Clinical Trials /

PVSRIPO in Combination With Nivolumab in Melanoma

NCT04125719

Description:

In this study, patients with metastatic melanoma who have at least one injectable lesion that has been refractory to PD-1 therapy (n=30 patients) will be enrolled. Cohort 1 will include 15 patients who progressed within 3 months (primary resistance) of starting PD-1 therapy and cohort 2 will be patients who progressed after at least 3 months of PD-1 therapy. Patients will receive up to 7 injections of PVSRIPO intra-lesionally in combination with Nivolumab. Nivolumab will be administered according to the FDA-approved dosing schedule of 480 mg intravenously every 4 weeks, beginning ~10 days after the first PVSRIPO infusion and will continue for 4 cycles. Nivolumab may be continued up to 2 years per standard of care after the completion of the PVSRIPO injections.

Related Conditions:
  • Melanoma
Recruiting Status:

Withdrawn

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PVSRIPO in Combination With Nivolumab in Melanoma
  • Official Title: A Phase IB Trial of PVSRIPO in Combination With Nivolumab in Patients With Recurrent PD-1 Refractory Melanoma

Clinical Trial IDs

  • ORG STUDY ID: Pro00101803
  • NCT ID: NCT04125719

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
PVSRIPOPrimay PD-1 resistance
NivolumabOpdivoPrimay PD-1 resistance

Purpose

In this study, patients with metastatic melanoma who have at least one injectable lesion that has been refractory to PD-1 therapy (n=30 patients) will be enrolled. Cohort 1 will include 15 patients who progressed within 3 months (primary resistance) of starting PD-1 therapy and cohort 2 will be patients who progressed after at least 3 months of PD-1 therapy. Patients will receive up to 7 injections of PVSRIPO intra-lesionally in combination with Nivolumab. Nivolumab will be administered according to the FDA-approved dosing schedule of 480 mg intravenously every 4 weeks, beginning ~10 days after the first PVSRIPO infusion and will continue for 4 cycles. Nivolumab may be continued up to 2 years per standard of care after the completion of the PVSRIPO injections.

Detailed Description

      Patients must have histologically proven unresectable melanoma, stage IIIB, IIIC, IIID, 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). Patients must have failed PD-1 therapy as
      judged by the treating physician.

      Patients will initially receive one injection of PVSRIPO intra-lesionally. Based on a phase 1
      study of the agent in adult patients with recurrent GBM, the starting amount to be delivered
      will be 1x108 tissue culture infectious dose (TCID50) prior to initiation of nivolumab.
      Nivolumab will be administered according to the FDA-approved dosing schedule of 480 mg
      intravenously every 4 weeks, beginning ~10 days after the first PVSRIPO infusion and will
      continue for 4 cycles. PVSRIPO will then be given intralesionally to multiple lesions (if
      present) at days 38, 66, and 94.

      At Day 108 after 4 doses of nivolumab and 4 treatments of PVSRIPO, imaging and a full disease
      assessment will be done and iRECIST determined. A patient with complete response (CR) or a
      partial response (PR) (at least at 75% decrease in the sum of all diameters of all target
      lesions plus new lesions) will continue on nivolumab for up to 2 years. For patients with PR
      (< 75% decrease), stable disease (SD), or progressive disease (PD), an additional 3
      treatments of PVSRIPO q4weeks can be given concurrently with 3 doses of monthly nivolumab.
      The lesions will be chosen at discretion of principal investigator (PI) and can be new
      lesions, previously injected lesions, or untreated lesions. At Day 234 (±7 days), (after 7
      total PVSRIPO injections and 8 doses of nivolumab), patients with PD will be off study, any
      patient with CR, PR, SD can receive up to 2 years total of nivolumab. If a patient has no
      remaining injectable lesions at any point during the study, PVSRIPO will not be given, but
      patients can continue on nivolumab.
    

Trial Arms

NameTypeDescriptionInterventions
Primay PD-1 resistanceExperimentalCohort 1 will include 15 patients who progressed within 3 months (primary resistance) of starting PD-1 therapy
  • PVSRIPO
  • Nivolumab
Secondary PD-1 resistanceExperimentalCohort 2 will include 15 patients who progressed after at least 3 months of PD-1 therapy
  • PVSRIPO
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Positive serum anti-poliovirus antibody 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 melanoma, stage IIIB, IIIC, IIID,
             or stage IV (AJCC version 8 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 must have progressed following ≥1 line of one prior systemic therapy,
             including immune checkpoint inhibitor (eg, anti- PD-1, ipilimumab, or anti PD-1 plus
             ipilimumab); and if BRAF V600 mutation-positive, after a BRAF inhibitor or BRAF
             inhibitor in combination with MEK inhibitor. Patients last dose of systemic therapy
             must have been within 9 months prior to signing consent for this study. Patients
             treated in the adjuvant setting and develop recurrence are also allowed.

          5. Cohort 1 will include 15 patients who progressed within 3 months (primary resistance)
             of starting PD-1 therapy and cohort 2 will be patients who progressed after at least 3
             months of PD-1 therapy.

          6. Patient must be ≥18 years of age.

          7. Patient must have an ECOG/Zubrod status of 0-1.

          8. Patient's disease must be bi-dimensionally measurable by caliper or radiological
             method as defined in the iRECIST criteria. The sum of target lesion diameters should
             be at least 10 mm.

          9. 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.

         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, patients may be transfused to meet this criteria

               2. Lymphocyte count ≥ 0.5 x 109/L (500 µL)

               3. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (1500 µL)

               4. Platelet count ≥ 100 x 109/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:

             i. Patients with documented liver metastases: AST and ALT ≤ 5 x ULN ii. Patients with
             documented liver or bone metastases: ALP ≤ 5 x ULN f. Serum bilirubin ≤ 1.5 x ULN with
             the following exception: i. Patients with known Gilbert disease: serum bilirubin level
             ≤ 3 x ULN g. Serum creatinine ≤ 1.5 x ULN h. Serum albumin ≥ 25 g/L (2.5 g/dL) i. For
             patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN

         12. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.

         13. Patients must have a life expectancy of > 6 months.

         14. Patient must provide a signed and dated written informed consent prior to registration
             and any study-related procedures.

         15. Ability to read and understand English and the ability to complete paper and
             electronic survey assessments.

         16. Ability to comply with the study protocol, in the investigator's judgement.

         17. For women of childbearing potential:

               1. Agreement to remain abstinent (refrain from heterosexual intercourse) or use
                  contraceptive methods with a failure rate of < 1% per year during the treatment
                  period and for 5 months after the last dose of study treatment. Note: A woman is
                  considered to be of childbearing potential if she is post-menarcheal, has not
                  reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no
                  identified cause other than menopause), and has not undergone surgical
                  sterilization (removal of ovaries and/or uterus).

             i. Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
             ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

             ii. The reliability of sexual abstinence should be evaluated in relation to the
             duration of the clinical trial and the preferred and usual lifestyle of the patient.
             Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation
             methods) and withdrawal are not acceptable methods of contraception.

         18. For men:

             a. Agreement to remain abstinent (refrain from heterosexual intercourse) or use a
             condom, and agreement to refrain from donating sperm, as defined below: i. With female
             partners of childbearing potential or pregnant female partners, men must remain
             abstinent or use a condom during the treatment period and for 7 months after the last
             dose of study treatment to avoid exposing the embryo. Men must refrain from donating
             sperm during this same period.

        ii. The reliability of sexual abstinence should be evaluated in relation to the duration of
        the clinical trial and the preferred and usual lifestyle of the patient. Periodic
        abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
        withdrawal are not acceptable methods of contraception.

        Exclusion Criteria:

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

               1. The patient has not received stereotactic radiotherapy within 7 days prior to
                  initiation of study treatment or whole-brain radiotherapy within 14 days prior to
                  initiation of study treatment.

               2. The patient has no ongoing requirement for corticosteroids as therapy for 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. Patients 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 be 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 requiring recurrent
             drainage procedures (once monthly or more frequently).

             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, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
             syndrome, or multiple sclerosis with the following exceptions:

               1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study.

               2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are
                  excluded) are eligible for the study provided all of 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 the previous 12 months

          7. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, 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 permitted.

          8. History of a Positive HIV test

          9. Known active hepatitis B virus (HBV) infection (chronic or acute).

             a. Patients who have had a negative HBsAg test and a positive total hepatitis B core
             antibody (HBcAb) test are eligible for the study.

         10. Known active hepatitis C virus (HCV) infection.

             a. If potential subjects have a history of a positive HCV antibody test, but negative
             HCV RNA test, subject may be eligible for the study

         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 prior to initiation of study treatment, unstable arrhythmia, or unstable
             angina.

         13. Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             course of the study.

         14. History of other malignancy within 5 years prior to screening, with the exception of
             those with a negligible risk of metastasis or death (e.g., 5-year OS of > 90%), such
             as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma,
             localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

         15. Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia.

         16. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment (note: Patients receiving prophylactic antibiotics (e.g., to
             prevent a urinary tract infection or chronic obstructive pulmonary disease
             exacerbation) are eligible for the study).

         17. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding that contraindicates the use of an investigational drug, may affect
             the interpretation of the results, or may render the patient at high risk from
             treatment complications.

         18. Prior allogeneic stem cell or solid organ transplantation.

         19. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study
             treatment, or anticipation of need for such a vaccine during the course of the study
             or within 5 months after the last dose of nivolumab.

         20. Treatment with investigational therapy within 15 days prior to initiation of study
             treatment

         21. Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2 [IL-2]) within 4 weeks or five half-lives of the drug
             (whichever is longer) prior to initiation of study treatment.

         22. Treatment with systemic immunosuppressive medication (including, but not limited to,
             corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and
             anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or
             anticipation of need for systemic immunosuppressive medication during the course of
             the study, with the following exceptions:

               1. Patients 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 for the study after
                  Principal Investigator approval has been obtained. 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.

               2. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids
                  for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose
                  corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible
                  for the study.

         23. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins.

         24. Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the nivolumab formulation.

         25. Pregnant or breastfeeding, or intending to become pregnant during the study or within
             5 months after the last dose of study treatment.

         26. Women of childbearing potential must have a negative serum pregnancy test result
             within 24 hours prior to the initial administration of the study drug and then every 4
             weeks during the treatment period.

         27. Patients with human serum albumin allergy.

         28. Patients with a previous history of neurological complications due to PV infection.

         29. Patients with a history of prior serious immune related adverse events while receiving
             PD-1 therapy.

         30. Patients with undetectable anti-tetanus toxoid IgG

         31. Patients with known history of agammaglobulinemia

         32. Patients with worsening steroid myopathy (history of gradual progression of bilateral
             proximal muscle weakness, and atrophy of proximal muscle groups.

         33. Prior allogeneic stem cell transplantation

         34. Psychiatric conditions or diminished capacity that could compromise the giving of
             informed consent, or interfere with study compliance; any underlying medical or
             psychiatric condition, which in the opinion of the investigator will make the
             administration of Nivolumab hazardous or obscure the interpretation of AEs, such as a
             condition associated with frequent diarrhea

         35. Prisoners, or subjects who are compulsory detained.

         36. Inablility to communicate in English.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Assess the percent of adverse events related to the combination of PVSRIPO + nivolumab in the treatment of patients with recurrent melanoma.
Time Frame:36 months
Safety Issue:
Description:Toxicities will be measured based on the number of adverse events as measured by clinical exams.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Darell D. Bigner, MD, PhD

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