Neural Stem Cell Based Virotherapy of Newly Diagnosed Malignant Glioma

NCT03072134 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: STU002039335P50CA221747-05
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

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.

Conditions

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

Keywords

Glioma; Glioblastoma; Astrocytoma; Brain Cancer; New Diagnosed Glioma; Temozolomide; Radiation; Neural Stem Cells; Virotherapy; Adenovirus; Oncolytic virotherapy

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Assessment of Tumor Response.

  Two years

• Progression-free Survival

  two years

• Overall Survival

  Two years

Study Arms (2)

Unresectable disease

EXPERIMENTAL

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

Biological: Neural stem cells loaded with an oncolytic adenovirus

Resectable disease

EXPERIMENTAL

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

Biological: Neural stem cells loaded with an oncolytic adenovirus

Interventions

Neural stem cells loaded with an oncolytic adenovirus 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.

Also known as: NSC-CRAd-Survivin-pk7

Resectable disease; Unresectable disease

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Northwestern University: lead
• National Cancer Institute (NCI): collaborator

Study Sites (2)

City of Hope

Duarte, California, 91010, United States

Location

Northwestern Memorial Hospital

Chicago, Illinois, 60611, United States

Location

Related Publications (8)

• 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.

  PMID: 23926209 BACKGROUND

• 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.

  PMID: 23821758 BACKGROUND

• 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.

  PMID: 21718006 BACKGROUND

• 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.

  PMID: 21629227 BACKGROUND

• 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.

  PMID: 19277041 BACKGROUND

• 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.

  PMID: 18632631 BACKGROUND

• 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.

  PMID: 17630837 BACKGROUND

• 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.

  PMID: 34214495 DERIVED

MeSH Terms

Conditions

Glioma; Astrocytoma; Oligodendroglioma; Glioblastoma; Brain Neoplasms; Adenoviridae Infections

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; DNA Virus Infections; Virus Diseases; Infections

Results Point of Contact

• Title: Christina Amidei, PhD
• Organization: Northwestern University

christina.amidei@nm.org

13126959124

Study Officials

• Maciej S Lesniak, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chairman

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

Study Record Dates

• First Submitted: February 20, 2017
• First Posted: March 7, 2017
• Study Start: April 24, 2017
• Primary Completion: April 6, 2020
• Study Completion: July 1, 2021
• Last Updated: January 20, 2023
• Results First Posted: January 20, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)