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Trial record 1 of 10 for:    PVSRIPO
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PVSRIPO With or Without Immune Checkpoint Blockade in Patients With Advanced PD-1 Refractory Melanoma

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: NCT04577807
Recruitment Status : Not yet recruiting
First Posted : October 8, 2020
Last Update Posted : October 20, 2020
Information provided by (Responsible Party):
Istari Oncology, Inc.

Brief Summary:
A Phase 2 study to investigate the efficacy and safety of PVSRIPO alone or in combination with a programmed death receptor-1 (anti-PD-1) inhibitor.

Condition or disease Intervention/treatment Phase
Melanoma Biological: PVSRIPO Biological: Anti-PD-1 Checkpoint Inhibitor Phase 2

Detailed Description:
This multi-center, open-label, randomized, Phase 2 will investigate the efficacy and safety of PVSRIPO alone (Arm 1) or in combination with an anti-PD-1 inhibitor (Arm 2). Following a 6 participant safety run-in, up to approximately 50 participants with cutaneous or mucosal melanoma who previously failed anti-PD-1 blockade will be randomized 1:1 to receive either PVSRIPO or PVSRIPO plus an anti-PD-1.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PVSRIPO in Combination With Immune Checkpoint Blockade in Advanced PD-1 Refractory Melanoma
Estimated Study Start Date : December 2020
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Arm 1: PVSRIPO Only
PVSRIPO (up to 6x10^8 TCID50) administered via direct injection to amenable melanoma lesions given every 3 or 4 weeks
Biological: PVSRIPO
PVSRIPO administered via direct lesion injection

Experimental: Arm 2: PVSRIPO and anti-PD-1
PVSRIPO (up to 6x10^8 TCID50) administered via direct injection to amenable melanoma lesions and anti-PD-1 therapy given every 3 or 4 weeks as per the anti-PD-1 approved package insert
Biological: PVSRIPO
PVSRIPO administered via direct lesion injection

Biological: Anti-PD-1 Checkpoint Inhibitor
Anti-PD-1 Checkpoint Inhibitor administered per package insert instructions

Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 24 months ]
    Number of subjects achieving complete (CR) or partial response (PR), per RECIST 1.1 criteria, confirmed by repeat measurement, at least 4 weeks apart

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

Secondary Outcome Measures :
  1. Overall Survival [ Time Frame: 24 months ]
    Overall survival (OS): time from randomization until death from any cause, through week 104

  2. Duration of Response [ Time Frame: 24 months ]
    Duration of Response (DOR): time from objective response (per RECIST 1.1) until unequivocal disease progression or death, whichever occurs first

  3. Disease Control Rate [ Time Frame: 24 months ]
    Disease control rate (DCR): the proportion of patients achieving CR, PR, or stable disease (SD) per RECIST1.1, as best response confirmed by repeat imaging at least 4 weeks apart.

  4. Durable Response Rate [ Time Frame: 24 months ]
    Durable Response Rate (DRR): the proportion of participants with CR or PR (per RECIST 1.1) lasting at least 6 months

Other Outcome Measures:
  1. Predictors of response to PVSRIPO or PVSRIPO in combination with anti-PD-1 therapy [ Time Frame: 24 months ]
    • Assessment and identification of genetic, cytologic, histologic and/or other markers that may correlate with response in tumor biopsies and PBMC samples.
    • Assessment of the changes in immune function markers from baseline in blood, samples, and/or tissue

  2. Anti-tumor response based on iRECIST criteria [ Time Frame: 24 months ]
    ORR/DOR, DRR and DCR based on iRECIST criteria

