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PVSRIPO for Patients With Unresectable Melanoma

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ClinicalTrials.gov Identifier: NCT03712358
Recruitment Status : Recruiting
First Posted : October 19, 2018
Last Update Posted : November 28, 2018
Sponsor:
Collaborator:
Duke University
Information provided by (Responsible Party):
Istari Oncology, Inc.

Brief Summary:
This study is a Phase I study of oncolytic polio/rhinovirus recombinant (PVSRIPO) to primarily characterize the safety and tolerability of PVSRIPO in patients with AJCC Stage IIIB, IIIC, or IV melanoma in a modified 3+3 phase 1 trial design. Lesion biopsies and blood samples will obtained pre- and post-injection throughout the study for routine histology/molecular genetic testing and immunologic analysis, respectively. Exploratory objectives include describing the response rates of PVSRIPO-injected versus non-injected lesion(s), the number of CD8 positive T cells present in the tumor biopsies before and after injection of PVSRIPO, and after PVSRIPO administration: the pathologic response in tumor biopsies, changes in the tumor microenvironment, and how systemic immune cell populations may change.

Condition or disease Intervention/treatment Phase
Melanoma Biological: PVSRIPO Phase 1

Detailed Description:

The Primary Objective of the study is to determine the safety profile of PVSRIPO in Stage IIIB, IIIC, and IV recurrent melanoma patients as determined by DLTs when PVSRIPO is injected intralesionally into 1 to 3 cutaneous or subcutaneous lesions. As planned, a minimum of 3 patients will be treated with PVSRIPO, up to a maximum of 9.

A modified 3+3 phase 1 trial design will be implemented over three dosing cohorts (cohorts 0-2), where patients will receive 1 (cohort 0), 2 (cohort 1) or 3 (cohort 2) injections into individual lesions; if more than 1 lesion is injected, injections will occur 21 days apart. In cohort 0, a minimum of 3 patients will have one lesion injected with PVSRIPO at 1x10^8 TCID50. If 0 or 1 of 3 have a dose limiting toxicity (DLT; any Grade 4 or higher non-hematologic toxicities probably, possibly, or definitely related to PVSRIPO; with the exception of vitiligo; any Grade 4 or higher hematologic toxicities probably, possibly, or definitely related to PVSRIPO)). within 21 days after injection, three patients will be enrolled to cohort 1, to receive PVSRIPO at a dose of 1x10^8 TCID50 on day 0 into one index lesion and a second injection at the same dose (1x10^8 TCID50 ) into a separate lesion on day 21 (±2 days). If 2 or more patients have a DLT in cohort 0, the dose will decrease to 5x10^7 TCID50 and 3 patients will have 1 lesion injected on day 0 and this reduced dose will be cohort 1. Additional cohorts will be based on the number of toxicities noted. A second injection of a second lesion may not be given in an individual patient if that patient experiences a DLT following their first injection.

If 2 of 3 patients in cohort 1 have a DLT, accrual will be temporarily suspended, for a more detailed review DLTs, before processing to enroll additional patients. If the trial resumes, it will proceed to a lower second dose per in Cohort 2, or possibly stop the trial. If 2 of the first 3 patients in cohort 2 have a DLT, safety will be re-assessed before treating a third patient at that dose level.

Biopsy material will be obtained from tumor tissue prior to first virus administration. This tissue material may be subjected to routine histology to confirm tumor recurrence by the study pathologist along with molecular genetic testing if there is sufficient tissue remaining. Patients may undergo biopsies of injected lesions up to 28 days prior to injection but no less than 7 days before injection, day 10, and day 84 following each injection, if the lesion is of sufficient size to obtain biopsy. Surgical excisions will also include examination of pathologic response. Non injected lesions may also be biopsied pre-treatment, day 10, and day 84, if tumor burden is sufficient. Whole blood for immunologic analyses will also be collected throughout the study period.

Routine study visits will occur through Day 126 (including required post injection visits: Day 84 (1st injection), Day 105 (2nd injection), or Day 126 (3rd injection), as applicable). Thereafter, visits will occur every 2-3 months following the required for up to 2 years for subjects who do not progress. For patients with progressive disease, chart review only will occur every 3 months starting at the time of progression.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of PVSRIPO for Patients With Unresectable Melanoma
Actual Study Start Date : November 26, 2018
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Cohort 0 (PVSRIPO)
A single dose of PVSRIPO into a single lesion.
Biological: PVSRIPO
Intralesional injection of PVSRIPO.

Experimental: Cohort 1 (PVSRIPO)
A single dose of PVSRIPO into 2 different lesions, 21 days apart, when applicable per dose escalation guidelines.
Biological: PVSRIPO
Intralesional injection of PVSRIPO.

Experimental: Cohort 2 (PVSRIPO)
A single dose of PVSRIPO into 3 different lesions, 21 days apart, when applicable per dose escalation guidelines.
Biological: PVSRIPO
Intralesional injection of PVSRIPO.




Primary Outcome Measures :
  1. Proportion of patients with DLTs by cohort [ Time Frame: 24 months ]
    To characterize the safety and tolerability of PVSRIPO in AJCC Stage IIIB, IIIC, or IV melanoma.


Other Outcome Measures:
  1. Response rates via measurement of cutaneous lesions every 3 weeks [ Time Frame: 24 months ]
    To describe the response rates via lesion size of PVSRIPO-injected versus non-injected lesion(s).

  2. Number of CD8 positive T cells by IHC on pre treatment and post treatment biopsy [ Time Frame: 4.1 months ]
    To describe the number of CD8 positive T cells present in the tumor biopsies before and after injection of PVSRIPO.

  3. The change in tumor pathology from baseline to after PVSRIPO injection. [ Time Frame: 4.1 months ]
    Determine the pathologic response in tumor biopsies after PVSRIPO by confirming presence or absence of viable tumor cells.

  4. The detection of viral replication in injected versus non injected lesions. [ Time Frame: 4.1 months ]
    Determine viral replication via a number of methods (e.g., qRT-PCR, ICH).

  5. The change in inflammatory cells and markers after PVSRIPO in injected versus non injected lesions. [ Time Frame: 4.1 months ]
    Determine changes in the tumor microenvironment from biopsies after PVSRIPO; includes but not limited to examination of CD8, PVR (CD155), PD-L1, CD4, FoxPE, and PD-1.

  6. Change relative to baseline in type and/or function of T cells via flow cytometry. [ Time Frame: 24 months ]
    Describe how systemic immune cell populations may change after treatment with PVSRIPO.



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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. Positive serum anti-poliovirus titer prior to biopsy.
  2. The patient must have received a boost immunization with trivalent inactivated IPOL™ (Sanofi-Pasteur) at least 1 week prior to administration of the study agent.
  3. Patient must have histologically proven unresectable, recurrent, melanoma, stage IIIB, IIIC, or stage IV (AJCC staging must be documented in patient's medical record, as determined by CT of the chest, abdomen and pelvis, and/or whole body PET scan, and MRI of the brain within 4 weeks prior to administration of study drug).
  4. Patients with BRAF mutations, must have failed at least 2 lines of therapy, specifically one BRAF targeted therapy and at least one anti-PD-1 based therapy. For BRAF wild type, patients must have failed at least one anti-PD-1 based therapy.
  5. Patient must be ≥ 18 years of age.
  6. Patient must have an ECOG/Zubrod status of 0-1.
  7. Patient's disease must be bi-dimensionally measurable by caliper or radiological method as defined in the irRC criteria.
  8. At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesions ≥ 10 mm in longest diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of ≥ 10 mm (Cohorts 0 and possibly 1). For cohorts where 2 or 3 injections are planned (Cohorts 1 and 2), the patient must have at least 2 injectable melanoma lesions (when 2 doses are planned) or 3 injectable melanoma lesions when 3 doses are planned.
  9. At least one measurable lesion that will not be injected.
  10. Serum lactate dehydrogenase (LDH) levels less than 1.5 x upper limit of normal (ULN).
  11. Patient must have adequate bone marrow, liver and renal function as assessed by the following:

    1. Hemoglobin > 9.0 g/dl
    2. White blood count (WBC) of > 2000 m3
    3. Absolute neutrophil count (ANC) > 1,000/mm3
    4. Platelet count > 75,000/mm3
    5. Total bilirubin < 2.0 x ULN
    6. ALT and AST < 2.5 x the ULN

Exclusion Criteria:

  1. Females who are pregnant or breast-feeding.
  2. Adults of reproductive potential not employing an effective method of birth control.
  3. Patients with severe, active co-morbidity, defined as follows:

    1. Patients with an active infection requiring treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C).
    2. Patients with impaired cardiac function or clinically significant cardiac disease, such as congestive heart failure requiring treatment (New York Heart Association Class ≥ 2), uncontrolled hypertension or clinically significant arrhythmia; QTcF > 470 msec on ECG if performed or congenital long QT syndrome; acute myocardial infarction or unstable angina pectoris < 3 months prior to study.
    3. Patients with known lung (FEV1 < 50%) disease or uncontrolled diabetes mellitus (HgbA1c>7).
    4. Patients with albumin allergy.
    5. Autoimmune disease: History of or current active autoimmune diseases, [e.g. including but not limited to inflammatory bowel diseases [IBD], rheumatoid arthritis, autoimmune thyroiditis, autoimmune hepatitis, systemic sclerosis (scleroderma and variants), systemic lupus erythematosus, autoimmune vasculitis, autoimmune neuropathies (such as Guillain-Barre syndrome)]. Vitiligo and adequately controlled endocrine deficiencies such as hypothyroidism are not exclusionary.
    6. Known immunosuppressive disease, human immunodeficiency virus (HIV) infection, or chronic Hepatitis B or C.
  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. Toxicities must have resolved to CTCAE grade 1 or less with the following exceptions (alopecia, fatigue, vitiligo).
  6. Patients with undetectable anti-tetanus toxoid IgG.
  7. Patients with known history of agammaglobulinemia.
  8. Patients on greater than 10 mg per day of prednisone within the 2 weeks prior to admission for PVSRIPO injection.
  9. Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups).
  10. 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.
  11. Clinically active cerebral or bone metastases.
  12. Greater than 3 visceral metastases (this does not include nodal metastases associated with visceral organs).
  13. Prior allogeneic stem cell transplantation.
  14. Concomitant therapy with any of the following: IL-2, interferon, or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (used in the management of cancer or non-cancer-related illnesses). However, during the course of the study, use of corticosteroids is allowed if used for treating irAEs, adrenal insufficiencies, or if administered at doses of prednisone 10 mg daily or equivalent.
  15. Active clinically serious infection > CTCAE Grade 2.
  16. Antineoplastic therapy, radiotherapy, or any other investigational drug within 15 days prior to first study drug administration.

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): NCT03712358


Contacts
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Contact: Georgia Beasley, MD 919-684-6858 Georgia.beasley@duke.edu
Contact: Andrea True Kelly, PhD 919-943-5023 atkelly@istarioncology.com

Locations
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United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: Georgia Beasley, MD    919-684-6858    Georgia.beasley@duke.edu   
Contact: Shauna Eggertson, RN    919-613-0400    shauna.eggertson@duke.edu   
Sponsors and Collaborators
Istari Oncology, Inc.
Duke University
Investigators
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Principal Investigator: Georgia Beasley, MD Duke University

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Responsible Party: Istari Oncology, Inc.
ClinicalTrials.gov Identifier: NCT03712358     History of Changes
Other Study ID Numbers: Pro00090774
First Posted: October 19, 2018    Key Record Dates
Last Update Posted: November 28, 2018
Last Verified: November 2018

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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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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas