Expired Study
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Chapel Hill, North Carolina 27599


Purpose:

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


Study summary:

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.


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.


NCT ID:

NCT03721068


Primary Contact:

Principal Investigator
George Hucks, MD
UNC Lineberger Comprehensive Cancer Center

Catherine Cheng
Phone: 919-445-4208
Email: catherine_cheng@med.unc.edu


Backup Contact:

Email: spencer.laing@med.unc.edu
Spencer Laing
Phone: 919-962-8618


Location Contact:

Chapel Hill, North Carolina 27599
United States



There is no listed contact information for this specific location.

Site Status: N/A


Data Source: ClinicalTrials.gov

Date Processed: February 04, 2019

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