| Eligibility |
Inclusion Criteria:
- Must have histologically confirmed neuroblastoma or osteosarcoma that is recurrent or
refractory and for which standard curative measures do not exist or are no longer
effective. Must have histologic verification of their disease at diagnosis or at
relapse
- Patients with osteosarcoma must have progressive, recurrent or refractory disease
after all curative measures, including first line chemotherapy
- Patients with osteosarcoma in the dose escalation cohort, must have evaluable or
measurable disease at enrollment
- Patients with osteosarcoma in the expansion cohort must have measurable disease by
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) at enrollment
- Patients with neuroblastoma in the dose escalation or dose the expansion cohort must
have:
- Prior progressive disease OR refractory disease present since diagnosis AND at
least one of the following:
- Any amount of tumor in bone marrow (BM)
- At least one MIBG-avid soft tissue or skeletal site
- For metaiodobenzylguanidine (MIBG)-nonavid disease, at least one FDG-PET-
positive soft tissue or skeletal site plus past histologic confirmation
- Progressive disease is defined as any disease progression occurring at any time
after the diagnosis of high-risk neuroblastoma. Refractory disease is defined as
an incomplete response of high-risk neuroblastoma to all treatments but without
disease progression
- Must be <40 years of age
- There is no limit to the number of prior treatment regimens. The following washout
periods prior to leukapheresis apply to patients undergoing leukapheresis on this
study. If a patient has cryopreserved peripheral blood mononuclear cells (PBMCs)
stored, the following washout periods are strongly recommended but not required and
the product is useable if it meets the criteria established in this Investigational
New Drug (IND)
- Myelosuppressive chemotherapy: Patients must not have received myelosuppressive
chemotherapy within 3 weeks of leukapheresis (6 weeks if prior nitrosourea).
- Hematopoietic growth factors: At least 7 days must have elapsed since the
completion of therapy with a growth factor. At least 14 days must have elapsed
after receiving pegfilgrastim.
- Biological agent, tyrosine kinase inhibitor, targeted agent, metronomic
chemotherapy: At least 7 days must have elapsed since the completion of therapy
with a biologic agent, tyrosine kinase inhibitor, targeted agent, or metronomic
non-myelosuppressive regimen.
- 131I-MIBG or other radioisotope therapy: At least 6 weeks must have elapsed since
prior therapy with 131I-MIBG. At least 6 weeks or 10 half-lives (whichever is
shorter) must have elapsed since prior therapy with any other radioisotope.
- Monoclonal antibodies and checkpoint inhibitors: At least 3 weeks or 5 half-lives
(whichever is shorter) must have elapsed since prior therapy that included a
monoclonal antibody or checkpoint inhibitor.
- Radiotherapy (XRT): 3 weeks must have elapsed since XRT, but at least 6 weeks if
central nervous system (CNS) or lung fields, with the exception that there is no
time restriction for palliative radiation with minimal bone marrow involvement
and the patient has measurable/evaluable disease outside the radiation port or
the site of radiation has documented progression.
- Vaccine therapy, anti-GD2 mAb therapy, or therapy with any genetically engineered
T cells: Patients may have received previous vaccine therapy, anti-GD2 monoclonal
antibody (mAb) therapy, or therapy with any genetically engineered T cells except
prior GD2 CAR T cell therapy. At least 3 weeks or 5 half-lives, whichever is
shorter, must have elapsed since any prior vaccine or monoclonal antibody
therapy. At least 42 days must have elapsed since prior modified T cell, natural
killer (NK) cell, or dendritic cell therapy.
- Allogeneic stem cell transplant/infusion: At least 12 weeks must have elapsed
since allogeneic stem cell transplant and without evidence of active graft versus
host disease (GVHD). Patients who received an autologous stem cell infusion
following myeloablative therapy should be at least 6 weeks from their infusion.
Patients who received an autologous stem cell infusion following
non-myeloablative therapy do not have a wash-out period; they are eligible once
they meet all other eligibility requirements, including recovery from acute side
effects. This criterion does not apply to patients with apheresis product or
usable T cell product available for use.
- Must meet parameters for apheresis per institutional guidelines. (This criterion does
not apply to patients with apheresis product or usable T cell product available for
use. Cryopreserved PBMCs stored from participation in other institutional cell therapy
or cell collection studies or standard of care may be used to generate the cellular
product on this study if they meet the criteria established in this IND
- Patients > 16 years of age must have Karnofsky = 50%. Patients = 16 years of age must
have Lansky scale = 50%; or Eastern Cooperative Oncology Group (ECOG) performance
status = 2
- Leukocytes >= 750/mcL
- Cytopenias deemed to be disease-related and not therapy-related are exempt from
this exclusion. Patients must not be refractory to transfusions
- Platelets >= 75,000/mcL
- Cytopenias deemed to be disease-related and not therapy-related are exempt from
this exclusion. Patients must not be refractory to transfusions
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT])
(For the purpose of this study, the upper limit of normal [ULN] for SGOT is 50 U/L and
the ULN for SGPT is 45 U/L) =< 5 x ULN
- Total bilirubin =< 2 x institutional upper limit of normal (ULN) for age. Patients
with Gilbert's syndrome are excluded from the requirement of a normal bilirubin and
patients will not be excluded if bilirubin elevation is due to tumor involvement.
(Gilbert's syndrome is found in 3-10% of the general population, and is characterized
by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or
overt hemolysis). Note: Adult values will be used for calculating hepatic toxicity and
determining eligibility
- Age, maximum serum creatinine (mg/dL):
- 1 month to < 6 months: 0.4 (male), 0.4 (female)
- 6 months to < 1 year: 0.5 (male), 0.5 (female)
- 1 to < 2 years: 0.6 (male), 0.6 (female)
- 2 to < 6 years: 0.8 (male), 0.8 (female)
- 6 to < 10 years: 1 (male), 1 (female)
- 10 to < 13 years: 1.2 (male), 1.2 (female)
- 13 to < 16 years: 1.5 (male), 1.2 (female)
- >= 16 years: 1.7 (male), 1.4 (female) OR Creatinine clearance or glomerular
filtration rate (GFR) >= 60 mL/min/1.73 m^2 for patients with levels above
institutional normal
- Cardiac ejection fraction >= 45% or shortening fraction >= 28%, no evidence of
physiologically significant pericardial effusion as determined by an echocardiogram
(ECHO). No clinically significant electrocardiogram (ECG) findings
- Pulmonary status: No clinically significant pleural effusion. Baseline oxygen
saturation > 92% on room air at rest
- No acute neurotoxicity greater than grade 2 with the exception of decreased tendon
reflex (DTR). Any grade of DTR is eligible
- Females of child-bearing potential and males of reproductive potential who are
sexually active must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry, for the duration of study
participation, and 4 months after completion of chemotherapy preparative
administration or until CAR is no longer detectable, whichever is later. Should a
female become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately
- Note: Females of childbearing potential are defined as those who are past the
onset of menarche and are not surgically sterile (i.e., bilateral salpingectomy,
bilateral oophorectomy, complete hysterectomy) or post menopausal
- All patients >= 18 years of age must be able to give informed consent or if unable to
give consent have a legal authorized representative (LAR) who can give consent for the
patient. For patients < 18 years old their LAR (i.e., parent or legal guardian) must
give informed consent. Pediatric patients will be included in age appropriate
discussion and verbal assent will be obtained for those > 7 years of age, when
appropriate, according to local policy
Exclusion Criteria:
- Receiving any other current investigational agents
- History of anaphylactic reactions attributed to anti-GD2 antibodies or to compounds of
similar chemical or biologic composition to GD2CART, cyclophosphamide, fludarabine, or
other agents used in this study. History of hypersensitivity to dornase alfa, Chinese
hamster ovary cell products, or any of the components of pulmozyme
- Patients who require systemic corticosteroid or other immunosuppressive therapy. (A
one-week washout from systemic corticosteroid or other immunosuppressive therapy is
permitted.) Use of physiologic doses of corticosteroids (up to 3 mg/m^2/day prednisone
equivalent) are permitted. Use of topical, ocular, intra-articular, intra-nasal, or
inhaled corticosteroids are permitted
- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements
- History of additional malignancy other than non-melanoma skin cancer or carcinoma in
situ (e.g., cervix, bladder, breast) unless untreated and stable or disease free for
at least 3 years
- Untreated central nervous system (CNS) metastasis. Patients with previous CNS tumor
involvement that has been treated and is stable for at least 6 weeks following
completion of therapy are permitted. Patients who are clinically stable as evidenced
by no requirements for corticosteroids, no evolving neurologic deficits, and no
progression of residual brain abnormalities without specific therapy, are permitted.
Patients with asymptomatic subcentemeric CNS lesions are permitted if no immediate
radiation or surgery is indicated
- CNS disorder such as cerebrovascular ischemia/hemorrhage, dementia, cerebellar
disease, or autoimmune disease with CNS involvement that in the judgement of the
investigator may impair the ability to evaluate neurotoxicity
- Presence of fungal, bacterial, viral, or other infection that is uncontrolled.
- Ongoing infection with human immunodeficiency virus (HIV), hepatitis B (hepatitis B
surface antigen [HBsAg] positive), or hepatitis C virus (anti-HCV positive) as the
immunosuppression contained in this study will pose unacceptable risk. A history of
HIV, hepatitis B, or hepatitis C is permitted if the viral load is undetectable per
quantitative polymerase chain reaction (PCR) and/or nucleic acid testing
- Primary immunodeficiency or history of systemic autoimmune disease (e.g., Crohns,
rheumatoid arthritis, systemic lupus) requiring systemic immunosuppression/systemic
disease modifying agents within the last 2 years
- Females of childbearing potential must have a negative serum or urine pregnancy test.
Pregnant females are excluded from this study because the effects of autologous
GD2CART on the developing human fetus are unknown and because the chemotherapy agents
used in this trial (cyclophosphamide and fludarabine) are category D agents with the
potential for teratogenic or abortifacient effects. Additionally, because there is an
unknown but potential risk for adverse events (AEs) in nursing infants secondary to
treatment of the mother with cyclophosphamide/fludarabine, breastfeeding should be
discontinued if the mother is treated with cyclophosphamide/fludarabine. These
potential risks may also apply to other agents used in this study.
- Patients with known GD2 negative tumors by validated immunohistochemistry (IHC) will
be excluded from enrollment given the change in risk profile
- In the investigator's judgment, unlikely to complete protocol-required study visits or
procedures, including follow-up visits, or comply with the study requirements for
participation. Or in the investigator's judgment, if the patient is likely to develop
significant toxicity and morbidity from CAR-T cell expansion mediated inflammation
based on location of tumor site.
|
