Brain Cancer, Glioblastoma, Gliosarcoma, Malignant Glioma
Conditions
Keywords
Cell Therapy, Gene Therapy, Immunotherapy, Brain Cancer, Glioma, Glioblastoma
Brief summary
Background: The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with gliomas that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. In this protocol, we are modifying the patient's white blood cells with a retrovirus that has the gene for epidermal growth factor receptor (EGFR) vIII incorporated in the retrovirus. Objective: The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (anti-EGFRvIII cells) are a safe and effective treatment for advanced gliomas. Eligibility: \- Adults age 18-70 with malignant glioma expressing the EGFRvIII molecule. Design: Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti-EGFRvIII cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.} Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the anti-EGFRvIII cells, and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment. Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans every month for the first year, and then every 1-2 months as long as their tumors are shrinking. Follow up visits will take up to 2 days.
Detailed description
BACKGROUND: \- Patients with recurrent gliomas have very limited treatment options. Epidermal growth factor receptor (EGFR). (EGFRvIII) is the most common mutant variant of EGFR and is present in 24-67% of patients with glioblastoma. * EGFRvIII expression promotes oncogenesis and is associated with poor prognosis. * EGFRvIII is not expressed in normal tissue and is an attractive target for immunotherapy. * We have constructed a retroviral vector that contains a chimeric antigen receptor (CAR) that recognizes the EGFRvIII tumor antigen, which can be used to mediate genetic transfer of this CAR with high efficiency without the need to perform any selection. OBJECTIVES: Primary Objectives * To evaluate the safety of the administration of anti-EGFRvIII CAR engineered peripheral blood lymphocytes in patients receiving the non-myeloablative, lymphodepleting preparative regimen and aldesleukin. * Determine the six month progression free survival of patients receiving anti-EGFRvIII CAR-engineered peripheral blood lymphocytes and aldesleukin following a nonmyeloablative, lymphodepleting preparative regimen. ELIGIBILITY: * Histologically proven glioblastoma or gliosarcoma expressing EGFRvIII as determined by immunohistochemistry (IHC) or Reverse transcription polymerase chain reaction (RT-PCR) * Failed prior standard treatment with radiotherapy with or without chemotherapy * Karnofsky performance score (KPS) greater than or equal to 60 * Cardiac, pulmonary and laboratory parameters within acceptable limits DESIGN: * The study will be conducted using a Phase I/II design. * Patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of ex vivo tumorreactive, CAR gene-transduced peripheral blood mononuclear cells (PBMC), plus intravenous (IV) aldesleukin. * Once the maximum tolerated cell dose (MTD) has been determined, the study will proceed to the phase II portion. * In the phase II portion of the trial, patients will be accrued to two cohorts: * Patients with recurrent malignant glioma receiving steroids at the time of treatment. * Patients with recurrent malignant glioma not receiving steroids at the time of treatment. * A total of 107 patients may be enrolled over a period of 7 years.
Interventions
DRUGFludarabine
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
DRUGCyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr.
BIOLOGICALEpidermal growth factor receptor(EGFRv)III Chimeric antigen receptor (CAR) transduced PBL
Day 0: Cells will be infused intravenously over 20-30 minutes. Patients will receive two cell doses, 2 hours apart.
DRUGAldesleukin
Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
-INCLUSION CRITERIA: 1. Patients with histologically proven glioblastomas or gliosarcomas that express epidermal growth factor receptor(EGFRv)III as assessed by immunohistochemistry (IHC) or polymerase chain reaction (PCR) confirmed by the National Cancer Institute (NCI) Laboratory of Pathology. 2. Patients must have progression of disease after radiotherapy (including patients that undergo surgery for recurrent disease and are rendered no evidence of disease (NED)). This includes recurrent glioblastoma (GBM) after receiving all standard first-line treatment, including surgery (if feasible due to neurosurgical and neuro-anatomical considerations) and adjuvant radiotherapy +/- chemotherapy. 3. Patients must either not be receiving steroids, or be on a stable dose of steroids for at least five days prior to registration. 4. Age greater than or equal to 18 years and less than or equal to age 70 years. 5. Ability of subject to understand and the willingness to sign a written informed consent document. 6. Willing to sign a durable power of attorney. 7. Karnofsky Performance Status (KPS) greater than or equal to 60 8. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for four months after treatment. 9. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. 10. Serology * Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive may have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.) * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patients must be tested for the presence of antigen by Reverse transcription polymerase chain reaction (RT-PCR) and be Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) negative. 11. Hematology * White blood cell (WBC) greater than or equal to 3000/mm(3) * Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3) without the support of filgrastim * Platelet count greater than or equal to 100,000/mm(3) * Hemoglobin greater than or equal to 8.0 g/dl. Subjects may be transfused to reach this cut-off. 12. Chemistry * Serum Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) less than or equal to 2.5 x ULN * Serum creatinine less than or equal to 1.6 mg/dl * Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome, who must have a total bilirubin equal to or less than 3.0 mg/dl. 13. Patients must be at least 4 weeks from radiation therapy. Additionally, patients must be at least 6 weeks from nitrosoureas, 4 weeks from temozolomide, 3 weeks from procarbazine, 2 weeks from vincristine and 4 weeks from last bevacizumab administration. Patients must be at least 4 weeks from other cytotoxic therapies not listed above and 2 weeks for non-cytotoxic agents (e.g., interferon, tamoxifen) including investigative agents. All toxicities from prior therapies should be resolved to Common Terminology Criteria in Adverse Events (CTCAE) less than or equal to grade 1 (except for toxicities such as alopecia, or vitiligo). 14. Subject's must be co-enrolled on protocol 03-C-0277
Exclusion criteria
1. A prior history of gliadel implantation in the past six months.. 2. Women of child-bearing potential who are pregnant or breast feeding because of the potentially dangerous effects of the treatment on the fetus or infant. 3. Active systemic infections, requiring anti-infective treatment, coagulation disorders, or any other active or uncompensated major medical illnesses 4. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 5. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities). 6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin. 7. History of coronary revascularization or ischemic symptoms. 8. Clinically significant hemorrhagic or ischemic stroke, including transient ischemic attacks and other central nervous system bleeding in the preceding 6 months that were not related to glioma surgery. History of prior intratumoral bleeding is not an
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Treatment Related Adverse Events | From 4 weeks after cell infusion up to 77 days | Aggregate of all adverse events ≥Grade 3 that are possibly, probably, and definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). Per CTCAE, Grade 3 adverse events are severe, Grade 4 is life threatening, and Grade 5 is death. |
| Progression Free Survival | Time from the date of registration to the date of first observation of progressive disease up to 6 months after end of treatment | Progression was assessed by the Response Assessment in Neuro-Oncology (RANO) criteria and is defined as the circumstance when the magnetic resonance imaging (MRI) scan is ranked -2 (definitely worse) or -3 (development of a new lesion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With an Objective Response | 4 weeks after cell infusion and monthly as feasible up to 12 months | Objective response was assessed by comparison with baseline dynamic contrast enhanced magnetic resonance imaging with perfusion using Neuro-oncology Working Group proposed guidelines. Complete Response is disappearance of all measurable and non-measurable disease for at least 4 weeks. Partial Response is \>/= 50% decrease in lesions for at least 4 weeks. Stable Disease does not meet the criteria for complete response, partial response or progression and requires stable lesions compared with baseline. Progression is \>/= 25% increase in lesions. |
| Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 1 month post transplant | CAR and vector presence were quantitated in peripheral blood mononuclear cell (PBMC) samples using established polymerase chain reaction (PCR) techniques |
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 51 dys Grp A, Cohort 1; Cohort 2:68 dys; Cohort 3:40 dys; Grp B, Cohort 1:67 dys; Cohort 2:48 dys; Cohort 3:55 dys; Cohort 4: 46 dys; Cohort 5:147 dys; C. Ster/No Ster Grp, Cohort 6:12 mos, 26 dys; Cohort 7:11 mos, 18 dys; Cohort 8:7 dys; Cohort 9:70 dys. | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. |
Countries
United States
Participant flow
Pre-assignment details
All patients were treated on the Ph I portion of the study. After encountering a patient mortality at dose level 8 and a grade 3 pulmonary toxicity at dose level 9 without seeing any clinical responses, the principal investigator and senior staff re-evaluated the protocol and elected to close the protocol rather than proceed into the Ph II portion.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group A (Steroids) - Cohort 2: 3x10(7) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group A (Steroids) - Cohort 3: 1x10(8) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group B (No Steroids) - Cohort 1: 1x10(7) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group B (No Steroids) - Cohort 2: 3x10(7) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group B (No Steroids) - Cohort 3: 1x10(8) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group B (No Steroids) - Cohort 4: 3x10(8) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Group B (No Steroids) - Cohort 5: 1x10(9) Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 3 |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) After Amendment H, steroid and no steroid groups were no longer separated. Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 3 |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) After Amendment H, steroid and no steroid groups were no longer separated. Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 3 |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) After Amendment H, steroid and no steroid groups were no longer separated. Day 0: Cells will be infused intravenously over 20-30 minutes. Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) After Amendment H, steroid and no steroid groups were no longer separated. Day 0: Cells will be infused intravenously over 20-30 minutes. Given as a split dose, 2 hours apart.
