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PVSRIPO and Pembrolizumab in Patients With Recurrent Glioblastoma (LUMINOS-101)

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ClinicalTrials.gov Identifier: NCT04479241
Recruitment Status : Recruiting
First Posted : July 21, 2020
Last Update Posted : April 15, 2021
Sponsor:
Information provided by (Responsible Party):
Istari Oncology, Inc.

Brief Summary:
This Phase 2 single arm trial in patients with rGBM will characterize the efficacy, safety, tolerability and initial efficacy of PVSRIPO intratumoral infusion followed by intravenous pembrolizumab 14 to 28 days later, and every 3 weeks, thereafter.

Condition or disease Intervention/treatment Phase
Glioblastoma Recurrent Glioblastoma Supratentorial Glioblastoma Brain Tumor Biological: PVSRIPO Biological: pembrolizumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2, Open-label, Single-arm Study Evaluating the Efficacy, Safety and Tolerability of PVSRIPO and the Immune Checkpoint Inhibitor Pembrolizumab in the Treatment of Patients With Recurrent Glioblastoma
Actual Study Start Date : October 21, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PVSRIPO Biological: PVSRIPO
PVSRIPO (5x10^7 TCID50) delivered intratumorally via convection enhanced delivery (CED).

Biological: pembrolizumab
Pembrolizumab (200 mg IV) given every 3 weeks.




Primary Outcome Measures :
  1. Objective Response Rate (ORR), Duration of response (DOR) and Durable Radiographic Response (DRR) [ Time Frame: 24 months ]

    Objective response rate (comprised of patients meeting an objective radiographic response or ORR): Patients achieving a CR or PR.

    DOR: Time from first ORR observed (once confirmed) until PD first observed (once confirmed) or death; whichever comes first.

    DRR: An ORR that persists for ≥ 6 months.

    All response must be confirmed via two consecutive MRI assessments at least 4 weeks apart. If on bevacizumab therapy when response first noted, response will be confirmed ≥ 8 weeks off bevacizumab, via MRI.


  2. Frequency and severity of treatment-emergent adverse events [ Time Frame: 24 months ]
    Assess safety and tolerability of PVSRIPO followed by pembrolizumab via frequency and severity of treatment-emergent adverse events (TEAE) via Common Terminology Criteria for Adverse Events (CTCAE, v5.0)


Secondary Outcome Measures :
  1. Disease control rate (DCR) [ Time Frame: 24 months ]
    Proportion of patients achieving stable disease (SD), CR or PR via protocol-specified response criteria

  2. Duration of disease control (DDC) [ Time Frame: 24 months ]
    DDC ≥ 6 months for those meeting DCR

  3. Progression free survival time [ Time Frame: 24 months ]
    If calculable, progression free survival (PFS) will be estimated based on the time from PVSRIPO infusion to death or confirmed progression

  4. Survival assessed by Kaplan-Meier methods [ Time Frame: 24 months ]
    Overall and landmark survival assessed by the proportion of patients alive at ≥ 6, ≥ 12 and at 24 months post-PVSRIPO infusion estimated by Kaplan-Meier methods.


Other Outcome Measures:
  1. Biomarker identification [ Time Frame: 24 months ]
    Assessment of tumor tissue and blood samples for identification of genetic, cytologic, histologic and/or other markers that correlate with anti-tumor response.

  2. Radiographic response/progression/PFS via iRANO [ Time Frame: 24 months ]
    Alternative assessment of radiographic response/progression/PFS via iRANO



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 years of age.
  2. Recurrent supratentorial glioblastoma confirmed via prior histology by the site's neuropathologist or designate.

    • Histologically confirmed recurrent glioblastoma within 6 weeks of PVSRIPO infusion will not require a biopsy to confirm active tumor prior to catheter placement
    • Progression of primary glioblastoma or transformation from a lower grade to a higher grade is acceptable for recurrence and as for primary glioblastoma, must be confirmed via prior histology by site pathologist
  3. Enhancing lesion ≥1 cm shortest diameter to ≤ 5.5 cm longest diameter in all planes.
  4. Before catheter placement based on screening MRI and at the time of catheter placement via CT prior to infusion, neurosurgical investigator must confirm placement of infusion catheter within or through the progressive enhancing tumor is feasible and at a safe distance relative to eloquent brain function, with the tip of the catheter being placed:

    1. Within the enhancing portion or in the vicinity of enhancement of target lesion (ie, infiltrative disease).
    2. ≥ 0.5 cm from ventricles.
    3. ≥ 1 cm deep into the brain.
    4. ≥ 0.5 cm from corpus callosum.
  5. First or second relapse supported by MRI or CT scan; relapse is defined as progression following initial/prior therapy(ies).
  6. Failed previous first line therapy: maximum surgical resection and radiotherapy (RT) (plus concomitant chemotherapy followed by maintenance chemotherapy if unknown or methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter). Patients who begin but do not complete chemotherapy/RT may still be considered for eligibility at the discretion of Sponsor.
  7. Karnofsky Performance Status ≥ 70 at screening and baseline.
  8. Undergone prior vaccination against PV and received a boost immunization with trivalent inactivated poliovirus vaccine (IPOL®) at least 1 week, but less than 6 weeks, prior to administration of PVSRIPO. Note: Patients who are unsure of their prior vaccination status/who have not been vaccinated must provide proof of vaccination and/or evidence of anti-PV immunity prior to enrollment, as applicable.
  9. Ability to safely discontinue anti-coagulant therapy(ies) prior to biopsy/catheter placement, as required per site/surgical guidelines.
  10. Hemoglobin ≥ 9 g/dL prior to biopsy/catheter placement.
  11. Platelet count ≥ 100,000/μL (unsupported); ≥ 125,000/ μL (can be supported via platelet transfusion) at biopsy/catheter placement.
  12. ANC ≥ 1000/μL prior to biopsy/catheter placement.
  13. Creatinine ≤ 1.2 x ULN prior to biopsy/catheter placement.
  14. Total bilirubin, ALT, AST, ALP ≤ 2.5 x ULN prior to biopsy/catheter placement.
  15. PT and aPTT ≤ 1.2 x ULN prior to biopsy/catheter placement.
  16. If undetectable ATT IgG at screen, Tdap booster vaccine ≥ 1 week prior to biopsy/catheter placement.
  17. Patients must be willing and able to understand and provide written informed consent.

Exclusion Criteria:

  1. Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti- CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) ≤ 12 weeks prior to PVSRIPO infusion (Note: does not apply for patients treated with pembrolizumab under this protocol who are eligible for PVSRIPO retreatment). Note: patients who had previously permanently discontinued any anti-PD-1 or PD-L1 therapy due to severe or life-threatening immune-related AE are excluded.
  2. Excluded are:

    1. Neoplastic lesions in the brainstem, cerebellum, or spinal cord.
    2. Radiological evidence of active/growing multifocal disease: no size increase > 0.5 cm in any direction of any other enhancing non-target lesions present at baseline confirmed via most recent, prior, consecutive MRIs at least 3 months apart.
    3. Tumors with ≥ 1cm of contrast-enhancing tumor component crossing the midline (crossing the corpus callosum).
    4. Extensive subependymal disease: multiple lesions or lesions covering > 50% of subependymal space. Tumor touching subependymal space allowed.
    5. Extensive leptomeningeal disease: multiple lesions or lesions covering > 50% of leptomeninges. Tumor touching leptomeninges allowed.
  3. Has received systemic immunosuppressive treatments other than systemic corticosteroids (eg, methotrexate, chloroquine, azathioprine) within six months of PVSRIPO infusion.
  4. Requires treatment with high dose systemic corticosteroids, defined as dexamethasone > 4 mg/day or equivalent, within 2 weeks of PVSRIPO infusion.
  5. Prior interstitial brachytherapy, implanted chemotherapy, stereotactic radiosurgery or therapeutics delivered by local injection or CED, including PVSRIPO (except for qualifying patients being retreated with PVSRIPO within this trial).
  6. Pregnant and/or breast feeding female; patient/female partner of childbearing potential who is unwilling to utilize protocol-defined acceptable form of contraception for duration of study.
  7. Impending/life-threatening cerebral herniation syndrome, per neurosurgeon/designate.
  8. Severe, active co-morbidity, defined as follows:

