Anaplastic Astrocytoma, Anaplastic Oligoastrocytoma, Anaplastic Oligodendroglioma, Astrocytoma, Grade III, Astrocytoma, Grade IV, Brain Cancer, Glioblastoma Multiforme, Glioma
Conditions
Keywords
Glioma, Glioblastoma, Astrocytoma, Brain Cancer, New Diagnosed Glioma, Temozolomide, Radiation, Neural Stem Cells, Virotherapy, Adenovirus, Oncolytic virotherapy
Brief summary
Malignant gliomas have a very poor prognosis with median survival measured in months rather than years. It is a disease in great need of novel therapeutic approaches. Based on the encouraging results of our preclinical studies which demonstrate improved efficacy without added toxicity, the paradigm of delivering a novel oncolytic adenovirus via a neural stem cell line in combination with radiation and chemotherapy is well-suited for evaluation in newly diagnosed malignant gliomas. The standard-of-care allows application of virotherapy as neoadjuvant therapy and assessment of the cooperative effects with radiation/chemotherapy without altering the standard treatment.
Detailed description
This is an open-label, phase 1, dose escalation trial that followed a 3x3 design. Three doses will be evaluated in the resectable cohorts: Cohort 1: 0.5x10\^8 NSCs loading 6.25x10\^10 vp; Cohort 2: 1.0x10\^8 NSCs loading 1.25x10\^11 vp; and Cohort 3: 1.5x10\^8 NSCs loading 1.875x10\^11 vp. Subjects enrolled have newly diagnosed high-grade glioma based on clinical and radiologic criteria; pathology will be confirmed at the time of surgical resection. Direct intra-tumoral injection of study product (NSC-CRAd-S-p7) will be done after resection but prior to closure. Subjects will then receive concomitant radiotherapy (RT) at a dose of 60Gy and chemotherapy with temozolomide (TMZ), 75 mg/m2, daily during RT. This will be followed by adjuvant TMZ dosed at 200 mg/m2 for 6 cycles. Subjects will be followed until disease progression with serial brain MRIs, and for survival up to 5 years. The non-resectable cohort will not opened due to limited product availability.
Interventions
BIOLOGICALNeural stem cells loaded with an oncolytic adenovirus
The primary objectives are to evaluate the safety of the combined therapy and determine the maximum tolerated dose (MTD) for a future Phase II study.
Sponsors
National Cancer Institute (NCI)
Northwestern University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Phase I study of neural stem cell based virotherapy in combination with standard radiation and chemotherapy for patients with newly diagnosed malignant glioma
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have presumed malignant glioma based on clinical and radiologic evaluation (pathologic confirmation of malignant glioma must be made at the time of stereotactic biopsy or resection prior to NSC-CRAd-S-pk7 injection; if this is not possible, the injection will not be performed and the subject will no longer be eligible for the study). * Tumor must be accessible for injection and must not be located in the brainstem, or contained within the ventricular system. * Planning to undergo standard radiation/chemotherapy * 18 years of age or older. * Performance status must be KPS ≥ 70 * SGOT (AST) \< 3x upper limit of normal * Serum creatinine \< 2mg/dl * Platelets \> 100,000/mm3 and WBC \> 3000/mm3
Exclusion criteria
* Prior or ongoing liver disease including known cirrhosis, hepatitis B or C infection but not to exclude patients with a distant history of resolved hepatitis A infection. * Immunosuppressive drugs (with exception of corticosteroid). * Known HIV+ patients. * Acute infections (viral, bacterial or fungal infections requiring therapy). * Pregnant or breast-feeding patients. * Evidence of metastatic disease or other malignancy (except squamous or basal cell skin cancers). * Prior radiation therapy to the brain or prior treatment for brain tumor Other serious co-morbid illness or compromised organ function.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Dose-limiting Toxicities | Two years | Using a 3+3 dose escalation design, three to six patients were to be enrolled per dose in each of the 3 cohorts. If no patients in the cohort experienced a dose-limiting toxicity (DLT), then the next cohort enrolled a minimum of 3 patients. If one of three patients experienced a DLT, then 3 more patients were evaluated at that dose level. If none of these three additional patients experienced a DLT, then dose escalation occurs, unless this is the highest dose, in which case dose escalation is stopped and the highest dose is declared the MTD. If 1 or more of these additional 3 patients had a DLT, then three additional patients may be entered, after discussion with the sponsor, at the next lowest does level if only three patients were treated previously at that dose. If two or more patients experienced a DLT Dose escalation will be stopped; 3 more patients could be added with sponsor approval at the next lower dose level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Tumor Response. | Two years | Per Response Assessment in Neuro-Oncology Criteria (RANO, 2017) for target lesions as assessed by MRI: Complete Response (CR): The enhancing tumor is no longer seen by neuroimaging; Partial Response (PR): Decrease of ≥ 50% in the product of two diameters with the patient on a stable or decreasing dose of steroids; Minor Response (MR): Decrease in diameter products of \< 50% with the patient on a stable or decreasing dose of steroids; Stable Disease (SD): The scan shows no change. Patients should be receiving stable or decreasing doses of steroids; Progression (P): Increase of \> 25% in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period. A concomitant decrease in steroid dose will rule out a progression designation during the first two months after completion of radiation; Pseudoprogression (PP): Radiological changes without concomitant neurological changes. |
| Progression-free Survival | two years | Median progression-free survival |
| Overall Survival | Two years | Median overall survival |
Countries
United States
Participant flow
Recruitment details
April 24, 2017 thru Nov 13, 2019 at Northwestern University and City of Hope.
Pre-assignment details
Arm A, for subjects with unresectable disease, was not opened due to limited product availability
Participants by arm
| Arm | Count |
|---|---|
| Arm B: Resectable Disease Cohort 1 Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus at dose level 0.5x10\^8 NSCs loading 6.25x10\^10 vp and then receive standard chemoradiotherapy.
Neural stem cells loaded with an oncolytic adenovirus: The primary objectives are to evaluate the safety of the combined therapy and determine the maximum tolerated dose (MTD) for a future Phase II study. | 3 |
| Arm B: Resectable Disease Cohort 2 Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus at dose level 1.0x10\^8 NSCs loading 1.25x10\^11 vp and then receive standard chemoradiotherapy.
Neural stem cells loaded with an oncolytic adenovirus: The primary objectives are to evaluate the safety of the combined therapy and determine the maximum tolerated dose (MTD) for a future Phase II study. | 3 |
| Arm B: Resectable Disease Cohort 3 Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus at dose level 1.5x10\^8 NSCs loading 1.875x10\^11 vp and then receive standard chemoradiotherapy.
Neural stem cells loaded with an oncolytic adenovirus: The primary objectives are to evaluate the safety of the combined therapy and determine the maximum tolerated dose (MTD) for a future Phase II study. | 6 |
| Total | 12 |
Baseline characteristics
| Characteristic | Arm B: Resectable Disease Cohort 1 | Arm B: Resectable Disease Cohort 2 | Arm B: Resectable Disease Cohort 3 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 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 |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 3 participants | 3 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 6 |
Outcome results
Primary
Percentage of Dose-limiting Toxicities
Using a 3+3 dose escalation design, three to six patients were to be enrolled per dose in each of the 3 cohorts. If no patients in the cohort experienced a dose-limiting toxicity (DLT), then the next cohort enrolled a minimum of 3 patients. If one of three patients experienced a DLT, then 3 more patients were evaluated at that dose level. If none of these three additional patients experienced a DLT, then dose escalation occurs, unless this is the highest dose, in which case dose escalation is stopped and the highest dose is declared the MTD. If 1 or more of these additional 3 patients had a DLT, then three additional patients may be entered, after discussion with the sponsor, at the next lowest does level if only three patients were treated previously at that dose. If two or more patients experienced a DLT Dose escalation will be stopped; 3 more patients could be added with sponsor approval at the next lower dose level.
Time frame: Two years
Population: No screen failures were encountered and all 12 patients were evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm B/Cohort 1 | Percentage of Dose-limiting Toxicities | 0 Percentage of dose-limiting toxicities |
| Arm B/Cohort 2 | Percentage of Dose-limiting Toxicities | 0 Percentage of dose-limiting toxicities |
| ArmB/Cohort 3 | Percentage of Dose-limiting Toxicities | 17 Percentage of dose-limiting toxicities |
Secondary
Assessment of Tumor Response.
Per Response Assessment in Neuro-Oncology Criteria (RANO, 2017) for target lesions as assessed by MRI: Complete Response (CR): The enhancing tumor is no longer seen by neuroimaging; Partial Response (PR): Decrease of ≥ 50% in the product of two diameters with the patient on a stable or decreasing dose of steroids; Minor Response (MR): Decrease in diameter products of \< 50% with the patient on a stable or decreasing dose of steroids; Stable Disease (SD): The scan shows no change. Patients should be receiving stable or decreasing doses of steroids; Progression (P): Increase of \> 25% in tumor area (two diameters) provided that the patient has not had his/her dose of steroids decreased since the last evaluation period. A concomitant decrease in steroid dose will rule out a progression designation during the first two months after completion of radiation; Pseudoprogression (PP): Radiological changes without concomitant neurological changes.
Time frame: Two years
Population: Nine of 12 patients had measureable disease post-surgery and were followed with serial MRIs.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm B/Cohort 1 | Assessment of Tumor Response. | Percentage of participants with tumor response: Partial | 8 Percentage of participants |
| Arm B/Cohort 1 | Assessment of Tumor Response. | Percentage of participants with tumor response: Pseudoprogression | 8 Percentage of participants |
| Arm B/Cohort 1 | Assessment of Tumor Response. | Percentage of participants with tumor response: Stable disease | 84 Percentage of participants |
Secondary
Overall Survival
Median overall survival
Time frame: Two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B/Cohort 1 | Overall Survival | 18.4 Months |
Secondary
Progression-free Survival
Median progression-free survival
Time frame: two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm B/Cohort 1 | Progression-free Survival | 9.1 Months |