Aldeskeukin 72,000 IU /kg intravenous (IV) or 720,000 IU /kg IV (based on total body weight) over 15 minutes every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum 15 doses).
Days -7 to -3: Fludarabine 25 mg /m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml dextrose 5% in water (D5W) with Mesna 15 mg/kg /day X 2 days over 1 hr. | 1 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Group A (Steroids) - Cohort 2: 3x10(7) | Group A (Steroids) - Cohort 3: 1x10(8) | Group B (No Steroids) - Cohort 1: 1x10(7) | Group B (No Steroids) - Cohort 2: 3x10(7) | Group B (No Steroids) - Cohort 3: 1x10(8) | Group B (No Steroids) - Cohort 4: 3x10(8) | Group B (No Steroids) - Cohort 5: 1x10(9) | Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Group A (Steroids) - Cohort 1: 1x10(7) | Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 2 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 17 Participants |
| Age, Continuous | 43.0 years | 52.0 years | 46.0 years | 57.0 years | 56.0 years | 53.0 years | 55.3 years STANDARD_DEVIATION 0.6 | 62.3 years STANDARD_DEVIATION 3.2 | 56.0 years STANDARD_DEVIATION 11.4 | 45.0 years | 47.0 years | 57.0 years | 54.3 years STANDARD_DEVIATION 7.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Prior Treatment Radiation, temozolomide, bevacizumab | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surgery, radiation, temozolomide | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 6 Participants |
| Prior Treatment Surgery, radiation, temozolomide, bevacizumab | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Prior Treatment Surgery,radiation,temozolomide,bevacizumab,AZD7451 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surgery, radiation, temozolomide, bevacizumab,BCNU | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surgery, radiation, temozolomide, carotuximab,beva | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surgery, radiation, temozolomide, IMA950 vaccine | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surgery, radiation, temozolomide, veliparib, beva | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surg,rad,temoz,EGFRvIIIvacc.vs.placebo tr,bev,treb | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surg,rad,temoz,EGFRvIIIvacc.vs.placebo trial,beva | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Prior Treatment Surg,rad,temozolomide,bevacizumab,EGFRvIII vaccine | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 3 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 16 Participants |
| Region of Enrollment United States | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 1 participants | 3 participants | 3 participants | 3 participants | 1 participants | 1 participants | 1 participants | 18 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 1 | 0 / 1 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 3 / 3 | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 1 | 0 / 3 | 0 / 3 | 0 / 3 | 1 / 1 | 1 / 1 |
Outcome results
Primary
Number of Treatment Related Adverse Events
Aggregate of all adverse events ≥Grade 3 that are possibly, probably, and definitely related to treatment. Adverse events were assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). Per CTCAE, Grade 3 adverse events are severe, Grade 4 is life threatening, and Grade 5 is death.
Time frame: From 4 weeks after cell infusion up to 77 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group A (Steroids) - Cohort 2: 3x10(7) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group A (Steroids) - Cohort 3: 1x10(8) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group B (No Steroids) - Cohort 1: 1x10(7) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group B (No Steroids) - Cohort 2: 3x10(7) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group B (No Steroids) - Cohort 3: 1x10(8) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group B (No Steroids) - Cohort 4: 3x10(8) | Number of Treatment Related Adverse Events | 0 adverse events |
| Group B (No Steroids) - Cohort 5: 1x10(9) | Number of Treatment Related Adverse Events | 0 adverse events |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Number of Treatment Related Adverse Events | 0 adverse events |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Number of Treatment Related Adverse Events | 0 adverse events |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Number of Treatment Related Adverse Events | 1 adverse events |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Number of Treatment Related Adverse Events | 1 adverse events |
Primary
Progression Free Survival
Progression was assessed by the Response Assessment in Neuro-Oncology (RANO) criteria and is defined as the circumstance when the magnetic resonance imaging (MRI) scan is ranked -2 (definitely worse) or -3 (development of a new lesion).
Time frame: Time from the date of registration to the date of first observation of progressive disease up to 6 months after end of treatment
Population: Combined steroids/no steroids, Cohort 8: participant experienced a treatment-related mortality (TRM).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) | Progression Free Survival | 1.1 months |
| Group A (Steroids) - Cohort 2: 3x10(7) | Progression Free Survival | 1.1 months |
| Group A (Steroids) - Cohort 3: 1x10(8) | Progression Free Survival | 1.3 months |
| Group B (No Steroids) - Cohort 1: 1x10(7) | Progression Free Survival | 1.9 months |
| Group B (No Steroids) - Cohort 2: 3x10(7) | Progression Free Survival | 2.0 months |
| Group B (No Steroids) - Cohort 3: 1x10(8) | Progression Free Survival | 1.5 months |
| Group B (No Steroids) - Cohort 4: 3x10(8) | Progression Free Survival | 1.2 months |
| Group B (No Steroids) - Cohort 5: 1x10(9) | Progression Free Survival | 1.1 months |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Progression Free Survival | 2.7 months |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Progression Free Survival | 1.1 months |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Progression Free Survival | 0 months |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Progression Free Survival | 2.0 months |
Secondary
Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment
CAR and vector presence were quantitated in peripheral blood mononuclear cell (PBMC) samples using established polymerase chain reaction (PCR) techniques
Time frame: 1 month post transplant
Population: Only 1/3 participants were evaluable in cohort 6 at one month, and 2/3 participants were evaluable in cohort 7 at one month. Due to a low number of events, nonspecific binding of anti-human Fab', and slow recovery of the lymphocyte compartment, the data reported should be interpreted with caution.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 23 K/µL |
| Group A (Steroids) - Cohort 2: 3x10(7) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 70 K/µL |
| Group A (Steroids) - Cohort 3: 1x10(8) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 36 K/µL |
| Group B (No Steroids) - Cohort 1: 1x10(7) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 67 K/µL |
| Group B (No Steroids) - Cohort 2: 3x10(7) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 7 K/µL |
| Group B (No Steroids) - Cohort 3: 1x10(8) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 43 K/µL |
| Group B (No Steroids) - Cohort 4: 3x10(8) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 28 K/µL |
| Group B (No Steroids) - Cohort 5: 1x10(9) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 25 K/µL |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 12 K/µL |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 67.5 K/µL |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | NA K/µL |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Circulating Chimeric Antigen Receptor (CAR+) Cells in Peripheral Blood at 1 Month Post Treatment | 8 K/µL |
Secondary
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: 51 dys Grp A, Cohort 1; Cohort 2:68 dys; Cohort 3:40 dys; Grp B, Cohort 1:67 dys; Cohort 2:48 dys; Cohort 3:55 dys; Cohort 4: 46 dys; Cohort 5:147 dys; C. Ster/No Ster Grp, Cohort 6:12 mos, 26 dys; Cohort 7:11 mos, 18 dys; Cohort 8:7 dys; Cohort 9:70 dys.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group A (Steroids) - Cohort 2: 3x10(7) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group A (Steroids) - Cohort 3: 1x10(8) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group B (No Steroids) - Cohort 1: 1x10(7) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group B (No Steroids) - Cohort 2: 3x10(7) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group B (No Steroids) - Cohort 3: 1x10(8) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group B (No Steroids) - Cohort 4: 3x10(8) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Group B (No Steroids) - Cohort 5: 1x10(9) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 3 Participants |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 3 Participants |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 3 Participants |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) | 1 Participants |
Secondary
Number of Patients With an Objective Response
Objective response was assessed by comparison with baseline dynamic contrast enhanced magnetic resonance imaging with perfusion using Neuro-oncology Working Group proposed guidelines. Complete Response is disappearance of all measurable and non-measurable disease for at least 4 weeks. Partial Response is \>/= 50% decrease in lesions for at least 4 weeks. Stable Disease does not meet the criteria for complete response, partial response or progression and requires stable lesions compared with baseline. Progression is \>/= 25% increase in lesions.
Time frame: 4 weeks after cell infusion and monthly as feasible up to 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Steroids) - Cohort 1: 1x10(7) | Number of Patients With an Objective Response | 0 Participants |
| Group A (Steroids) - Cohort 2: 3x10(7) | Number of Patients With an Objective Response | 0 Participants |
| Group A (Steroids) - Cohort 3: 1x10(8) | Number of Patients With an Objective Response | 0 Participants |
| Group B (No Steroids) - Cohort 1: 1x10(7) | Number of Patients With an Objective Response | 0 Participants |
| Group B (No Steroids) - Cohort 2: 3x10(7) | Number of Patients With an Objective Response | 0 Participants |
| Group B (No Steroids) - Cohort 3: 1x10(8) | Number of Patients With an Objective Response | 0 Participants |
| Group B (No Steroids) - Cohort 4: 3x10(8) | Number of Patients With an Objective Response | 0 Participants |
| Group B (No Steroids) - Cohort 5: 1x10(9) | Number of Patients With an Objective Response | 0 Participants |
| Combined Steroids/no Steroids) - Cohort 6: 3x10(9) | Number of Patients With an Objective Response | 0 Participants |
| Combined Steroids/no Steroids) - Cohort 7: 1x10(10) | Number of Patients With an Objective Response | 0 Participants |
| Combined Steroids/no Steroids) - Cohort 8: 3-6x10(10) | Number of Patients With an Objective Response | 0 Participants |
| Combined Steroids/no Steroids) - Cohort 9: 3x10(10) | Number of Patients With an Objective Response | 0 Participants |