Malignant Glioma
Conditions
Keywords
Glioblastoma, Glioma, PVSRIPO, Duke, Pro00077024, Brain tumor, Istari, Recurrent, GBM, rGBM
Brief summary
This is a phase 2 study of lerapolturev, an oncolytic polio/rhinovirus recombinant, in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma.
Detailed description
This is a Phase 2 study of lerapolturev, an oncolytic polio/rhinovirus recombinant, in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma. The objective of this study is to investigate the safety and efficacy (anti-tumor response and survival) of lerapolturev in recurrent WHO grade IV malignant glioma. Patients will be administered lerapolturev intratumorally via convection-enhanced delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. Retreatment with lerapolturev is allowed, provided retreatment eligibility criteria are met.
Interventions
BIOLOGICALlerapolturev
A single dose of lerapolturev, an oncolytic polio/rhinovirus recombinant
DRUGLomustine
one cycle of oral lomustine
Sponsors
Duke University
Istari Oncology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Study began as parallel (randomized two arm study) and was revised to single group.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
SUMMARY: 1. Patients must have a recurrent (first or second recurrence only, including this recurrence; transformation from a lower grade tumor to a WHO grade IV malignant glioma will be considered a first recurrence) supratentorial WHO grade IV malignant glioma based on imaging studies with measurable disease (a minimum measurement of 1 cm and maximum of 5.5 cm of contrast-enhancing tumor) with prior histopathology consistent with a WHO grade IV malignant glioma confirmed by the site's neuropathologist or the neuropathologist's designate. 2. Male patients who are sexually active are eligible if he and/or his partner(s) meets the criteria outlined in the protocol. Female subjects are eligible if he and/or his partner(s) meets the criteria outlined in the protocol. 3. Age ≥ 18 years of age. 4. Karnofsky Performance Status (KPS) Score ≥ 70%. 5. Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy. 6. Total bilirubin, serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase ≤ 2.5 x normal prior to biopsy. 7. Neutrophil count ≥ 1000 prior to biopsy. 8. Hemoglobin ≥ 9 prior to biopsy. 9. Platelet count ≥ 100,000/μL unsupported is necessary for eligibility on study; however, because of risks of intracranial hemorrhage with catheter placement, platelet count ≥ 125,000/μL is required for the patient to undergo biopsy and catheter insertion, which can be attained with the help of platelet transfusion. 10. Creatinine ≤ 1.2 x normal range prior to biopsy. 11. Positive serum anti-PV titer prior to biopsy. 12. The patient must have received a boost immunization with trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week, but less than 6 weeks, prior to administration of the study agent. 13. At the time of biopsy, prior to administration of virus, the presence of recurrent tumor must be confirmed by histopathological analysis. 14. A signed IRB-approve informed consent form (ICF). 15. Able to undergo brain MRI with and without contrast.
Exclusion criteria
SUMMARY: 1. Females who are pregnant or breast-feeding. 2. Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons, their designate, and the reviewer designated by the sponsor. 3. Patients with severe, active co-morbidity, defined as in the protocol. 4. Patients with a previous history of neurological complications due to PV infection. 5. Patients who have not recovered from the toxic effects of prior chemo- and/or radiation therapy. Guidelines for this recovery period are dependent upon the specific therapeutic agent being used. 6. Patients may not have received tumor treating fields (≤ 1 week), chemotherapy or bevacizumab ≤ 4 weeks \[except for nitrosourea and lomustine (≤ 6 weeks); metronomic dosed chemotherapy, such as daily temozolomide, etoposide or cyclophosphamide (≤ 1 week)\] prior to starting the study drug. 7. Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy. 8. Patients may not be less than 12 weeks from radiation therapy of the brain, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation. 9. Prior to enrollment, has not completed all standard of care treatments, including surgical procedure and radiation therapy (at least 59Gy) as outlined in the protocol. 10. Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord; radiological evidence of multiple areas of active (growing) disease (active multifocal disease); tumors with contrast-enhancing tumor component crossing the midline (crossing the corpus callosum); extensive subependymal disease (tumor touching subependymal space is allowed); or extensive leptomeningeal disease (tumor touching leptomeninges is allowed). 11. Patients with undetectable anti-tetanus toxoid immunoglobulin G (IgG). 12. Patients with known history of agammaglobulinemia. 13. Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to admission for lerapolturev infusion. 14. Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups). 15. Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin. 16. For patients randomized prior to V7, a known history of hypersensitivity to lomustine, dacarbazine, or any components of lomustine. 17. Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Radiographic Response | up to 5 years | Assess objective anti-tumor response based on iRANO criteria. |
| Duration of Objective Radiographic Response | up to 5 years | Assess time of confirmed response to confirmed disease progression or death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival | up to 5 years | Overall Survival (months), calculated using the Kaplan-Meier method |
| Landmark Survival | at 24 and 36 months post-lerapolturev infusion | Overall survival (months) at 24 and 36 months, calculated using the Kaplan-Meier method |
| Disease Control Rate | up to 5 years | the percentage of participants achieving complete response, partial response, or stable disease |
| Safety of Lerapolturev | up to 52 weeks | Number of participants experiencing Grade 3, 4 or 5 adverse events considered possibly, probably, or definitely related to protocol treatment |
Countries
United States
Participant flow
Recruitment details
The lerapolturev + lomustine arm was closed after interim review. Recruitment to the lerapolturev alone arm remained open.
Pre-assignment details
Safety set includes all enrolled participants who had an infusion catheter placed. Full-analysis set includes all randomized participants who received lerapolturev treatment.
Participants by arm
| Arm | Count |
|---|---|
| Lerapolturev lerapolturev administered once intratumorally by convection-enhanced delivery | 93 |
| Lerapolturev + Lomustine lerapolturev administered once intratumorally by convection-enhanced delivery plus one dose of lomustine at 8 weeks post-lerapolturev dosing | 27 |
| Total | 120 |
Baseline characteristics
| Characteristic | Lerapolturev | Lerapolturev + Lomustine | Total |
|---|---|---|---|
| Age, Continuous | 56 years STANDARD_DEVIATION 12.4 | 50 years STANDARD_DEVIATION 13.6 | 54 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 87 Participants | 27 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 3 Participants |
| Karnofsky Performance Status 100 | 7 Participants | 2 Participants | 9 Participants |
| Karnofsky Performance Status 70 | 5 Participants | 0 Participants | 5 Participants |
| Karnofsky Performance Status 80 | 21 Participants | 8 Participants | 29 Participants |
| Karnofsky Performance Status 90 | 60 Participants | 17 Participants | 77 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) White | 83 Participants | 26 Participants | 109 Participants |
| Region of Enrollment United States | 93 participants | 27 participants | 120 participants |
| Sex: Female, Male Female | 28 Participants | 11 Participants | 39 Participants |
| Sex: Female, Male Male | 65 Participants | 16 Participants | 81 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 8 / 94 | 4 / 26 | 12 / 121 |
| other Total, other adverse events | 94 / 94 | 26 / 26 | 121 / 121 |
| serious Total, serious adverse events | 37 / 94 | 12 / 26 | 50 / 121 |
Outcome results
Primary
Duration of Objective Radiographic Response
Assess time of confirmed response to confirmed disease progression or death
Time frame: up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lerapolturev | Duration of Objective Radiographic Response | NA months |
| Lerapolturev + Lomustine | Duration of Objective Radiographic Response | NA months |
Primary
Number of Participants With Objective Radiographic Response
Assess objective anti-tumor response based on iRANO criteria.
Time frame: up to 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lerapolturev | Number of Participants With Objective Radiographic Response | 5 Participants |
| Lerapolturev + Lomustine | Number of Participants With Objective Radiographic Response | 2 Participants |
Secondary
Disease Control Rate
the percentage of participants achieving complete response, partial response, or stable disease
Time frame: up to 5 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lerapolturev | Disease Control Rate | 51 percentage of participants |
| Lerapolturev + Lomustine | Disease Control Rate | 48 percentage of participants |
Secondary
Landmark Survival
Overall survival (months) at 24 and 36 months, calculated using the Kaplan-Meier method
Time frame: at 24 and 36 months post-lerapolturev infusion
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lerapolturev | Landmark Survival | Probability of being alive at 24 months | 0.12 proportion probability |
| Lerapolturev | Landmark Survival | Probability of being alive at 36 months | 0.07 proportion probability |
| Lerapolturev + Lomustine | Landmark Survival | Probability of being alive at 24 months | 0.19 proportion probability |
| Lerapolturev + Lomustine | Landmark Survival | Probability of being alive at 36 months | 0.11 proportion probability |
Secondary
Median Overall Survival
Overall Survival (months), calculated using the Kaplan-Meier method
Time frame: up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lerapolturev | Median Overall Survival | 7.0 months |
| Lerapolturev + Lomustine | Median Overall Survival | 7.1 months |
Secondary
Safety of Lerapolturev
Number of participants experiencing Grade 3, 4 or 5 adverse events considered possibly, probably, or definitely related to protocol treatment
Time frame: up to 52 weeks
Population: The safety set includes all participants who had an infusion catheter placed.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lerapolturev | Safety of Lerapolturev | 17 Participants |
| Lerapolturev + Lomustine | Safety of Lerapolturev | 8 Participants |