    1. Infection requiring IV treatment/unexplained febrile illness (Tmax > 99.5°F/37.5°C)
    2. Known immunosuppressive disease/human immunodeficiency virus infection
    3. Known active hepatitis B or C infection via positive viral DNA or RNA, respectively
    4. Unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4)
    5. Known lung disease with forced expiratory volume in 1st second of expiration < 50%
    6. Uncontrolled diabetes mellitus (eg, hemoglobin A1C level > 7.0% with treatment)
    7. History of other malignancy requiring active treatment within 2 years of biopsy/catheter placement with the exception of those with a negligible risk of metastasis or death (eg, resected cutaneous basal cell carcinoma, or other cancers with 5-year OS of >90%)
  9. Known albumin allergy.
  10. Uncontrolled unexplained bleeding and/or hemoptysis within 4 weeks of planned PVSRIPO infusion.
  11. Inability to undergo brain MRI with and without contrast. History of severe/anaphylactic reaction to gadolinium contrast agent is excluded. Mild allergy (eg, rash) acceptable with prophylactic acetaminophen and diphenhydramine.
  12. History of neurological complications due to PV infection.
  13. Not recovered from toxic side effects (alopecia acceptable) and/or no current or prior tumor treatments within the following timeframe relative to biopsy/catheter placement:

    1. Chemotherapy or bevacizumab ≤ 4 weeks (except for nitrosourea (6 weeks) or metronomic dosed chemotherapy/targeted therapies such as daily temozolomide, etoposide or cyclophosphamide (1 week)).
    2. Tumor treating fields ≤ 7 days.
    3. RT of brain ≤ 12 weeks, except for progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation.
  14. History of agammaglobulinemia.
  15. Known hypersensitivity to pembrolizumab, or any components of pembrolizumab.
  16. Active autoimmune disease requiring systemic immunomodulatory treatment within the past 12 months; physiologic replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
  17. History of other malignancy requiring active treatment within 2 years of biopsy/catheter placement with the exception of those with a negligible risk of metastasis or death (eg, resected cutaneous basal cell carcinoma, or other cancers with 5-year OS of >90%)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04479241


Contacts
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Contact: LeAnn Jackson, MPH 919-245-7662 ljackson@istarioncology.com
Contact: Lisa Franklin 919-696-4596 lfranklin@istarioncology.com

Locations
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United States, California
University of California San Francisco Not yet recruiting
San Francisco, California, United States, 94143
Contact: Nicholas Butowski       Nicholas.Butowski@ucsf.edu   
Principal Investigator: Nicholas Butowski, MD         
United States, Connecticut
UConn Health Not yet recruiting
Farmington, Connecticut, United States, 06030
Contact: Annie Quratulain, MPH       qali@uchc.edu   
Principal Investigator: Kevin Becker, MD         
Sub-Investigator: Ketan Bulsara, MD         
United States, Florida
Baptist MD Anderson Cancer Center Recruiting
Jacksonville, Florida, United States, 32207
Contact: Robert Cavaliere@bmcjax.com, MD       ResearchBMDA@bmcjax.com   
Contact: Darlene Brabant       darlene.brabant@bmcjax.com   
Principal Investigator: Robert Cavaliere, MD         
United States, Massachusetts
Massachusetts General Hospital Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Arielle Spivey       ASPIVEY@mgh.harvard.edu   
Principal Investigator: William Curry, MD         
Beth Israel Deaconess Medical Center Not yet recruiting
Boston, Massachusetts, United States, 02215
Principal Investigator: Rafael Vega, MD, PhD         
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Julia Hayden       Julia_Hayden@DFCI.HARVARD.EDU   
Principal Investigator: Patrick Wen, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Daniel Landi       daniel.landi@duke.edu   
Contact: Stevie Threat       stevie.threatt@duke.edu   
Principal Investigator: Daniel Landi, MD         
United States, Ohio
University Hospitals Cleveland Medical Center Recruiting
Cleveland, Ohio, United States, 44106
Contact: Andrew Sloan       andrew.sloan@uhhospitals.org   
Contact: Christopher Murphy       christopher.murphy@uhhospitals.org   
Principal Investigator: Andrew Sloan, MD, FACS         
The Ohio State University Not yet recruiting
Columbus, Ohio, United States, 43210
Principal Investigator: Shirley Ong, MD         
United States, Oregon
Oregon Health and Science University Not yet recruiting
Portland, Oregon, United States, 97239
Contact: Prakash Ambady       ambady@ohsu.edu   
Contact: Riley Roth-Carter       rothcarr@ohsu.edu   
Principal Investigator: Prakash Ambady, MD         
Sponsors and Collaborators
Istari Oncology, Inc.
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Responsible Party: Istari Oncology, Inc.
ClinicalTrials.gov Identifier: NCT04479241    
Other Study ID Numbers: PVSRIPO ICI rGBM 201
First Posted: July 21, 2020    Key Record Dates
Last Update Posted: April 15, 2021
Last Verified: April 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents