Allogenic Adipose-Derived Mesenchymal Stem Cells for the Treatment of Recurrent Glioblastoma in Patients Undergoing Craniotomy

Study Overview
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Brief Summary
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This phase I trial tests the safety, side effects, and best dose of allogenic adipose-derived mesenchymal stem cells (AMSCs) in treating patients with glioblastoma that has come back (recurrent) who are undergoing brain surgery (craniotomy). Glioblastoma is the most common and most aggressive form of primary and malignant tumor of the brain. Currently, the standard of care for this disease includes surgical resection, followed by radiation with chemotherapy and tumor treating fields. Despite this aggressive therapy, the survival after finishing treatment remains low and the disease often reoccurs. Unfortunately, the available therapy options for recurrent GBM are minimal and do not have a great effect on survival. AMSCs are found in body fat and when separated from the fat, are delivered into the surgical cavity at the time of surgery. When in direct contact with tumor cells, AMSCs affect tumor growth, residual tumor cell death, and chemotherapy resistance. The use of AMSCs delivered locally into the surgical cavity of recurrent GBM during a craniotomy could improve the long-term outcomes of these patients by decreasing the progression rate and invasiveness of malignant cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To establish the maximum tolerated dose (MTD) of locally delivered adipose-derived mesenchymal stem cells (AMSCs) in patients with recurrent glioblastoma (GBM). SECONDARY OBJECTIVES: I. To assess the safety and toxicity profile of locally delivered AMSCs in patients with recurrent GBM. II. To assess overall survival (OS) in recurrent GBM patients treated with locally delivered AMSCs. III. To assess progression free survival (PFS) in recurrent GBM patients treated with locally delivered AMSCs. CORRELATIVE OBJECTIVES: I. To explore the systemic immune response after application of AMSCs through cytokine analysis on peripheral blood samples. II. To explore the local changes on the brain parenchyma by analyzing tissue at recurrence. III. To explore the presence of AMSCs on brain tissue at recurrence. OUTLINE: This is a dose-escalation study. Patients receive AMSCs intratumorally (IT) and undergo Ommaya reservoir placement during a craniotomy on study. Patients also undergo magnetic resonance imaging (MRI) on study and during follow-up, as well as blood sample and cerebrospinal fluid (CSF) sample collection on study.

Official Title
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Phase 1, Dose Escalation, Non-Randomized, Open Label, Clinical Trial Evaluating the Safety and Preliminary Efficacy of Allogenic Adipose-Derived Mesenchymal Stem Cells (AMSCs) for Recurrent Glioblastoma

Conditions
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Recurrent Glioblastoma

Intervention / Treatment
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* Biological: Allogeneic Adipose-derived Mesenchymal Stem Cells
* Procedure: Biospecimen Collection
* Procedure: Craniotomy
* Procedure: Magnetic Resonance Imaging
* Procedure: Ommaya Reservoir Tap


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants >= 18 years < 65 years of age Karnofsky Performance Scale (KPS) >= 60 Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only Patients with a previous histological diagnosis of GBM that show recurrence at the same location, who are candidates to- and will undergo a redo craniotomy for excision of recurrent tumor Patients have undergone previous standard of care as outlined by Stupp et al. (2004) which include maximal safe resection followed by concomitant radiation therapy and chemotherapy with oral temozolomide There is measurable disease according to the immunotherapy response assessment in neuro-oncology (iRANO) criteria Serum creatinine and urea <= 2 times the upper limit of normal (=< 3 weeks prior to registration) Alanine transaminase (ALT), aspartate transferase (AST) and alkaline phosphatase =< 3 times the upper limit of normal, and bilirubin =< 2.5 mg/dL (=< 3 weeks prior to registration) Prothrombin time =< 1.5 times upper limit of normal (=< 3 weeks prior to registration) International normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 times the upper limit of normal (=< 3 weeks prior to registration) Hemoglobin >= 9 g/dL (=< 3 weeks prior to registration) Platelets >= 100 x 10^9/L (=< 3 weeks prior to registration) Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (=< 3 weeks prior to registration) Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Patient or legally authorized representative (LAR) is able to fully understand and provide written and verbal consent for the protocol Willingness to provide mandatory blood specimens for correlative research Willingness to provide mandatory tissue specimens for correlative research Willingness to undergo Ommaya reservoir placement and provide cerebrospinal fluid (CSF) samples for correlative research Exclusion Criteria: Patients who are undergoing needle biopsy only or non-eligible for a surgical intervention Tumors located in the brain stem, midbrain, or thalamus Previous treatment with bevacizumab Radiographic evidence of leptomeningeal disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (AMSCs)<br>Patients receive AMSCs IT and undergo Ommaya reservoir placement during a craniotomy on study. Patients also undergo MRI on study and during follow-up, as well as blood sample and CSF sample collection on study. | Biological: Allogeneic Adipose-derived Mesenchymal Stem Cells<br>* Receive IT<br>* Other names: Allogeneic Mesenchymal Stem/Stromal Cells;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Craniotomy<br>* Undergo craniotomy<br>* Other names: Open Craniotomy;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Nuclear Magnetic Resonance Imaging;Procedure: Ommaya Reservoir Tap<br>* Undergo Ommaya reservoir placement for collection of CSF<br>* Other names: Ommaya Reservoir Access;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) | Defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients). Will use the standard cohort 3+3 design. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) | All patients who have received any treatment will be considered evaluable for assessing adverse event rates. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Will follow the Common Terminology Criteria for Adverse Events version 5.0 to record and grade (1-5) any potential AEs. | Up to 1 year | 
| Best response | Best response per patient is defined to be the best objective status recorded from treatment application until disease progression or death (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Best response assignment will depend on the achievement of both measurement and confirmation criteria. | Up to 5 years | 
| Response rate (RR) | RR is defined as the number of patients who have achieved complete response or partial response per immunotherapy response assessment for neuro-oncology for recurrent glioblastoma after application of allogeneic adipose-derived mesenchymal stem cells (AMSCs) divided by total number of evaluable patients. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population. | Up to 5 years | 
| Progression free survival | The quality of survival will be measured by performance status. The data on time-related variables will be summarized descriptively. | From time of AMSCs application until the first occurrence of progression or death, assessed up to 5 years | 
| Overall survival | The quality of survival will be measured by performance status. The data on time-related variables will be summarized descriptively. | From beginning the time of AMSCs application to the date of death, assessed up to 5 years |