PVSRIPO With/Without Lomustine

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02986178
Recruitment Status : Recruiting
First Posted : December 8, 2016
Last Update Posted : November 12, 2018
Duke University
Information provided by (Responsible Party):
Istari Oncology, Inc.

Brief Summary:
This is a randomized phase 2 study of oncolytic polio/rhinovirus recombinant (PVSRIPO) alone or in combination with the chemotherapy drug lomustine in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma.

Condition or disease Intervention/treatment Phase
Malignant Glioma Biological: PVSRIPO Drug: Lomustine Phase 2

Detailed Description:
This is a randomized phase 2 study of oncolytic polio/rhinovirus recombinant (PVSRIPO) alone or in combination with the chemotherapy drug lomustine in adult patients with recurrent World Health Organization (WHO) grade IV malignant glioma. The primary objective of this study is to assess the efficacy of a single dose of PVSRIPO alone or in combination with a single dose of lomustine among adults with WHO grade IV malignant glioma at first or second recurrence relative to the survival observed in a historical control group. The secondary objective is to determine the safety of each PVSRIPO treatment cohort in recurrent WHO grade IV malignant glioma patients. Within each cohort, the proportion of patients who experience grade 3, 4, or 5 AEs that are possibly, probably, and definitely related to protocol treatment will be estimated. Subjects will be randomized to receive either PVSRIPO alone, or PVSRIPO in combination with a single dose of lomustine 8 weeks after PVSRIPO infusion, to evaluate the impact of these treatment regimens on 24-month survival relative to historical controls. PVSRIPO will be delivered intratumorally by convection-enhanced delivery (CED) using an intracerebral catheter placed within the enhancing portion of the tumor. Based on experience with a Phase 1 study at Duke, previously published reports, and institutional review board (IRB)- and FDA-approved trials using similar infusion techniques, patients will be infused at a rate of 0.5 mL/hr. A Medfusion™ 3500 infusion pump (Smiths Medical, Minneapolis, MN) or any other comparable FDA-cleared syringe infusion pump approved by the sponsor or their designee, will be pre-programmed to a delivery rate of 0.5 mL/hr. Subjects randomized to the lomustine arm will receive a single oral dose of 110 mg/m^2 lomustine 8 weeks after PVSRIPO administration. If a subject has been treated with bevacizumab in the time since PVSRIPO infusion, the lomustine dose will be dispensed as an oral therapy at 90 mg/m^2 one time only 8 weeks after PVSRIPO infusion. The target accrual for the study is 62 patients, 31 patients per arm. All patients who are randomized and receive PVSRIPO treatment will be included in efficacy and safety analyses.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Multicenter, Phase 2 Study of Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) Alone or in Combination With Lomustine in Recurrent WHO Grade IV Malignant Glioma Patients
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : May 2021
Estimated Study Completion Date : May 2023

Arm Intervention/treatment
Experimental: Polio/Rhinovirus Recombinant (PVSRIPO)
Polio/Rhinovirus Recombinant (PVSRIPO)
Biological: PVSRIPO
A single dose of an oncolytic polio/rhinovirus recombinant (PVSRIPO)

Experimental: Polio/Rhinovirus Recombinant (PVSRIPO) + Lomustine
Polio/Rhinovirus Recombinant (PVSRIPO) + Lomustine
Biological: PVSRIPO
A single dose of an oncolytic polio/rhinovirus recombinant (PVSRIPO)

Drug: Lomustine
A single oral dose of 110 mg/m2 lomustine 8 weeks after PVSRIPO administration. If a subject has been treated with bevacizumab in the time since PVSRIPO infusion, the lomustine dose will be dispensed as an oral therapy at 90 mg/m2 one time 8 weeks after PVSRIPO infusion.
Other Name: Gleostine

Primary Outcome Measures :
  1. 24-month overall survival [ Time Frame: 24 months after administration of PVSRIPO ]
    The percentage of participants alive at 24 months after the administration of PVSRIPO. Overall survival is calculated from the date of administration of PVSRIPO until the date of death, or the date of last follow-up if alive. Kaplan-Meier methods are used to estimate overall survival.

Secondary Outcome Measures :
  1. Percentage of participants with grade 3, 4, or 5 treatment-related adverse events [ Time Frame: Up to 24 months; events will be assessed continuously from the time of catheter placement for PVSRIPO administration until 30 days after a participant goes off study. ]
    The percentage of particpants with grade 3, 4 or 5 adverse events possibly, probably or definitely related to administration of PVSRIPO or Lomustine.

