Description:
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.
Title
- Brief Title: Study of CAR T-Cells Targeting the GD2 With IL-15+iCaspase9 for Relapsed/Refractory Neuroblastoma or Relapsed/Refractory Osteosarcoma
- Official Title: A Phase I Study of Autologous Activated T-Cells Expressing a 2nd Generation GD2 Chimeric Antigen Receptor, IL-15, and iCaspase9 Safety Switch Administered To Patients With Relapsed/Refractory Neuroblastoma or Relapsed/Refractory Osteosarcoma
Clinical Trial IDs
- ORG STUDY ID:
LCCC 1743-ATL
- NCT ID:
NCT03721068
Conditions
- Neuroblastoma
- Osteosarcoma
Interventions
Drug | Synonyms | Arms |
---|
iC9.GD2.CAR.IL-15 T-cells | | iC9.GD2.CAR.IL-15 T-cells |
Cyclophosphamide | | iC9.GD2.CAR.IL-15 T-cells |
Fludarabine | | iC9.GD2.CAR.IL-15 T-cells |
Purpose
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.
Detailed 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.
Trial Arms
Name | Type | Description | Interventions |
---|
iC9.GD2.CAR.IL-15 T-cells | Experimental | 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. | - iC9.GD2.CAR.IL-15 T-cells
- Cyclophosphamide
- Fludarabine
|
Eligibility 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.
Maximum Eligible Age: | 18 Years |
Minimum Eligible Age: | 18 Months |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | 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 or relapsed/refractory osteosarcoma |
Time Frame: | 4 weeks |
Safety Issue: | |
Description: | Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (AEs) (CTCAE, version 5.0), a descriptive terminology which can be utilized for AE reporting. A grading (severity) scale is provided for each AE term/symptom: Grade 1 (Mild; asymptomatic); Grade 2 (Moderate; minimal, local or noninvasive intervention indicated); Grade 3 (Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling); Grade 4 (Life-threatening consequences; urgent intervention indicated); Grade 5 (Death related to AE). Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death). |
Secondary Outcome Measures
Measure: | Identify the maximum tolerated dose (MTD) of iC9.GD2.CAR.IL-15 T cells administered to pediatric subjects with relapsed or refractory neuroblastoma or relapsed/refractory osteosarcoma |
Time Frame: | 4 weeks |
Safety Issue: | |
Description: | Tolerability of iC9.GD2.CAR.IL-15 T cells will be assessed by NCI-CTCAE criteria and the CRS grading criteria outlined in Section 12.4 and neurotoxicity/ICANS will be graded according to criteria outlined in Section 12.5 |
Measure: | Expansion and persistence of iC9.GD2.CAR.IL-15 cells in vivo |
Time Frame: | 15 years |
Safety Issue: | |
Description: | 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 |
Measure: | 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) or relapsed/refractory osteosarcoma by RECIST v1.1 |
Time Frame: | 6 weeks |
Safety Issue: | |
Description: | 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) for subjects with neuroblastoma. The overall response rate (ORR = complete (CR) + partial (PR) responses) for subjects with osteosarcoma will be measured using Response evaluation criteria in solid tumors (RECIST) version 1.1 |
Measure: | Overall survival (OS) in pediatric subjects with relapsed or refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells |
Time Frame: | 15 years |
Safety Issue: | |
Description: | OS will be measured from the date of administration of iC9.GD2.CAR.IL-15 T cells to the date of death |
Measure: | Progression free survival (PFS) in pediatric subjects with relapsed or refractory neuroblastoma or relapsed/refractory osteosarcoma treated with iC9.GD2.CAR.IL-15 T cells |
Time Frame: | 15 years |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | UNC Lineberger Comprehensive Cancer Center |
Trial Keywords
- Autologous Chimeric Antigen Receptor (CAR) T Cells
- Interleukin (IL)-15
- Disialoganglioside (GD2)
- Caspase 9
- Pediatric
- Rimiducid
- AP1903
- modified T cells
- CAR T
Last Updated
July 7, 2021