A Study of EGFR806 CAR T-Cell Immunotherapy for Treating Children and Young Adults with Recurrent / Refractory Solid Tumors
- Histologically diagnosed malignant, non-central nervous system (CNS) solid tumor expressing EGFR by immunohistochemistry (IHC) staining performed by an accredited laboratory
- Evidence of refractory or recurrent disease as defined below for which there is no known curative therapy * Solid tumors except neuroblastoma (any of the following): ** New site of measurable disease by radiographic imaging or histologic confirmation ** New site of evaluable disease by radiographic imaging (including fludeoxyglucose F-18 [FDG]-positron emission tomography [PET]) or histologic confirmation ** Greater than 20% increase in at least one tumor dimension documented by computed tomography (CT)/magnetic resonance imaging (MRI), AND a minimum absolute increase of 5 mm in longest dimension of existing lesion(s); previously irradiated lesions may be included ** New bone marrow disease with infiltration of > 5% tumor cells ** Persistent measurable disease or FDG-PET avid bone metastasis that has failed to achieve complete remission to upfront conventional therapy (surgery, radiotherapy and/or chemotherapy) and standard salvage therapy * Neuroblastoma (NB) (any of the following) ** New disease site documented on I-123 metaiodobenzylguanidine (MIBG) or CT/MRI; or any new bone site that is FDG-PET avid (in subject known to have MIBG non-avid tumor), AND has MRI findings consistent with tumor, OR has a biopsy of any lesion showing NB or ganglioneuroblastoma ** Greater than 20% increase in a least one dimension of soft tissue mass documented by CT/MRI AND a minimum absolute increase of 5 mm in longest dimension in existing lesion(s); previously irradiated lesions may be included ** Bone marrow biopsy meeting revised International Neuroblastoma Response Criteria (INRC) for progressive disease ** Stable persistent disease, such that response at the completion of upfront therapy or salvage therapy is less than partial response (PR), AND has a biopsy of at least one site showing viable solid tumor consistent with initial diagnosis ** Responding persistent disease, defined as at least a partial response (PR) to frontline therapy (i.e. subject has had at least a PR to frontline therapy but still has residual disease by I-123 MIBG scan, CT/MRI, or bone marrow aspirate/biopsies); subjects in this category are REQUIRED to have histologic confirmation of viable NB from at least one residual site or tumor seen on routine bone marrow morphology is sufficient
- Able to tolerate apheresis or already has an apheresis product available for use in manufacturing
- Life expectancy >= 8 weeks
- Lansky or Karnofsky score >= 50. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for purposes of assessing performance status
- Subject has fully recovered from significant acute toxic effects of all prior chemotherapy, immunotherapy, and radiotherapy
- All chemotherapy has been discontinued >= 7 days prior to enrollment (this does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01)
- All biologic therapy has been discontinued >= 7 days prior to enrollment (this does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01)
- Subject is >= 3 half-lives or 30 days, whichever is shorter, from time of last dose of anti-tumor directed antibody therapy at time of enrollment (this does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01)
- In subjects who have received genetically modified cell therapy, it must not be detectable at time of enrollment
- At time of enrollment, subject is >= 6 weeks from myeloablative therapy and autologous and/or allogeneic stem cell transplant (all timed from stem cell infusion). Subjects who received an autologous stem cell infusion following non-myeloablative therapy do not have a wash-out period and are eligible once they meet all other eligibility requirements. This criterion does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01
- All corticosteroid therapy (unless physiologic replacement dosing) has been discontinued >= 7 days prior to enrollment (this does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01)
- Neuroblastoma subjects only: at time of enrollment, subject is >= 12 weeks from I131 MIBG therapy (this does not apply to subjects with apheresis product or usable T cell product available for use in STRIvE-01)
- Absolute lymphocyte count (ALC) >= 500 cells/uL
- Absolute neutrophil count (ANC) >= 500 cells/uL
- Hemoglobin >= 8 g/dL * Subjects receiving blood product transfusion are acceptable as long as they are not determined to be transfusion refractory
- Platelets >= 100,000/uL * Subjects receiving blood product transfusion are acceptable as long as they are not determined to be transfusion refractory
- Serum creatinine =< the upper limit of normal (ULN) Age: 1 to < 2 years (yrs); maximum serum creatinine (mg/dL): 0.6 (male and female) Age: 2 to < 6 yrs; maximum serum creatinine (mg/dL): 0.8 (male and female) Age: 6 to < 10 yrs; maximum serum creatinine (mg/dL): 1 (male and female) Age: 10 to < 13 yrs; maximum serum creatinine (mg/dL): 1.2 (male and female) Age: 13 to < 16 yrs; maximum serum creatinine (mg/dL): 1.5 (male) and 1.4 (female) Age: >= 16 yrs; maximum serum creatinine (mg/dL): 1.7 (male) and 1.4 (female)
