Summary

This phase I trial studies the side effects and best dose of modified immune cells (autologous iC9.GD2.CAR.IL-15 T cells) for treating patients with high risk neuroblastoma or osteosarcoma that has come back (recurrent) or does not respond to treatment (refractory), or ganglioneuroblastoma. Antibodies and T cells are two different ways the body fights disease. When T cells have part of an antibody attached to them they are better at recognizing and killing tumor cells. The treatment that is being research on this trial, autologous iC9.GD2.CAR.IL-15 T cells, combines T cells and antibodies in order to create a more effective treatment. An antibody called anti-GD2 joins to T cells in the blood and can detect and stick to neuroblastoma cells because they have a substance on the outside of them called GD2. The IL-15 gene, which cells use to communicate with one another, is added so that the T cells can attack tumor cells more effectively. The iC9 gene is added as an "off-switch" so that it can stop the T cells from working if serious side effects are experienced. This study is being done to see if giving autologous iC9.GD2.CAR.IL-15 T cells is safe, tolerable, and helpful in treating neuroblastoma, ganglioneuroblastoma, or osteosarcoma.

Objectives

PRIMARY OBJECTIVE:
I. To determine the safety and tolerability of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes (autologous iC9.GD2.CAR.IL-15 T cells) administered to adult and pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.

SECONDARY OBJECTIVES:
I. To identify the maximum tolerated dose (MTD) of iC9.GD2.CAR.IL-15 T cells in pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.
II. To identify the maximum tolerated dose (MTD) of iC9.GD2.CAR.IL-15 T cells in adult subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma.
III. To assess expansion and persistence of iC9.GD2.CAR.IL-15 T cells in vivo.
III. To evaluate the anti-tumor response rate to iC9.GD2.CAR.IL-15 T cell administration in subjects with relapsed/refractory neuroblastoma per Revised International Neuroblastoma Response Criteria (INRC) or subjects with relapsed/refractory osteosarcoma by RECIST version (v) 1.1.
IV. To determine overall survival (OS) in pediatric subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
V. To evaluate the anti-tumor response rate to iC9.GD2.CAR.IL-15 T cell administration in subjects with relapsed/refractory neuroblastoma per Revised International Neuroblastoma Response Criteria (INRC).
VI. To determine overall survival (OS) in subjects relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
VII. To determine overall survival (OS) in subjects with relapsed/refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells.
VIII. To determine progression free survival (PFS) in subjects with relapsed/refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells.
IX. To determine progression free survival (PFS) in subjects with relapsed/refractory neuroblastoma treated with iC9.GD2.CAR.IL-15 T cells.

EXPLORATORY OBJECTIVES:
I. To measure proxy-reported symptoms in pediatric subjects at baseline and over time in osteosarcoma subjects treated with iC9.GD2.CAR.IL-15 T cells.
II. To measure proxy-reported symptoms in pediatric subjects at baseline and over time in neuroblastoma subjects treated with iC9.GD2.CAR.IL-15 T cells.
III. To evaluate utility of metaiodobenzylguanidine (mIBG) semiquantitative scoring (Curie scoring system) in predicting response to iC9.GD2.CAR.IL-15 T cells in subjects with neuroblastoma.
IV. To retrospectively analyze GD2 expression in neuroblastoma subjects' samples.
V. To retrospectively analyze GD2 expression in osteosarcoma subjects’ samples.
VI. To determine the utility of the safety switch in iC9.GD2.CAR.IL-15 T cells in subjects with relapsed/refractory neuroblastoma by allowing for administration of rimiducid (0.4 mg/kg/dose) to subjects with severe pain despite appropriate medical interventions (such as gabapentin for neuropathic pain or narcotics) or grade >= 3 immune effector cell-associated neurotoxicity syndrome (ICANS) that does not improve to grade =< 1 within 72 hours with standard of care (SOC) interventions and grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus following infusion of iC9.GD2.CAR.IL-15 T cells.
VII. To determine the utility of the safety switch in iC9.GD2.CAR.IL-15 T cells in subjects with relapsed/refractory osteosarcoma by allowing for administration of rimiducid (0.4 mg/kg/dose) to subjects with severe pain despite appropriate medical interventions (such as gabapentin for neuropathic pain or narcotics) or grade >= 3 ICANS that does not improve to grade =< 1 within 72 hours with SOC interventions and grade 4 ICANS of any duration that have evidence of cerebral edema and/or generalized convulsive status epilepticus following infusion of iC9.GD2.CAR.IL-15 T cells.
VIII. To measure changes in IL-15 levels at baseline and over time in subjects treated with iC9.GD2.CAR.IL-15 T cells.
IX. To determine whether there are correlations between CAR T cell behavior and the integration locations of iC9.GD2.CAR.IL-15.

OUTLINE: This is a dose-escalation study of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes.

