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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03072134
Other study ID # STU00203933
Secondary ID 5P50CA221747-05
Status Completed
Phase Phase 1
First received
Last updated
Start date April 24, 2017
Est. completion date July 1, 2021

Study information

Verified date December 2022
Source Northwestern University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 12
Est. completion date July 1, 2021
Est. primary completion date April 6, 2020
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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.

Study Design


Intervention

Biological:
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.

Locations

Country Name City State
United States Northwestern Memorial Hospital Chicago Illinois
United States City of Hope Duarte California

Sponsors (2)

Lead Sponsor Collaborator
Northwestern University National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (7)

Ahmed AU, Thaci B, Alexiades NG, Han Y, Qian S, Liu F, Balyasnikova IV, Ulasov IY, Aboody KS, Lesniak MS. Neural stem cell-based cell carriers enhance therapeutic efficacy of an oncolytic adenovirus in an orthotopic mouse model of human glioblastoma. Mol Ther. 2011 Sep;19(9):1714-26. doi: 10.1038/mt.2011.100. Epub 2011 May 31. — View Citation

Ahmed AU, Thaci B, Tobias AL, Auffinger B, Zhang L, Cheng Y, Kim CK, Yunis C, Han Y, Alexiades NG, Fan X, Aboody KS, Lesniak MS. A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy. J Natl Cancer Inst. 2013 Jul 3;105(13):968-77. doi: 10.1093/jnci/djt141. — View Citation

Ahmed AU, Tyler MA, Thaci B, Alexiades NG, Han Y, Ulasov IV, Lesniak MS. A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma. Mol Pharm. 2011 Oct 3;8(5):1559-72. doi: 10.1021/mp200161f. Epub 2011 Jun 30. — View Citation

Nandi S, Ulasov IV, Tyler MA, Sugihara AQ, Molinero L, Han Y, Zhu ZB, Lesniak MS. Low-dose radiation enhances survivin-mediated virotherapy against malignant glioma stem cells. Cancer Res. 2008 Jul 15;68(14):5778-84. doi: 10.1158/0008-5472.CAN-07-6441. — View Citation

Tobias AL, Thaci B, Auffinger B, Rincon E, Balyasnikova IV, Kim CK, Han Y, Zhang L, Aboody KS, Ahmed AU, Lesniak MS. The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma. Stem Cells Transl Med. 2013 Sep;2(9):655-66. doi: 10.5966/sctm.2013-0039. Epub 2013 Aug 7. — View Citation

Ulasov IV, Sonabend AM, Nandi S, Khramtsov A, Han Y, Lesniak MS. Combination of adenoviral virotherapy and temozolomide chemotherapy eradicates malignant glioma through autophagic and apoptotic cell death in vivo. Br J Cancer. 2009 Apr 7;100(7):1154-64. doi: 10.1038/sj.bjc.6604969. Epub 2009 Mar 10. — View Citation

Ulasov IV, Zhu ZB, Tyler MA, Han Y, Rivera AA, Khramtsov A, Curiel DT, Lesniak MS. Survivin-driven and fiber-modified oncolytic adenovirus exhibits potent antitumor activity in established intracranial glioma. Hum Gene Ther. 2007 Jul;18(7):589-602. doi: 10.1089/hum.2007.002. — View Citation

Outcome

Type Measure Description Time frame Safety issue
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. Two years
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. Two years
Secondary Progression-free Survival Median progression-free survival two years
Secondary Overall Survival Median overall survival Two years
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