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

  • STATUS
    Recruiting
  • End date
    Jun 19, 2039
  • participants needed
    18
  • sponsor
    UNC Lineberger Comprehensive Cancer Center
Updated on 24 April 2022
renal function
cancer
interleukin
fludarabine
cyclophosphamide
filgrastim
granulocyte colony stimulating factor
systemic therapy
measurable disease
karnofsky performance status
bone marrow procedure
shortening fraction
colony stimulating factor
kidney function tests
gm-csf
neutrophil count
tumor cells
g-csf
refractory neuroblastoma
pulse oximetry
cancer chemotherapy
pegfilgrastim
cellular therapy
left ventricular fractional shortening
tumor vaccine
high-risk neuroblastoma
dinutuximab
ganglioneuroblastoma
refractory osteosarcoma

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.

Description

We plan to conduct a single center, open-label, Phase I clinical trial to establish a safe dose (i.e., number of cells/kg) of autologous iC9.GD2.CAR.IL-15 T-cells in pediatric patients with relapsed or refractory neuroblastoma. The study will enroll a minimum of 10 subjects; all subjects will undergo lymphodepleting chemotherapy prior to the cell infusion as outlined in section 4.2.2. The continual reassessment method (CRM) will be used to estimate the maximum-tolerated dose (MTD) of cells that can be administered in dose escalation cohorts comprised of 2-6 subjects. The final MTD will be the dose with estimated probability of DLT closest to the target toxicity rate of 20%. The three cell doses that will be evaluated are outlined in the table below starting at the lowest dose level 1: 0.5 x 106 CAR+ cells/kg iC9.GD2.CAR.IL-15 T cells. Cohort enrollment will be staggered and each subject must complete at least 2 weeks of 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 safety assessment period before cohort enrollment of subjects 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 106 CAR+ cells/kg. After dose escalation is completed, an expansion cohort will enroll up to 8 subjects at the maximum tolerated dose (MTD) to further assess the safety and efficacy of iC9.GD2.CAR.IL-15 T-cells. In the expansion phase, subjects will receive iC9.GD2.CAR.IL-15 T-cells at the maximum tolerated dose (MTD) with lymphodepletion given prior to a cell product administration.

Cell Procurement

Up to 3 mL/kg of peripheral blood will be obtained (in up to 3 collections) from patients for cell procurement. For subjects with inadequate lymphocyte count or who are unable to donate adequate amounts of peripheral blood, a leukopheresis may be performed to isolate sufficient T cells. The parameters for pheresis will be up to 2 blood volumes. Approximately 4-6 weeks later, subjects for whom cells have been successfully generated and who meet eligibility criteria for lymphodepletion will undergo lymphodepleting chemotherapy.

Lymphodepleting Regimen

All subjects will be given lymphodepleting chemotherapy with cyclophosphamide and fludarabine. This will consist of four days total and should be timed to be completed 2-14 days before planned infusion of CAR T-cells.

Cyclophosphamide will be given IV 500 mg/m2/day on days 1-2 and fludarabine will be given IV 30 mg/m2/day on days 1-4. No mesna will be required, although it may be used at investigator discretion.

Administration of iC9.GD2.CAR.IL-15 T cells

Post lymphodepletion, subjects who meet eligibility criteria for cellular therapy will receive iC9.GD2.CAR.IL-15 T cells within 2-14 days after completing the lymphodepleting chemotherapy regimen. We will administer T-cells post lymphodepletion as dosed above.

After dose escalation is completed, an expansion cohort will enroll up to 8 subjects to further assess the safety and efficacy of iC9.GD2.CAR.IL-15 T-cells. In the expansion phase, patients who meet criteria outlined in Section 4.2.5 will be allowed to receive a second cell infusion.

Duration of Therapy

Therapy in LCCC 1743-ATL involves infusion of iC9.GD2.CAR.IL-15 CAR T cells. Treatment will be administered unless:

  • Subject decides to withdraw from study treatment, or
  • General or specific changes in the subject's condition render the subject unacceptable for further treatment in the judgment of the investigator.
  • Subject is ineligible for a second infusion

Duration of Follow-up

Subjects will be followed for up to 15 years for RCR evaluation or until death, whichever occurs first. In addition to this follow-up, subjects removed from study treatment for unacceptable adverse events will be followed until resolution or stabilization of the adverse event.

Subjects who receive new therapy after receiving a cell infusion will still be required to complete abbreviated follow up procedures.

Details
Condition Neuroblastoma, Osteosarcoma
Treatment cyclophosphamide, Fludarabine, iC9.GD2.CAR.IL-15 T-cells
Clinical Study IdentifierNCT03721068
SponsorUNC Lineberger Comprehensive Cancer Center
Last Modified on24 April 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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)
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
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
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
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
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
1.13 As determined by the enrolling physician, subject is willing and able to comply with
study procedures
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)
Inhaled steroids are allowed
2.1 Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while
the mother is being treated on study)
2.2 Has a known additional malignancy that is active and/or progressive requiring
treatment
2.3 History of hypersensitivity reactions to murine protein-containing products
2.4 History of hypersensitivity to cyclophosphamide or fludarabine. 3.2.5 Systemic
steroid use except as below
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
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 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
3.2 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
3.4 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
3.5 Adequate organ function as defined in the table below; all labs to be obtained within
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
4 Eligibility criteria to be met prior to lymphodepletion
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
4.3 Adequate organ function as defined in the table below
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
Serum Creatinine (mg/dL) Male Female
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
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
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
to <2 years ≤0.6 ≤0.6
to <6 years ≤0.8 ≤0.8
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
4.8 Subject has not received aldesleukin (IL-2) within 28 days of starting
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
4.9 Subject has not received
supported with transfusions to prevent life-threatening bleeding as per investigator
filgrastim (G-CSF) (or biosimilar) within 7 days of starting lymphodepletion
discretion. NB: Bone marrow involvement is only relevant to neuroblastoma subjects
sargramostim (GM-CSF) within 14 days of starting lymphodepletion
pegfilgrastim within 21 days of starting lymphodepletion
clearance 30-70 mL/min/1.73m^2) should have their fludarabine dose reduced by 20%
4.10 Systemic steroid use is prohibited, except as below
and be monitored closely for excessive toxicity
4.4 Treatment with any investigational drug within 21 days of lymphodepletion or any
Inhaled steroids are allowed
tumor vaccines within the previous six weeks prior to lymphodepletion
Physiologic replacement for adrenal insufficiency is allowed at doses of
4.5 Adequate performance status as defined by Lansky or Karnofsky performance status of ≥
hydrocortisone 6-12 mg/m^2/day or equivalent
(Lansky for <16 years of age)
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
4.7 Available autologous transduced activated T cells product meets the certificate of
analysis
to lymphodepletion
• Physiologic replacement for adrenal insufficiency is allowed at doses of hydrocortisone
-12 mg/m^2/day or equivalent
Other than the above, systemic steroids must be stopped 48 hours prior to
lymphodepletion and not used after infusion unless clinically required
4.11 Prior autologous stem cell transplant is allowed as long as it occurred ≥4 weeks
prior to lymphodepletion
4.18 No evidence of uncontrolled infection or sepsis
4.12 Prior therapeutic ^131 I-MIBG is allowed as long as it is completed ≥4 weeks prior
4.13 Prior anti-GD2 therapy (such as dinutuximab) is allowed as long as it is completed
≥4 weeks prior to lymphodepletion
4.14 Subject did not have major surgery within 14 days of starting lymphodepletion
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
4.16 Subject is not taking a prohibited or contraindicated medication listed in Section
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
6.2 Adequate organ function as defined in the table below
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)
5 Eligibility criteria to be met prior to cell infusion after lymphodepletion
5.1 Subject is a good candidate for treatment per investigator's discretion. 3.5.2 No
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
Subjects with moderate impairment of renal function (normalized creatinine
infusion
System Laboratory Value Hematological _Absolute Neutrophil Count (ANC) ≥ 0.8 x 10^9/L
6.5 Subject has not received
Platelets (transfusion independent) ≥ 50 x 10^9/L Renal_ Age Maximum Serum Creatinine
filgrastim (G-CSF) (or biosimilar) within 7 days of starting lymphodepletion
(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
sargramostim (GM-CSF) within 14 days of starting lymphodepletion
to <13 years ≤1.2 ≤1.2 13 to <16 years ≤1.5 ≤1.4
pegfilgrastim within 21 days of starting lymphodepletion
≥16 years ≤1.7 ≤1.4
6.6 Systemic steroid use is prohibited, except as below
Hepatic Total Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age Alanine
aminotransferase (ALT) ≤ 500 U/L
Inhaled steroids are allowed
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
-70 mL/min/1.73m2) should have their fludarabine dose reduced by 20% and be monitored
closely for excessive toxicity
6.3 Adequate performance status as defined by Lansky or Karnofsky performance status of ≥
(Lansky for <16 years of age)
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
Physiologic replacement for adrenal insufficiency is allowed at doses of
hydrocortisone 6-12 mg/m2/day or equivalent
Other than the above, systemic steroids must be stopped 48 hours prior to
evidence of uncontrolled infection or sepsis
lymphodepletion and not used after infusion unless clinically required
6.7 Subject did not have major surgery within 14 days of starting lymphodepletion
6.8 Subject is not taking a prohibited or contraindicated medication listed in Section
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
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
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
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