Patients receive lymphodepletion chemotherapy consisting of cyclophosphamide intravenously (IV) over 1 hour on days 1-2 and fludarabine phosphate IV over 30 minutes on days 1-4 in the absence of disease progression or unacceptable toxicity. Lymphodepletion may be repeated if necessary per physician discretion. Within 2-14 days after completion of lymphodepletion chemotherapy, patients receive autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes IV over 5-10 minutes. Patients who experience clinical benefit and meet certain criteria have the option to receive a second infusion of autologous iC9-GD2CAR-CD28-CD3zeta-IL-15-expressing T-lymphocytes IV at the discretion of treating physician. Patients undergo echocardiography during screening and bone marrow biopsy, tumor biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI) and blood sample collection throughout the study.

After completion of study treatment, patients are followed up on days 2 and 4, weeks 1, 2, 3, 4, and 6, and months 3, 6, 9, and 12. Subsequently, patients with iC9.GD2.CAR.IL-15 T cells detected are followed every 6 months for 4 years, then yearly for up to 15 years. All other patients are followed up yearly for 15 years.

Eligibility

1. Written Health Insurance Portability and Accountability Act (HIPAA) authorization signed by the subject if 18 years old or older, or by a legal guardian (if subject is <18 years old)
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 OR confirmation of osteosarcoma at diagnosis
5. High risk neuroblastoma with persistent/refractory 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 OR relapsed or refractory osteosarcoma that is not responsive to standard treatment
6. Measurable or evaluable disease per Revised International Neuroblastoma Response Criteria for subjects with neuroblastoma OR measurable disease by RECIST v1.1 criteria for subjects with osteosarcoma
7. Adequate central nervous system function as defined by: * No known central nervous system (CNS) disease * No seizure disorder requiring antiepileptic drug therapy
8. Adequate cardiac function as defined by either a left ventricular ejection fraction (LVEF) = 50% OR shortening fraction of = 27% by echocardiogram, within 90 days of procurement
9. Adequate pulmonary function as defined by: * No chronic oxygen requirement and room air pulse oximetry > 90%
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, be willing to abstain from heterosexual activity 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
14. PRIOR TO PROCUREMENT: Written informed consent to undergo cell procurement signed by legal guardian must be obtained prior to procurement. Written assent required as applicable for age 15-17 years old
15. PRIOR TO PROCUREMENT: Imaging and bone marrow study results from within 90 days prior to procurement to assess presence of active disease. Bone marrow studies are only relevant for neuroblastoma subjects.
16. PRIOR TO PROCUREMENT: Subjects who have received murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA). Test can be pending at the time of cell procurement; only those patients with confirmed absence of HAMA will have cells generated.
17. PRIOR TO PROCUREMENT: Hemoglobin >= 9.0 g/dL (obtained within 7 days of procurement) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. Neuroblastoma (NB): Bone marrow involvement is only relevant to neuroblastoma subjects
18. PRIOR TO PROCUREMENT: Absolute neutrophil count (ANC) >= 0.8 x 10^9/L (obtained within 7 days of procurement) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
19. PRIOR TO PROCUREMENT: Platelets (transfusion independent) >= 50 x 10^9/L (obtained within 7 days of procurement) * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
20. PRIOR TO PROCUREMENT: Maximum serum creatine (mg/dL) (obtained within 7 days of procurement) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 16 years (=< 1.5 for male and =< 1.4 for female) * Age >= 16 years (=< 1.7 for male and =< 1.4 for female) * Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
21. PRIOR TO PROCUREMENT: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (obtained within 7 days of procurement)
22. PRIOR TO PROCUREMENT: Alanine aminotransferase (ALT) =< 500 U/L (obtained within 7 days of procurement)
23. PRIOR TO PROCUREMENT: International normalized ratio (INR) =< 2 x ULN (obtained within 7 days of procurement)
24. PRIOR TO PROCUREMENT: 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
25. PRIOR TO LYMPHODEPLETION: 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 15-17 years old
26. PRIOR TO LYMPHODEPLETION: Subjects must have imaging and bone marrow study (bone marrow only applicable for neuroblastoma subjects) results within 14 days prior to lymphodepletion (used as baseline measure for documentation of progression before the lymphodepletion). Subjects who have received bridging chemotherapy must have imaging and bone marrow study results at least 3 weeks after most recent therapy
27. PRIOR TO LYMPHODEPLETION: Absolute neutrophil count (ANC) >= 0.8 x 10^9/L * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
28. PRIOR TO LYMPHODEPLETION: Platelets (transfusion independent) >= 50 x 10^9/L * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
29. PRIOR TO LYMPHODEPLETION: Maximum serum creatine (mg/dL) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 16 years (=< 1.5 for male and =< 1.4 for female) * Age >= 16 years (=< 1.7 for male and =< 1.4 for female) ** Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
30. PRIOR TO LYMPHODEPLETION: Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
31. PRIOR TO LYMPHODEPLETION: ALT =< 500 U/L
32. PRIOR TO LYMPHODEPLETION: Treatment with any investigational drug within 21 days of lymphodepletion or any tumor vaccines within the previous six weeks prior to lymphodepletion
33. PRIOR TO LYMPHODEPLETION: Adequate performance status as defined by Lansky or Karnofsky performance status of >= 60 (Lansky for < 16 years of age)
34. PRIOR TO LYMPHODEPLETION: 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
