PVSRIPO for Recurrent Glioblastoma (GBM) (PVSRIPO)
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|ClinicalTrials.gov Identifier: NCT01491893|
Recruitment Status : Active, not recruiting
First Posted : December 14, 2011
Results First Posted : September 28, 2018
Last Update Posted : November 27, 2018
|First Submitted Date ICMJE||December 1, 2011|
|First Posted Date ICMJE||December 14, 2011|
|Results First Submitted Date ICMJE||June 27, 2018|
|Results First Posted Date ICMJE||September 28, 2018|
|Last Update Posted Date||November 27, 2018|
|Actual Study Start Date ICMJE||April 25, 2012|
|Actual Primary Completion Date||June 27, 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
||Maximum Tolerated Dose [ Time Frame: 28 days post administration of PVS-RIPO ]
The highest dose level for which the estimated probability that a patient experiences a dose-limiting toxicity (DLT) is less than 20%. Any grade 3 or any Grade 4 toxicity that is not reversible within 2 weeks, or any life-threatening event, or treatment-related death will be considered a DLT. Any grade 2 or higher serious autoimmune toxicities particularly those affecting vital organs (e.g. cardiac, renal, CNS) will be considered a DLT.
|Change History||Complete list of historical versions of study NCT01491893 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||PVSRIPO for Recurrent Glioblastoma (GBM)|
|Official Title ICMJE||Dose-finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent WHO Grade IV Malignant Glioma|
Purpose of the Study:
To determine the maximally tolerated dose (MTD) and the Recommended Phase 2 Dose (RP2D) of PVSRIPO when delivered intracerebrally by convection-enhanced delivery (CED). To obtain correlative mechanistic evidence of PVSRIPO's effects on infected WHO Grade IV malignant glioma tumors and to estimate progression-free survival (PFS) and overall survival (OS) in recurrent WHO Grade IV malignant glioma patients. To obtain information about clinical response rates to intratumoral inoculation of PVSRIPO. To estimate the efficacy of PVSRIPO administered at the optimal dose.
PVSRIPO is a genetically recombinant, non-pathogenic poliovirus:rhinovirus chimera with a tumor-specific conditional replication phenotype. It consists of the genome of the live attenuated poliovirus serotype 1 (SABIN) vaccine (PV1S) with its cognate internal ribosomal entry site (IRES) element replaced with that of human rhinovirus type 2 (HRV2). PVSRIPO has been manufactured at NCI-Frederick, NCI, NIH.
Catheter Implantation: PVSRIPO will be delivered directly into the tumor. A stereotactic biopsy will be performed prior to virus administration for frozen section confirmation of viable tumor and further analysis. The biopsy needle will be placed with stereotactic guidance by a Cosman-Robert-Wells, MRI-compatible, stereotactic head frame or similar frameless device. Immediately following the stereotactically-guided tumor biopsy, a catheter will be implanted in the operating room (OR) at a site the same or different from that used for the biopsy using sterile techniques. A CT may be used to confirm catheter placement post-operatively.
Agent infusion: The entire volume of the agent to be delivered will be pre-loaded into a syringe by the investigational pharmacist and connected to the catheter under sterile conditions in the Neuro-Surgical Intensive Care Unit (NSICU) or neuro step down unit just prior to the beginning of infusion. Drug infusion will occur in the NSICU or neuro step down unit so that all other emergency facilities will be available. Patients will be infused through a Medfusion 3500 or 3010 infusion pump pre-programmed to a delivery rate of 500 microliters/hour. The total amount of the inoculum delivered to the patient will be 3 ml. The virus injection procedure will be completed within 6.5 hours. The catheter will be removed following the post-PVSRIPO infusion MRI.
Biopsy sampling and analyses: Biopsy material will be obtained from tumor tissue prior to virus administration. This tissue material will be subjected to routine histology to confirm tumor recurrence by the study neuropathologist, Dr. R. McLendon or his designate. Molecular genetic tests will also be conducted on extracts of tumor cells from the protocol-specified biopsy prior to PVSRIPO infusion. After acquiring sufficient tissue for standard clinical pathologic testing, up to three additional core biopsies will be obtained, if possible. The additional core biopsies will be used for genetic analysis, including full genome or full exome sequencing, as well as other molecular genetic testing. This testing will include, but is not limited to, DNA sequencing, gene amplification, and gene expression. Additional pathology tests on the protocol-specified biopsy tissue may be included, if a sufficient amount of tissue remains after standard clinical pathologic testing.
Selected patients who benefited from the initial infusion of PVSRIPO within this protocol will be eligible for a second infusion. All procedures previously described will be followed; however, the addition of a single dose of lomustine 8 weeks after PVSRIPO administration will alter the schedule of events that was previously described.
During the dose escalation phase of the study, the starting amount (dose level 1) of PVSRIPO to be delivered was 1.0 x 10^8 tissue culture infectious dose (TCID50). Dose level 2 was 3.3 x 10^8 TCID50, dose level 3 was 1.0 x 10^9 TCID50, dose level 4 was 3.3 x 10^9 TCID50, and dose level 5 wase 1.0 x 10^10 TCID50. 50% Tissue Culture Infective Dose (TCID50) is the unit of measure of infectious virus titer.
To minimize the number of patients treated at low-dose levels during the dose escalation phase, we used a two-step continual reassessment method (CRM) design that included an escalation step and a model-guided step. In the dose escalation phase, dose levels were rapidly escalated as preclinical data suggested that dose-limiting toxicity (DLT) would not occur at any of the five dose levels that were being evaluated. Decisions concerning dose escalation for subsequent patients were based upon the occurrence of DLT during the first 4 weeks after treatment administration. Initially, each patient was observed for ≥ 4 weeks before the next patient was treated. Starting at dose level 1, one patient was to be treated at each higher dose level. If no DLT was observed within 4 weeks of administration, then the next patient was to be treated at the next higher dose. If no DLTs were observed among patients treated on the first four dose levels, subsequent patients were to be treated at dose level 5. The escalation step was to be interrupted if a patient assigned to one of the first 4 dose levels or more than 20% of patients treated at dose level 5 experienced a DLT. In that case, further dose escalation or de-escalation would be guided by the likelihood-based implementation of the CRM, in which the one-parameter hyperbolic tangent model would be used to estimate the probability of DLT at each of the 5 dose levels based upon available data. The highest dose level for which this estimated probability is less than 20% would be identified as the maximum tolerated dose (MTD).
After completion of the dose escalation phase and determination of the MTD, the study protocol was amended to allow continued patient accrual to a dose expansion phase, in order to aid in the determination of the Recommended Phase II Dose (RP2D), and to garner more information about patient safety. The RP2D of PVSRIPO is the safe, therapeutic dose where patients have not experienced undue side effects from PVSRIPO or from the management of cerebral inflammation secondary to PVSRIPO administration. To address difficulties tapering patients off of steriods, the dose was reduced to dose level 2 (3.3 x 10^8 TCID50) for the dose expansion phase. After 6 patients were treated at dose level 2 in the dose expansion phase, due to continued difficulties tapering patients off steroids, the protocol was amended to further reduce the dose to dose level -1 (5.0 x 10^7 TCID50) with the goal of limiting the occurrence of known possible side effects of prolonged steroid use in patients who otherwise benefit from this investigational therapy. After the treatment of 24 patients at dose level -1, despite the fact that these patients were able to remain off significant doses of steroids, the patients benefiting the most from PVSRIPO appeared to be those who had experienced minimal or easily controllable inflammation. Hence, the protocol was amended to reduce the PVSRIPO dose to dose level -2 (1.0 x 10^7 TCID50) with the goal of limiting the occurrence of undesirable burden from inflammation and its treatment on as many subjects (and caregivers) as possible. Based upon additional animal studies, dose level -2 (1.0 x 10^7 TCID50) would also be a therapeutic dose. Reduction to dose level -2 was not due to concerns for the safety of the patients on dose level -1, but due to the observation that less inflammatory reaction appeared to be a predictor of better survival and treatment response. After treating 15 patients at dose level -2, based upon pre-clinical and clinical data collected on dose levels -1 and -2, there was no evidence of pre-clinically or clinically important differences between these dose levels. Therefore, the decision was made to treat all future study patients at dose level -1 (5.0 x 10^7 TCID50).
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 1|
|Study Design ICMJE||Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Intervention ICMJE||Biological: Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)
Recombinant nonpathogenic polio-rhinovirus chimera (PVSRIPO)
Other Name: Live attenuated, oral (Sabin) serotype 1 poliovirus vaccine
|Study Arms ICMJE||
|Publications *||Desjardins A, Gromeier M, Herndon JE 2nd, Beaubier N, Bolognesi DP, Friedman AH, Friedman HS, McSherry F, Muscat AM, Nair S, Peters KB, Randazzo D, Sampson JH, Vlahovic G, Harrison WT, McLendon RE, Ashley D, Bigner DD. Recurrent Glioblastoma Treated with Recombinant Poliovirus. N Engl J Med. 2018 Jul 12;379(2):150-161. doi: 10.1056/NEJMoa1716435. Epub 2018 Jun 26.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Active, not recruiting|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Estimated Study Completion Date ICMJE||June 2021|
|Actual Primary Completion Date||June 27, 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
Eligibility Criteria for Retreatment:
Subjects can be considered for PVSRIPO retreatment if they meet some of the pertinent inclusion and exclusion criteria above. In addition, the subject must also satisfy the following criteria:
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01491893|
|Other Study ID Numbers ICMJE||Pro00031169
NS20023 ( Other Grant/Funding Number: National Institute of Neurological Disorders and Stroke )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Istari Oncology, Inc.|
|Study Sponsor ICMJE||Istari Oncology, Inc.|
|PRS Account||Istari Oncology, Inc.|
|Verification Date||October 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP