5.0)Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental Activities of Daily Living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event


Secondary Outcome Measures :
  1. Expansion and persistence of iC9.GD2.CAR.IL-15 cells in vivo [ Time Frame: 15 years ]
    Persistence of iC9.GD2.CAR.IL-15 T cells in vivo will be determined by quantitative Polymerase chain reaction (PCR) and flow cytometry in peripheral blood samples

  2. Anti-tumor response rate to iC9.GD2.CAR.IL-15 t cell administration in pediatric subjects with relapsed or refractory neuroblastoma per Revised International Neuroblastoma Response Criteria (INCR) [ Time Frame: 6 weeks ]
    The overall response rate (ORR = complete (CR) + partial (PR) + minor (MR) responses) to iC9.GD2.CAR.IL-15 T cell infusion will be determined using the revised International Neuroblastoma Response Criteria (INRC)

  3. Overall survival (OS) in pediatric subjects with relapsed or refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells [ Time Frame: 15 years ]
    OS will be measured from the date of administration of iC9.GD2.CAR.IL-15 T cells to the date of death

  4. Progression free survival (PFS) in pediatric subjects with relapsed or refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells [ Time Frame: 15 years ]
    PFS is defined from the date of administration of iC9.GD2.CAR.IL-15 T cells to the date of signs and symptoms of treatment failure or relapse from CR or PR, or death from any cause.



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Ages Eligible for Study:   18 Months to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age greater than 18 months and less than 18 years at the time of consent.
  2. Adequate performance status as defined by Lansky or Karnofsky performance status of ≥ 60 (Lansky for <16 years of age).
  3. Life expectancy >12 weeks.
  4. Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial diagnosis. Bone marrow samples are acceptable as confirmation of neuroblastoma.
  5. High risk neuroblastoma with persistent or relapsed disease, defined as:

    • First or greater relapse of neuroblastoma following completion of aggressive multi-drug frontline therapy.
    • First episode of progressive neuroblastoma during aggressive multi-drug frontline therapy.
    • Persistent/refractory neuroblastoma as defined by less than a complete response (by the revised INRC) at the conclusion of at least 4 cycles of aggressive multidrug induction chemotherapy on or according to a high-risk neuroblastoma protocol (such as A3973 or ANBL0532).
    • Patients must be diagnosed with high risk neuroblastoma at initial diagnosis or if non-high risk at time of initial diagnosis must have had evidence of metastatic progression when >18 months of age. (See Section 12.9 for COG and INRG definitions if needed)
  6. Subjects must have measurable or evaluable disease per Revised International Neuroblastoma Response Criteria (See Section 12.6)
  7. Adequate central nervous system function as defined by:

    • No known CNS disease
    • No seizure disorder requiring antiepileptic drug therapy
  8. Adequate cardiac function as defined by:

    • Shortening fraction of ≥27% by echocardiogram

  9. Adequate pulmonary function as defined by:

    • No chronic oxygen requirement and room air pulse oximetry >94%.

  10. Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to cell procurement. NOTE: Premenarchal females do not require pregnancy testing.
  11. Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets <1% failure rate for protection from pregnancy in the product label.
  12. Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy.
  13. As determined by the enrolling physician, subject is willing and able to comply with study procedures.

Exclusion Criteria:

Subjects meeting any of the following exclusion criteria will not be able to participate in this study (procurement, lymphodepletion and cell infusion).

  1. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
  2. Has a known additional malignancy that is active and/or progressive requiring treatment.
  3. History of hypersensitivity reactions to murine protein-containing products.
  4. History of hypersensitivity to cyclophosphamide or fludarabine.
  5. Systemic steroid use except as below:

    • Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone 6-12 mg/m2/day or equivalent.
    • Inhaled steroids are allowed.
    • Other than the above, systemic steroids must be stopped >14 days prior to procurement, but may be resumed after procurement if needed as per treating physician. Systemic steroids must be stopped 48 hours prior to lymphodepletion and not used after infusion unless clinically required.
  6. Uncontrolled infection requiring systemic therapy.
  7. Subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for Hepatitis B surface antigen, or negative for HCV antibody or HCV viral load. Tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells.

