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

• Status: Recruiting
• Trial end date: 2038-09-19
• Target enrollment: 0
• Participant gender: All

Summary

The body has different ways of fighting infections and disease. No single way seems perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are molecules that fight infections and protect your body from diseases caused by bacteria and toxic substances. Antibodies work by sticking to those bacteria or substances, which stops them from growing and causing bad effects. T cells are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been enough to cure most patients. This study is designed to combine both T cells and antibodies in order to create a more effective treatment. The treatment that is being researched is called autologous T lymphocyte chimeric antigen receptor cells (CAR) cells targeted against the disialoganglioside (GD2) antigen that express Interleukin (IL)-15, and the inducible caspase 9 safety switch (iC9), also known as iC9.GD2.CAR.IL-15 T cells.

In previous studies, it has been shown that when T cells have part of an antibody attached to them they are better at recognizing and killing cancer cells. The antibody that will be used in this study is called anti-GD2. This antibody floats around in the blood and can detect and stick to cancer cells called neuroblastoma cells because they have a substance on the outside of the cells called GD2. For this study, the anti-GD2 antibody has been changed so instead of floating freely in the blood, it is now joined to the T cells. However, it is unknown how long the iC9.GD2.CAR.IL-15 T cells last in the body, so their chances of fighting cancer cells are not well known.

To improve the tumor fighting power of GD2-CAR-T cells, our researchers have added two additional components to these cells. The IL-15 gene was added so that the GD2-CAR-T cells can attack tumor cells more effectively. Interleukin-15 (IL-15) is a chemical that cells use to communicate with one another. Other research using IL-15 in combination with CAR-T cells has shown there is an increase in the body's ability to allow the CAR-T cells to survive and grow in the body. The iC9 gene was added as an "off switch" so it can stop the activity of the GD2-CAR-T cells if you experience any serious bad side effects. Bad side effects seen previously in patients receiving the GD2 antibody alone include pain. In this study, the "stop switch" can be used to turn off the GD2-CAR-T cells if you experience intense pain that does not respond to normal pain treatments.

The primary purpose of this study is to determine whether receiving iC9.GD2.IL-15 T cells is safe and tolerable in patients with relapsed/refractory neuroblastoma.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center
• Treatments: Cyclophosphamide; Fludarabine

Criteria

SUBJECT ELIGIBILITY

All clinical and laboratory data required for determining eligibility must be available in the subject's medical/research record which will serve as the source document.

Because of the nature of iC9.GD2.CAR.IL-15 T cell product preparation, subjects will be assessed for initial study enrollment eligibility (prior to cell procurement) and then will have to meet criteria prior to starting lymphodepletion and prior to T cell infusion.

Note: During the period between cell procurement and lymphodepletion, subjects are allowed to receive additional standard of care chemotherapy (bridging chemotherapy) to stabilize their disease if the treating physician feels it is in the subject's best interests. Subjects may receive bridging chemotherapy and/or retinoic acid and/or radiation therapy as deemed necessary by treating physician during period from cell procurement until start of lymphodepleting chemotherapy.

3.1 Inclusion Criteria for the Study: 3.1.1 Written HIPAA authorization signed by legal guardian. 3.1.2 Adequate performance status as defined by Lansky or Karnofsky performance status of ≥ 60 (Lansky for <16 years of age).

3.1.3 Life expectancy ≥12 weeks. 3.1.4 Histological confirmation of neuroblastoma or ganglioneuroblastoma at initial diagnosis. Bone marrow samples are acceptable as confirmation of neuroblastoma.

OR

Confirmation of osteosarcoma at diagnosis 3.1.5 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. (See Section 12.8for COG and INRG definitions if needed) OR relapsed or refractory osteosarcoma that is not responsive to standard treatment.

3.1.6 Measurable or evaluable disease per Revised International Neuroblastoma Response Criteria (See Section 12.5) for subjects with neuroblastoma OR measurable disease by RECIST v1.1 criteria (See Section 12.12) for subjects with osteosarcoma.

3.1.7 Adequate central nervous system function as defined by: • No known CNS disease

• No seizure disorder requiring antiepileptic drug therapy 3.1.8 Adequate cardiac function as defined by:

• Shortening fraction of ≥27% by echocardiogram 3.1.9 Adequate pulmonary function as defined by:

• No chronic oxygen requirement and room air pulse oximetry >94%. 3.1.10 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.

3.1.11 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.

3.1.12 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.

3.1.13 As determined by the enrolling physician, subject is willing and able to comply with study procedures.

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

3.2.1 Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

3.2.2 Has a known additional malignancy that is active and/or progressive requiring treatment.

3.2.3 History of hypersensitivity reactions to murine protein-containing products.

3.2.4 History of hypersensitivity to cyclophosphamide or fludarabine. 3.2.5 Systemic steroid use except as below:

• Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone 6-12 mg/m^2/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.

3.2.6 Uncontrolled infection requiring systemic therapy. 3.2.7 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.

3.3 Eligibility criteria to be met prior to procurement 3.3.1 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.

3.3.2 Age greater than 18 months and less than 18 years at the time of consent. 3.3.3 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.

3.3.4 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.

3.3.5 Adequate organ function as defined in the table below; all labs to be obtained within 7 days of procurement

System Laboratory Value Hematological* Hemoglobin ≥ 9.0 g/dL Absolute Neutrophil Count (ANC) ≥ 0.8 x 10^9/L Platelets (transfusion independent) ≥ 50 x 10^9/L Renal Age Maximum Serum Creatinine (mg/dL) Male Female

1 to <2 years ≤0.6 ≤0.6 2 to <6 years ≤0.8 ≤0.8 6 to <10 years ≤1 ≤1 10 to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4

≥16 years ≤1.7 ≤1.4

Hepatic Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age Alanine aminotransferase (ALT) ≤ 500 U/L Coagulation International Normalized Ratio (INR) ≤ 2 × ULN

• 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.

3.3.1 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.

3.4 Eligibility criteria to be met prior to lymphodepletion

3.4.1 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.

3.4.2 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.

3.4.3 Adequate organ function as defined in the table below:

System Laboratory Value Hematological* Absolute Neutrophil Count (ANC) ≥ 0.8 x 10^9/L Platelets (transfusion independent) ≥ 50 x 10^9/L Renal** Age Maximum Serum Creatinine (mg/dL) Male Female

1. to <2 years ≤0.6 ≤0.6

2. to <6 years ≤0.8 ≤0.8

6 to <10 years ≤1 ≤1 10 to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4

≥16 years ≤1.7 ≤1.4

Hepatic Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age Alanine aminotransferase (ALT) ≤ 500 U/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.

• 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.

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

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

3.4.6 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.

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

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

3.4.9 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.

3.4.10 Systemic steroid use is prohibited, except as below:

• Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone 6-12 mg/m^2/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.

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

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

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

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

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

3.4.16 Subject is not taking a prohibited or contraindicated medication listed in Section 4.2.12 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.

3.4.17 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).

3.4.18 No evidence of uncontrolled infection or sepsis.

3.5 Eligibility criteria to be met prior to cell infusion after lymphodepletion

3.5.1 Subject is a good candidate for treatment per investigator's discretion. 3.5.2 No evidence of uncontrolled infection or sepsis.

3.6 Eligibility Criteria Prior to Lymphodepltion for Second Infusion (Optional) 3.6.1 Subjects must not have received bridging therapy after their initial iC9.GD2.CAR.IL-15 cell infusion.

3.6.2 Adequate organ function as defined in the table below:

System Laboratory Value Hematological* Absolute Neutrophil Count (ANC) ≥ 0.8 x 10^9/L Platelets (transfusion independent) ≥ 50 x 10^9/L Renal** Age Maximum Serum Creatinine (mg/dL) Male Female 1 to <2 years ≤0.6 ≤0.6 2 to <6 years ≤0.8 ≤0.8 6 to <10 years ≤1 ≤1 10 to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4

≥16 years ≤1.7 ≤1.4

Hepatic Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age Alanine aminotransferase (ALT) ≤ 500 U/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.

**Subjects with moderate impairment of renal function (normalized creatinine clearance 30-70 mL/min/1.73m2) should have their fludarabine dose reduced by 20% and be monitored closely for excessive toxicity.

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

3.6.4 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.

3.6.5 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.

3.6.6 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.

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

3.6.8 Subject is not taking a prohibited or contraindicated medication listed in Section 4.2.12 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.

3.6.9 No evidence of uncontrolled infection or sepsis. 3.6.10 Subject has completed the initial safety evaluation period without DLTs. 3.6.11 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. 3.6.12 Subject has derived clinical benefit from the initial infusion as assessed by the investigator (stable disease or better to the initial infusion). 3.6.13 Subject has sufficient stored iC9.GD2.CAR.IL-15 T-cells for re-infusion.

3.7 Eligibility Criteria Prior to Second Infusion (Optional) 3.7.1 Subject is a good candidate for treatment per investigator's discretion. 3.7.2 No evidence of uncontrolled infection or sepsis.