Other Outcome Measures:
  1. The changes visualized on imaging due to intratumoral inoculation of PVSRIPO alone or in combination with lomustine will be assessed [ Time Frame: Up to week 52 ]
    In each treatment group, the components of the inflammatory reaction will be summarized

  2. Assessment of immunologic changes stemming from the administration of PVSRIPO alone or in combination with lomustine utilizing peripheral blood samples collected at defined intervals. [ Time Frame: Up to 24 months ]
    Peripheral blood will be collected at defined intervals for correlative immune-monitoring study.

  3. Assessment of tumor genetic markers as possible predictors of response. [ Time Frame: Up to 24 months ]
    The Cox model will explore the impact of various genetic tumor markers on survival time.

  4. Assessment of quantitative gut microbiome profile. [ Time Frame: Up to 24 months ]
    Utilizing stool samples, the quantitative gut microbiome profile will be assessed before and after PVSRIPO or PVSRIPO and lomustine for quantitive gut profile analysis

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

Inclusion Criteria

  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). Tumor size and location requirements will need to be confirmed by the reviewer designated by the Sponsor. Prior histopathology consistent with a WHO grade IV malignant glioma confirmed by the site's neuropathologist or the neuropathologist's designate
  2. If the subject is male and sexually active, he is eligible to enter and participate in this study if his partner(s) meets the criteria outlined in 2a or if he or his partner(s) is using one of the methods of birth control outlined in 2b. If the subject is female, she is eligible to enter and participate in this study if she meets the following criteria:

    1. Non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is postmenopausal or surgically sterile). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this study, is defined as 1 year without menses); or
    2. Childbearing potential, has a negative serum pregnancy test at screening, and agrees to use one of the following methods of birth control: approved hormonal contraceptives (e.g. birth control pills, patches, implants, or infusions), an intrauterine device, or a barrier method of contraception (e.g. a condom or diaphragm) used with spermicide.
    3. If the male has had a vasectomy or is using a condom with spermicide, the female partner does not need to use additional birth control noted in 2a and 2b.
  3. Age ≥ 18 years of age at the time of entry into the study
  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 informed consent form (ICF) approved by the IRB will be required for patient enrollment into the study. Patients or their legally authorized representative (LAR) must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study
  15. Able to undergo brain MRI with and without contrast

Exclusion Criteria

  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 follow:

    1. Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C)
    2. Patients with known immunosuppressive disease or known human immunodeficiency virus infection
    3. Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4)
    4. Patients with known lung (forced expiratory volume in the first second of expiration [FEV1] < 50%) disease or uncontrolled diabetes mellitus
    5. Patients with albumin allergy
    6. Patients with gadolinium allergy
  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, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation
  9. Patients who have not completed all standard of care treatments, including surgical procedure and radiation therapy (at least 59Gy)

    1. If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial
    2. If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial
  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 PVSRIPO 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. Patients with 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

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 identifier (NCT number): NCT02986178

Contact: Heny Friedman, MD 919-681-3138
Contact: Andrea True Kelly, PhD 919-943-5023

United States, California
UCSF Neurological Surgery Recruiting
San Francisco, California, United States, 94941
Contact: Nicholas Butowski, MD    415-353-2966   
Contact: Eduardo R Almaraz    415-514-5529   
United States, Florida
Boca Raton Regional Hospital Recruiting
Boca Raton, Florida, United States, 334486
Contact: Frank D Vrionis, MD,MPH,PhD    561-955-4244   
Contact: Pilar Zuniga    561-955-3723   
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: William T Curry, MD    617-724-8770   
United States, North Carolina
Preston Robert Tisch Brain Tumor Center at Duke University Recruiting
Durham, North Carolina, United States, 27710
Contact: David Ashley, MBBS, FRACP, PhD    919-684-5301      
Contact: Stevie Threatt    919-684-5301      
Sponsors and Collaborators
Istari Oncology, Inc.
Duke University
Principal Investigator: David Ashley, MBBS, FRACP, PhD Duke University
Study Director: Darell Bigner, MD, PhD Istari Oncology, Inc.

Additional Information:
Responsible Party: Istari Oncology, Inc. Identifier: NCT02986178     History of Changes
Other Study ID Numbers: Pro00077024
First Posted: December 8, 2016    Key Record Dates
Last Update Posted: November 12, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Istari Oncology, Inc.:
Brain tumor

Additional relevant MeSH terms:
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents