Neoplasms

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Glioblastoma

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Anaplastic Astrocytoma

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Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

BIRC5 protein, human

Patients with unresectable tumors will undergo a biopsy followed by injection of neural stem cells loaded with the virus and then receive standard chemoradiotherapy.

Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus and then receive standard chemoradiotherapy.

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.

Neural stem cells loaded with an oncolytic adenovirus

Maciej S Lesniak, MD

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.

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.

A Phase I study of neural stem cell based virotherapy in combination with standard radiation and chemotherapy for patients with newly diagnosed malignant glioma

Neural Stem Cell Based Virotherapy of Newly Diagnosed Malignant Glioma

Neural Stem Cell Oncolytic Adenoviral Virotherapy of Newly Diagnosed Malignant Glioma

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.

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.

National Cancer Institute (NCI)

Northwestern University

Professor and Chairman

Number of patients in each cohort affected by serious adverse events

Patients with resectable tumors underwent surgical resection followed by injection of neural stem cells loaded with the virus (0.5x10\^8 NSCs loading 6.25x10\^10 vp) and then received standard chemoradiotherapy.

Resectable Disease Cohort 1

Patients with resectable tumors underwent surgical resection followed by injection of neural stem cells loaded with the virus (.0x10\^8 NSCs loading 1.25x10\^11 vp) and then received standard chemoradiotherapy.

Resectable Disease Cohort 2

Patients with resectable tumors underwent surgical resection followed by injection of neural stem cells loaded with the virus (1.5x10\^8 NSCs loading 1.875x10\^11 vp) and then received standard chemoradiotherapy.

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 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.

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 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.

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 1.5x10\^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.

Arm B: Resectable Disease Cohort 3

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Christina Amidei, PhD

Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus (dose: 0.5x10\^8/NSCs/6.25x10\^10 vp) and then receive standard chemoradiotherapy. No dose limiting toxicities were experienced in this cohort.

Arm B/Cohort 1

Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus (dose: 1.0x10\^8 NSCs/1.25x10\^10 vp) and then receive standard chemoradiotherapy. No dose limiting toxicities were experienced in this cohort.

Arm B/Cohort 2

.5x10\^8 NSCs/1.875x10\^10 vp

Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus (dose: 1.5x10\^8 NSCs/1.875x10\^10 vp) and then receive standard chemoradiotherapy. One dose limiting toxicity event was experienced in this cohort, prompting 3 additional patients being added to the cohort; no dose limiting toxicities were experienced in this addition to the cohort, and this dose was determined to be the MTD.

ArmB/Cohort 3

No screen failures were encountered and all 12 patients were evaluable.

Percentage of Dose-limiting Toxicities

Percentage of participants with tumor response: Partial

Percentage of participants with tumor response: Pseudoprogression

Percentage of participants with tumor response: Stable disease

Analyses were conducted for the entire cohort (N=12) for secondary objectives.

Total Cohort

Nine of 12 patients had measureable disease post-surgery and were followed with serial MRIs.

Assessment of Tumor Response.

Progression-free Survival

Overall Survival

Patients with resectable tumors will undergo a resection followed by injection of neural stem cells loaded with the virus and then receive standard chemoradiotherapy. The unresectable cohort was not able to be opened due to limited product availability.

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.

Spots Global Cancer Trial Database for new diagnosed glioma