- Total bilirubin =< 3 times ULN for age OR conjugated bilirubin =< 2 mg/dL AND
- Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 times ULN
- Shortening fraction >= 28% OR ejection fraction >= 50% by echocardiogram
- Oxygen saturation >= 93 % on room air without supplemental oxygen or mechanical ventilation, and no dyspnea at rest
- Negative virology tests within 3 months prior to enrollment (all of the following): * Negative human immunodeficiency virus (HIV) antigen & antibody * Negative hepatitis B surface antigen * Negative hepatitis C antibody (if hepatitis C antibody is positive, subject must have a subsequent negative hepatitis C quantitative polymerase chain reaction [qPCR])
- Subjects of child-bearing potential or capable of fathering a child must agree to use highly effective contraception from the time of initial CAR T cell infusion through 12 months following the final CAR T cell infusion on study
- Active malignancy (including primary CNS malignancy) other than primary malignant solid tumor diagnosis (CNS intracranial metastases are allowed)
- Current relevant CNS pathology including paresis, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injury, dementia, cerebellar disease, organic brain syndrome, psychosis, coordination or movement disorder (patients with non-febrile seizure disorder controlled on anti-epileptic medication and without seizure activity within 3 months are eligible)
- If history of allogeneic stem cell transplant: active graft versus host disease (GVHD), or receiving immunosuppressive therapy for treatment or prevention of GVHD within 4 weeks prior to enrollment
- Subject has active severe infection, defined as: * Positive blood culture within 48 hours of enrollment, OR * Fever > 38.2 degrees Celsius (C) AND clinical signs of infection within 48 hours of enrollment
- Receiving external beam radiation therapy at the time of enrollment
- Primary immunodeficiency syndrome
- Receiving any anti-cancer agents or chemotherapy
- Pregnant or breastfeeding
- Subject and/or legally authorized representative unwilling or unable to provide consent/assent for participation in the study and 15-year follow-up period, required if CAR T cell therapy is administered
- Presence of any condition that, in the opinion of the investigator, would prohibit the patient from undergoing treatment under this protocol
I. To estimate the maximum tolerated dose (MTD) of autologous CD4+/CD8+ EGFR806 specific 4-1BB-CD3zeta-EGFRt-expressing CAR T cells (EGFR806-specific CAR T cells) (Arm A) and of dual transduced autologous CD4+/CD8+ 4-1BB-CD3zeta-EGFR806-CAR-EGFRt/4-1BB-CD3zeta- CD19-CAR-HER2tG-expressing CARs T cells (EGFR806xCD19 CAR T cells) (Arm B).
II. To estimate the dose limiting toxicities (DLTs) and describe the full toxicity profile for each study arm.
III. To assess the feasibility of manufacturing EGFR806 or EGFR806xCD19 dual transduced T cells from subject-derived lymphocytes.
IV. To assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express an EGFR806-specific CAR (Arm A).
V. To assess the safety and tolerability of cellular immunotherapy utilizing ex-vivo expanded autologous T cells genetically modified to express the EGFR806 CAR in combination with a CD19 CAR (Arm B).
I. To determine the duration and magnitude of in vivo persistence of adoptively transferred T cells in the peripheral blood and compare engraftment between the T cell products administered in Arm A and Arm B.
II. To evaluate for presence of adoptively transferred T cells in tumor tissue and/or normal tissue if a tissue biopsy, tumor biopsy or resection is clinically indicated.
I. To quantitate anti-tumor responses by measuring changes in tumor burden using disease-specific evaluations and describe survival characteristics following CAR T cell infusion.
II. To assess the efficacy of cetuximab in ablating transferred T cells and ameliorating acute toxicities in treated subjects.
III. To analyze blood, bone marrow, cerebral spinal fluid (CSF), normal tissue and/or tumor tissue for biomarkers of safety and/or anti-tumor activity.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 arms.
ARM A: Patients receive autologous CD4+/CD8+ EGFR806 specific 4-1BB-CD3zeta-EGFRt-expressing CAR T cells (EGFR806-specific CAR T cells) intravenously (IV) on day 0.
ARM B: Patients receive EGFR806-specific CAR T cells IV and autologous CD4+/CD8+ 4-1BB-CD3zeta-EGFR806-CAR-EGFRt/4-1BB-CD3zeta- CD19-CAR-HER2tG-expressing CARs T cells IV on day 0.
After receiving study treatment, patients are followed at least weekly for the first month, then approximately every month for the rest of the 1st, then approximately every 3 months for 6 months, every 6 months through Year 5, and then every year through Year 15 following infusion of investigational product.
Trial Phase Phase I
Trial Type Treatment
Fred Hutch / University of Washington Cancer Consortium
Catherine Michelle Albert
- Primary ID RG1001776
- Secondary IDs NCI-2018-03727, STRIvE-01
- Clinicaltrials.gov ID NCT03618381