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GD2 is a well-characterized tumor antigen in neuroblastoma that is also expressed on osteosarcoma and some other sarcomas. This study uses third-generation anti-GD2 chimeric antigen receptor (CAR) T cells, expected to be more active than the first-generation product studied earlier; as an added safety measure the vector includes a suicide switch (ICD9) that can be activated by a small molecule to kill the engineered cells if serious toxicity occurs. The Phase 1 trial enrolled children and young adults with osteosarcoma, neuroblastoma or melanoma that had been treated with standard frontline therapy and was judged incurable with standard treatment.
The summary above is a plain-language rendering of the official record. The original English title is shown for reference.
Criteria are reproduced from the ClinicalTrials.gov record in the original English. Only the trial team can determine eligibility.
* INCLUSION CRITERIA:
1. Diagnosis
(a) Osteosarcoma, neuroblastoma and melanoma that have been treated with standard frontline therapy and are judged to be incurable with standard therapy, based upon the fact that they are unresectable, metastatic, progressive/persistent or recurrent.
Evaluable disease must be present.
i) For all histologies except osteosarcoma and neuroblastoma, pathologic review of frozen tissue must document GD2+ expression. Positive expression is defined as at least 2+ expression (0-4+ scale) in \>50 percent of the tumor cells using anti-GD2 mAb 14G2a. If adequate archived frozen tissue is available, this may be utilized, or if not, patients may undergo biopsy following enrollment to obtain tissue to assess GD2 expression, with the following restrictions.
ii) Patients with histologies other than osteosarcoma or neuroblastoma must have adequate accessible tumor for biopsy (at least 1 cm diameter).
iii) Procedures employed to acquire biopsies for tumor lysates will be limited to percutaneous needle or core biopsies, thoracoscopic excision or open biopsies of readily accessible lesions. Pulmonary lesions may be biopsied but extensive surgery such as thoracotomy or laparotomy should not be employed.
iv) Patients who will require biopsy should not be enrolled if in the opinion of the principal investigator, the tumor site places the patient at substantial risk from the biopsy procedure.
2. Weight greater than or equal to 15 kg
3. Age less than or equal to 35 years old at the time of enrollment.
4. Prior Therapy:
1. The patient s malignancy must have relapsed after or failed to respond to frontline curative therapy and/or there must not be any curative treatment options available at the time of study entry.
2. There is no limit to the number of prior treatment regimens. However, patients must have fully recovered from the acute toxic effects of prior chemotherapy, immunotherapy, or radiotherapy prior to study enrollment. Any grade 3 or 4 non-hematologic toxicity of any previous therapy must have resolved to grade 2 or less.
3. Myelosuppressive chemotherapy: Patients must not have received myelosuppressive chemotherapy within 3 weeks of enrollment (6 weeks if prior nitrosourea).
4. 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.
5. At least 7 days must have elapsed since the completion of therapy with a biologic agent, targeted agent, tyrosine kinease inhibitor or a metronomic nonmyelosuppressive regimen.
6. Monoclonal antibodies: At least 4 weeks must have elapsed since prior therapy that included a monoclonal antibody.
7. Radiotherapy: 3 weeks must have elapsed since XRT
5. Performance status:
ECOG 0, 1 or 2, or for children less than or equal to 10 years of age, Lansky greater than or equal to 60.
6. Cardiac function:
Left ventricular ejection fraction greater than or equal to 40 percent or fractional shortening greater than or equal to 28 percent.
7. Liver function:
Serum total bilirubin \< 2 mg/dl, serum AST and ALT less than or equal to 3 x upper limit of normal. Patients with Gilbert s syndrome are excluded from the requirement of a normal bilirubin and patients will not be excluded if liver enzyme 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, as is standard on POB phase I trials.
8. Renal function:
Age-adjusted normal serum creatinine according to the following table or a creatinine clearance greater than or equal to 60 ml/min/1.73 m(2).
Age less than or equal to 5 Maximum serum creatinine (mg/dl) 0.8
Age greater than 5 and less than or equal to 10 Maximum serum creatinine (mg/dl) 1.0
Age greater than 10 and less than or equal to 15 Maximum serum creatinine (mg/dl) 1.2
Age greater than 15 Maximum serum creatinine (mg/dl) 1.5
9. Marrow function:
ANC must be \> 750/mm(3), platelet count must be greater than or equal to 75,000/mm(3) (not achieved by transfusion).
10. Ability to give informed consent.
For patients \<18 years of age, their legal guardian must give informed consent. Pediatric patients will be included in age-appropriate discussion in order to obtain verbal assent.
11. Durable power of attorney form offered (patients (Bullet)18 years of age only).
12. Birth Control
Female and male patients (and when relevant their partners) must be willing to practice birth control (including abstinence) during and for two months after treatment, if of childbearing potential.
EXCLUSION CRITERIA:
1. Concurrent Illnesses
Clinically significant systemic illness (e.g. serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the judgment of the PI would compromise the patient s ability to tolerate protocol therapy or significantly increase the risk of complications.
Peripheral nerve symptoms from prior therapies or from tumor compression \> grade 1.
2. Untreated CNS metastasis
Extradural masses that have not invaded the brain parenchyma or parameningeal tumors without evidence for leptomeningeal spread will not render the patient ineligible. Patients with previous CNS tumor involvement that has been treated and is stable for at least 6 weeks following completion of therapy are eligible.
3. Prior Therapy
Previous treatment with genetically engineered GD2-CAR T cells. Previous vaccine therapy, anti-GD2 mAb therapy or therapy with other genetically engineered T cells is not an exclusion criteria.
4. Lactating or pregnant females (due to risk to fetus or newborn).
5. Active HIV, HBV or HCV infection.
6. Immune Therapies
Patients who require systemic corticosteroid or other immunosuppressive therapy. Immunosuppressive therapy must be stopped at least 14 days prior to cell infusion.
INCLUSION OF WOMEN AND MINORITIES:
Both men and women of all races and ethnic groups are eligible for this trial.