A. Eligibility criteria to be met prior to procurement A.1 Written informed consent to undergo cell procurement signed by legal guardian must be obtained prior to procurement. Written assent required as applicable for age <15 years old.

A.2 Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to cell procurement. NOTE: Premenarchal females do not require pregnancy testing.

B. Eligibility criteria to be met prior to lymphodepletion B.1 Written informed consent to enroll in the iC9.GD2.CAR.IL-15 cell therapy trial signed by legal guardian must be obtained prior to starting lymphodepletion. Written assent required as applicable for age <15 years old.

B.2 Subjects who received bridging chemotherapy or radiation therapy must repeat imaging within 14 days prior to lymphodepletion (used as baseline measure for documentation of progression before the lymphodepletion). Required is anatomic imaging (MRI or CT) and functional imaging with MIBG (or PET if mass is MIBG-nonavid). A mass which is neither MIBG-avid nor PET-avid will require biopsy to confirm neuroblastoma or ganglioneuroblastoma.

B.3 Treatment with any investigational drug within 21 days of lymphodepletion or any tumor vaccines within the previous six weeks prior to lymphodepletion.

B.4 Adequate performance status as defined by Lansky or Karnofsky performance status of ≥ 60 (Lansky for <16 years of age).

B.5 Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to lymphodepletion. NOTE: Premenarchal females do not require pregnancy testing.

B.6 Available autologous transduced activated T cells product meets the certificate of analysis.

B.7 Subject has not received aldesleukin (IL-2) within 28 days of starting lymphodepletion.

B.8 Subject has not received:

  • filgrastim (G-CSF) (or biosimilar) within 7 days of starting lymphodepletion;
  • sargramostim (GM-CSF) within 14 days of starting lymphodepletion;
  • pegfilgrastim within 21 days of starting lymphodepletion.

B.9 Systemic steroid use is prohibited, except as below:

  • Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone 6-12 mg/m2/day or equivalent.
  • Inhaled steroids are allowed.
  • Other than the above, systemic steroids must be stopped 48 hours prior to lymphodepletion and not used after infusion unless clinically required.

B.10 Prior autologous stem cell transplant is allowed as long as it occurred ≥4 weeks prior to lymphodepletion.

B.11 Prior therapeutic 131I-MIBG is allowed as long as it is completed ≥4 weeks prior to lymphodepletion.

B.12 Prior anti-GD2 therapy (such as dinutuximab) is allowed as long as it is completed ≥4 weeks prior to lymphodepletion.

B.13 Subject did not have major surgery within 14 days of starting lymphodepletion.

B.14 Subjects that have received bridging therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion.

B.15 Subject is not taking a prohibited or contraindicated medication listed in Section 4.2.11 prior to lymphodepletion. Contraindicated medications should be discontinued at least two weeks prior to the scheduled lymphodepletion or by at least 5 half-lives of the contraindicated medication, whichever is shorter.

B.16 Subject does not have disease progression that would, in the opinion of the treating physician, place the subject at significant potential risk, such as location of lesion that would have high risk with tumor swelling (examples include airway or spinal canal).

B.17 No evidence of uncontrolled infection or sepsis.

C. Eligibility criteria to be met prior to cell infusion after lymphodepletion C.1 No evidence of uncontrolled infection or sepsis.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03721068


Contacts
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Contact: Catherine Cheng 919-445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing 919-962-8618 spencer.laing@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599-7295
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Investigators
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Principal Investigator: George Hucks, MD UNC Lineberger Comprehensive Cancer Center

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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT03721068     History of Changes
Other Study ID Numbers: LCCC 1743-ATL
First Posted: October 26, 2018    Key Record Dates
Last Update Posted: February 20, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Autologous Chimeric Antigen Receptor (CAR) T Cells
Interleukin (IL)-15
Disialoganglioside (GD2)
Caspase 9
Pediatric

Additional relevant MeSH terms:
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Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroblastoma
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists