Neural Stem Cell Based Virotherapy of Newly Diagnosed Malignant Glioma

NCT ID: NCT03072134

Last Updated: 2023-01-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-24
• Study Completion Date: 2021-07-01

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.

Conditions

Glioma; Anaplastic Astrocytoma; Anaplastic Oligodendroglioma; Anaplastic Oligoastrocytoma; Glioblastoma Multiforme; Astrocytoma, Grade III; Astrocytoma, Grade IV; Brain Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Unresectable disease

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

Group Type: EXPERIMENTAL

Neural stem cells loaded with an oncolytic adenovirus

Intervention Type: BIOLOGICAL

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.

Resectable disease

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

Group Type: EXPERIMENTAL

Neural stem cells loaded with an oncolytic adenovirus

Intervention Type: BIOLOGICAL

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.

Interventions

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.

Intervention Type: BIOLOGICAL

Other Intervention Names

NSC-CRAd-Survivin-pk7

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Maciej Lesniak

Professor and Chairman

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Maciej S Lesniak, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

City of Hope

Duarte, California, United States

Northwestern Memorial Hospital

Chicago, Illinois, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 23926209 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23821758 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21718006 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21629227 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 19277041 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18632631 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 17630837 (View on PubMed)

Fares J, Ahmed AU, Ulasov IV, Sonabend AM, Miska J, Lee-Chang C, Balyasnikova IV, Chandler JP, Portnow J, Tate MC, Kumthekar P, Lukas RV, Grimm SA, Adams AK, Hebert CD, Strong TV, Amidei C, Arrieta VA, Zannikou M, Horbinski C, Zhang H, Burdett KB, Curiel DT, Sachdev S, Aboody KS, Stupp R, Lesniak MS. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 2021 Aug;22(8):1103-1114. doi: 10.1016/S1470-2045(21)00245-X. Epub 2021 Jun 29.

Reference Type: DERIVED

PMID: 34214495 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

5P50CA221747-05

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU00203933

Identifier Type: -

Identifier Source: org_study_id