35. PRIOR TO LYMPHODEPLETION: Available autologous transduced activated T cells product meets the certificate of analysis
36. PRIOR TO LYMPHODEPLETION: Subject has not received aldesleukin (IL-2) within 28 days of starting lymphodepletion
37. PRIOR TO LYMPHODEPLETION: Subject has not received: * Filgrastim (granulocyte-colony stimulating factor [G-CSF]) (or biosimilar) within 7 days of starting lymphodepletion * Sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) within 14 days of starting lymphodepletion * Pegfilgrastim within 21 days of starting lymphodepletion
38. PRIOR TO LYMPHODEPLETION: Subject must not be receiving systemic corticosteroids at doses equivalent of =10mg prednisone daily or its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed * For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. 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
39. PRIOR TO LYMPHODEPLETION: Prior autologous stem cell transplant is allowed as long as it occurred >= 4 weeks prior to lymphodepletion
40. PRIOR TO LYMPHODEPLETION: Prior therapeutic 131 iodine (I)-MIBG is allowed as long as it is completed >= 4 weeks prior to lymphodepletion
41. PRIOR TO LYMPHODEPLETION: Prior anti-GD2 therapy (such as dinutuximab) is allowed as long as it is completed >= 4 weeks prior to lymphodepletion
42. PRIOR TO LYMPHODEPLETION: Subject did not have major surgery within 14 days of starting lymphodepletion
43. PRIOR TO LYMPHODEPLETION: Subjects that have received bridging therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion
44. PRIOR TO LYMPHODEPLETION: Subject is not taking a prohibited or contraindicated medication 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
45. PRIOR TO LYMPHODEPLETION: 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)
46. PRIOR TO LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
47. PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: Subject is a good candidate for treatment per investigator's discretion
48. PRIOR TO CELL INFUSION AFTER LYMPHODEPLETION: No evidence of uncontrolled infection or sepsis
49. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subjects must not have received bridging therapy after their initial iC9.GD2.CAR.IL-15 cell infusion.
50. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Absolute neutrophil count (ANC) >= 0.8 x 10^9/L * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
51. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Platelets (transfusion independent) >= 50 x 10^9/L * Subjects with known bone marrow involvement are eligible even if they have not met the above hematological eligibility criteria. However, those subjects must be able to be supported with transfusions to prevent life-threatening bleeding as per investigator discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
52. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Maximum serum creatine (mg/dL) * Age 1 to < 2 years (=< 0.6 for male and =< 0.6 for female) * Age 2 to < 6 years (=< 0.8 for male and =< 0.8 for female) * Age 6 to < 10 years (=< 1 for male and =< 1 for female) * Age 10 to <13 years (=< 1.2 for male and =< 1.2 for female) * Age 13 to < 16 years (=< 1.5 for male and =< 1.4 for female) * Age >= 16 years (=< 1.7 for male and =< 1.4 for female) ** Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity
53. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Total bilirubin =< 1.5 x upper limit of normal (ULN) for age
54. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Aspartate aminotransferase (ALT) =< 500 U/L
55. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Adequate performance status as defined by Lansky or Karnofsky performance status of >= 60 (Lansky for < 16 years of age).
56. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): 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
57. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has not received: * Filgrastim (granulocyte-colony stimulating factor [G-CSF]) (or biosimilar) within 7 days of starting lymphodepletion * Sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]) within 14 days of starting lymphodepletion * Pegfilgrastim within 21 days of starting lymphodepletion
58. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject must not be receiving systemic corticosteroids at doses equivalent of = 10mg prednisone daily or its equivalent; those receiving < 10mg daily may be enrolled at discretion of investigator. Inhaled steroids are allowed * For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m^2/day is allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator, though not to exceed 10mg prednisone per day. 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
59. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject did not have major surgery within 14 days of starting lymphodepletion.
60. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject is not taking a prohibited or contraindicated medication 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.
61. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): No evidence of uncontrolled infection or sepsis.
62. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has completed the initial safety evaluation period without dose limiting toxicities (DLTs).
63. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has not experienced additional toxicity(ies) directly attributable to the initial T-cell infusion that would place them at excessive risk with re-infusion.
64. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has derived clinical benefit from the initial infusion as assessed by the investigator (stable disease or better to the initial infusion).
65. PRIOR TO LYMPHODEPLETION FOR SECOND INFUSION (OPTIONAL): Subject has sufficient stored iC9.GD2.CAR.IL-15 T-cells for re-infusion.
66. PRIOR TO SECOND INFUSION (OPTIONAL): Subject is a good candidate for treatment per investigator’s discretion.
67. PRIOR TO SECOND INFUSION (OPTIONAL): No evidence of uncontrolled infection or sepsis.

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