  3. Anti-tumor response outcomes based on subgroup [ Time Frame: 24 months ]
    • ORR/DOR, DRR and DCR in participants with acquired versus primary PD-1 resistance, as defined by Kluger, et al (Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. J Immunother Cancer. 2020;8(1):e000398. doi:10.1136/jitc-2019-000398)
    • ORR/DOR, DRR and DCR in patients with and without BRAF mutations
    • ORR/DOR, DRR and DCR in patients based on LDH levels at baseline
    • ORR/DOR, DRR and DCR in patients based on time since last dose of anti-PD1 therapy prior to randomization (≤ or >6 weeks)
    • ORR/DOR, DRR and DCR in participants from PVSRIPO monotherapy following crossover to PVSRIPO plus anti-PD-1

  4. Survival outcomes based on subgroup [ Time Frame: 24 months ]
    • OS in subjects according to treatment arm and AJCC Stage at baseline
    • OS in participants with primary versus acquired PD-1 resistance, as defined by Kluger et al
    • OS in patients with and without BRAF mutation
    • OS in participants based on baseline LDH level

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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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. ≥ 18 years of age
  2. Prior CDC-recommended vaccination series against PV, and has received a boost immunization with PV Inactivated (IPOL®; Sanofi-Pasteur SA) at least 1 week, but less than 6 weeks, prior to Day 1

    a. Note: Patients who are unsure of their vaccination status must provide evidence of anti-PV immunity prior to enrollment, as applicable

  3. Biopsy proven (within 4 months of Day 1) unresectable cutaneous or mucosal melanoma

    a. Note: Ocular melanoma is excluded.

  4. Has ≥ 2 melanoma lesions that are accurately measurable by caliper or a radiological method according to RECIST 1.1 criteria
  5. At least 1 injectable cutaneous, subcutaneous or nodal melanoma lesion ≥10 mm in longest diameter or, multiple injectable melanoma lesions which in aggregate have a longest diameter of ≥10 mm
  6. Had radiographically confirmed disease progression after receiving at least 6 weeks of treatment with an FDA-approved anti-PD-1 therapy (as monotherapy or in combination), without experiencing a toxicity requiring permanent discontinuation of the anti-PD-1. Patients treated with anti-PD-1 in the adjuvant setting and who have confirmed progression after at least 6 weeks of anti-PD-1 therapy are allowed.

    a. NOTE: Patients with known BRAF mutation must have also failed or refused to receive BRAF-targeted therapy (alone or in combination with MEK inhibitor) to be eligible.

  7. Eastern Cooperative Oncology Group (ECOG) status of 0-1
  8. Serum lactate dehydrogenase (LDH) levels ≤ 3 x upper limit of normal (ULN)
  9. Adequate bone marrow, liver and renal function as assessed by the following:

    1. Hemoglobin ≥ 9.0 g/dl, patients may be transfused
    2. Lymphocyte count ≥ 0.5 x 10^9/L (500 µL)
    3. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500 µL)
    4. Platelet count ≥ 100 x 10^9/L (100,000 µL) without transfusion
    5. AST, ALT, and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN), with the following exceptions: Patients with documented liver metastases: AST and ALT ≤ 5 x ULN; Patients with documented liver or bone metastases: ALP ≤ 5 x ULN
    6. Serum bilirubin ≤ 1.5 x ULN with the following exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
    7. Estimated creatinine clearance ≥ 30 ml/min, per MDRD equation
    8. Serum albumin ≥ 25 g/L (2.5 g/dL)
    9. For patients not receiving therapeutic anticoagulation: INR, PT, PTT (or aPTT) ≤ 1.5 x ULN
  10. Life expectancy of >12 weeks
  11. Signed informed consent form (ICF) indicating that participant understands the purpose of, and procedures required for the study, and is willing/able to participate in the study

Exclusion Criteria:

  1. Symptomatic, untreated, or actively progressing CNS metastases. Participants with a history of treated CNS lesions are eligible, provided the following criteria are met:

    1. No stereotactic radiotherapy within 7 days, or whole-brain radiotherapy within 14 days of Day 1
    2. No ongoing requirement for corticosteroids to manage CNS disease. Anticonvulsant therapy at a stable dose is permitted.
    3. Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan
  2. History of leptomeningeal disease
  3. Uncontrolled tumor-related pain. Participants requiring pain medication must be on a stable regimen at study entry.

    1. Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period
    2. Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
  4. Uncontrolled pleural effusion, pericardial effusion, or ascites a. Patients with indwelling catheters (e.g., PleurX™) are allowed.
  5. Uncontrolled or symptomatic hypercalcemia (>1.5 mmol/L ionized calcium or calcium >12 mg/dL or corrected serum calcium >ULN)
  6. Active or history of autoimmune disease or immune deficiency within previous 2 years, with the following exceptions:

    1. History of autoimmune-related hypothyroidism that is managed by thyroid replacement hormone
    2. Type 1 diabetes mellitus that is well-controlled by an established insulin regimen
    3. Eczema, psoriasis, or lichen simplex chronicus with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded), provided all of the following conditions are met:

    i. Rash must cover <10% of body surface area

    ii. Disease is well-controlled at baseline and requires only low-potency topical corticosteroids

    iii. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within 12 months of Day 1

  7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan

    a. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.

  8. History of a Positive HIV RNA test (HIV 1 or 2 RNA by PCR)
  9. Known active hepatitis B virus (HBV) infection (chronic or acute)

    a. NOTE: Participants with a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test are allowed.

  10. Known active hepatitis C virus (HCV) infection

    a. NOTE: History of positive HCV antibody test, but negative HCV RNA test is allowed.

  11. Active tuberculosis
  12. Significant cardiovascular disease, such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months of Day 1, unstable arrhythmia, or unstable angina
  13. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (shorter interval for kinase inhibitors or other short half-life drugs may be allowed with Sponsor approval) prior to treatment, or has not recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.

    a. Note: Anti-PD-1 within 4 weeks of Day 1 is allowed. If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

  14. History of other malignancy within 2 years of Day 1, with the exception of those with a negligible risk of metastasis or death (e.g., resected cutaneous basal cell carcinoma, or other cancers with 5-year OS of >90%)
  15. Severe infection within 4 weeks of Day 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

    a. Prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are allowed.

  16. Prior allogeneic stem cell or solid organ transplantation
  17. Treatment with a live, attenuated vaccine within 4 weeks of Day 1
  18. Treatment with systemic immunosuppressive medication within 4 weeks of Day 1, with the following exceptions:

    1. Participants who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible with Sponsor approval
    2. Use of mineralocorticoids (e.g., fludrocortisone), or systemic prednisone equivalent corticosteroid doses of <10mg per day are eligible for the study
    3. Use of topical corticosteroids with occlusive dressings is prohibited
  19. Known hypersensitivity to pembrolizumab, nivolumab or any of the respective excipients
  20. A pregnant or nursing female, or women of child-bearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception starting from signed ICF through 150 days after last anti-PD-1 dose
  21. History of human serum albumin allergy
  22. History of neurological complications due to polio virus infection
  23. History of agammaglobulinemia
  24. History of worsening steroid myopathy (e.g., gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups)
  25. Concurrent participation in a separate clinical trial during this study without Sponsor approval
  26. Any underlying medical condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromises the well-being) or that could prevent, limit, or confound protocol-specified assessments

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): NCT04577807

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Contact: Lisa Franklin 919-241-7509
Contact: Andrea True Kelly, PhD 919-241-7509

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United States, Pennsylvania
Research Site
Pittsburgh, Pennsylvania, United States, 15232
Contact: Lisa Franklin         
Sponsors and Collaborators
Istari Oncology, Inc.
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Responsible Party: Istari Oncology, Inc. Identifier: NCT04577807    
Other Study ID Numbers: PVSRIPO ICI M201
First Posted: October 8, 2020    Key Record Dates
Last Update Posted: October 20, 2020
Last Verified: October 2020

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