Clinical Trials /

SBRT as a Vaccination for Metastatic Melanoma

NCT04042506

Description:

Immunotherapy with PD-1 blockade is a first-line treatment for patients with advanced melanoma, but unfortunately most patients progress on this therapy. Recent evidence suggests that radiation can enhance the immune response in the presence of checkpoint blockade. The investigators aim to determine if radiation can elicit increased immune responses in patients who have stable or progressive disease on nivolumab.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: SBRT as a Vaccination for Metastatic Melanoma
  • Official Title: In Situ Vaccination With Stereotactic Body Radiation Therapy (SBRT) as a Strategy to Overcome Resistance to Immune Checkpoint Blockade: a Phase II Clinical Trial of SBRT and Anti-PD-1 Therapy With Immunologic Correlates

Clinical Trial IDs

  • ORG STUDY ID: J18145
  • SECONDARY ID: IRB00188445
  • NCT ID: NCT04042506

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]OpdivoExtracranial SBRT and Nivolumab

Purpose

Immunotherapy with PD-1 blockade is a first-line treatment for patients with advanced melanoma, but unfortunately most patients progress on this therapy. Recent evidence suggests that radiation can enhance the immune response in the presence of checkpoint blockade. The investigators aim to determine if radiation can elicit increased immune responses in patients who have stable or progressive disease on nivolumab.

Detailed Description

      To determine safety of stereotactic body radiation therapy (SBRT) in presence of ICB in
      patients with advanced unresectable melanoma. Toxicity will be deemed acceptable if the rate
      of Grade 3+ adverse events (CTC v4) is ≤ 33%, with relevant AEs defined as either of the
      following occurring between the start of SBRT and 12 weeks following SBRT completion:

        -  Any grade 3-5 metabolic or hematological toxicity that is related, probably related or
           possibly related to nivolumab or SBRT.

        -  Any grade 3-5 non-hematological toxicity that is related, probably related or possibly
           related to SBRT.

      Secondary Endpoints:

      • To determine whether SBRT results in a clinical abscopal effect on unirradiated lesions.
      The hypothesized rate of abscopal effect is >14%.

      Exploratory Correlative studies:

        -  In select patients for whom TCRseq reveals clonal expansion in non-irradiated tumor and
           serial blood specimens, the relevance of such expansion to tumor-specific responses will
           be investigated using mutation-associated neoantigens (MANAFEST) assays.

        -  Serial stool specimens will be studied to correlate potential changes in microbiome with
           abscopal effect.

        -  To determine whether SBRT promotes clonal expansion of melanoma-specific T-cells, in
           both peripheral blood and within TME of non-irradiated lesions.

        -  To determine whether TCR clonal expansion correlates with clinically observed abscopal
           response.

        -  To identify additional immunological biomarkers in the non-irradiated (abscopal) TME
           using intratumoral gene expression profiling to assess for induction and upregulation of
           a Type I IFN signature among responders1-3. IHC in TME will be used to characterize
           modulation of immune cell populations pre- and post-SBRT, and to assess correlation of
           PD-L1 and other immune-checkpoint receptor expression with responsiveness to SBRT and
           changes in TME post-SBRT.
    

Trial Arms

NameTypeDescriptionInterventions
Extracranial SBRT and NivolumabExperimentalStereotactic body radiation therapy (SBRT) will be given to a single extracranial metastatic site in combination with nivolumab. Patients will receive nivolumab 480mg intravenously (IV) every 4 weeks (1 cycle = 8 weeks), as well as SBRT dose of 8-10 Gy x 3 fractions (at maximum 3 doses per week) delivered to 1 extracranial site between days 1-14 of Cycle 1. Nivolumab will be continued until confirmed progression, unacceptable toxicity, or total of 6 Cycles (whichever occurs first).
  • Nivolumab 10 MG/ML Intravenous Solution [OPDIVO]

Eligibility Criteria

        Inclusion Criteria:

          -  Signed Written Informed Consent

          -  Willing and able to provide informed consent

          -  Age ≥ 18 years

          -  Target Population

          -  Histological confirmation of melanoma

          -  Advanced unresectable (AJCC Stage III or IV) disease (cutaneous, mucosal, acral or
             ocular)

          -  Stable disease or progression (RECIST 1.1) after anti-PD-1 monotherapy (≥ 16 weeks and
             ≥ 2 CT assessments). The maximum time period off anti-PD-1 monotherapy, prior to
             protocol therapy, cannot exceed 2 months.

          -  Prior systemic treatment regimen in the advanced/metastatic setting is allowed (BRAF
             inhibitor, chemotherapy, cytokine/biologic therapy or clinical trial)

          -  Prior treatment with anti-CTLA-4 checkpoint inhibitor is allowed

          -  Minimum of 2 or more measurable lesions by RECIST 1.1, with at least 1 lesion
             accessible for clinical, US, or CT-guided needle biopsy. If 2 lesions, then one of
             those must measure 4cm in maximum diameter and be amenable for biopsy; this lesion
             will be utilized for abscopal effect determination as well. Otherwise, if 3 or more
             lesions are present, one lesion will receive SBRT, 2nd lesion will be used for
             radiographic abscopal response assessment, and 3rd lesion will be used for pre- and
             post-treatment biopsies.

          -  ECOG Performance Status of 0-1

        Exclusion Criteria:

          -  Target Disease Exceptions

          -  Prior radiation within 6 months of enrollment (excluding brain metastases), or at any
             time to one of the 3 lesions for treatment/assessment

          -  If patient has >1 lesion which requires immediate/urgent management with RT due to
             present or impending clinical consequences (uncontrolled pain, risk of loss of
             function), such a patient will not be enrolled on this trial

          -  Medical History and Concurrent Diseases

               -  Major toxicity from prior anti-PD-1 which precludes continuation of anti-PD-1
                  therapy.

               -  Pregnancy or inability to use contraception (if childbearing age)

               -  Any active or recent history of a known or suspected autoimmune disease or recent
                  history of a syndrome that required systemic corticosteroids (> 10 mg daily
                  prednisone equivalent) or immunosuppressive medications except for syndromes
                  which would not be expected to recur in the absence of an external trigger.
                  Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due
                  to autoimmune thyroiditis only requiring hormone replacement are permitted to
                  enroll. Patients with psoriasis not requiring active, systemic treatment are
                  allowed.

               -  Any condition requiring systemic treatment with corticosteroids (> 10 mg daily
                  prednisone equivalents) or other immunosuppressive medications within 14 days
                  prior to first dose of study drug. Inhaled steroids and adrenal replacement
                  steroid doses up to 10 mg daily prednisone equivalents are permitted in the
                  absence of active autoimmune disease

               -  Uncontrolled adrenal insufficiency

               -  Requirement for anti-coagulation with Coumadin, low molecular weight heparin and
                  anti-thrombin inhibitors will be accepted if anticoagulation has been stable for
                  at least 4 weeks and no recent history of prior bleeding complications.

               -  Prior malignancy active within the previous 3 years except for locally curable
                  cancers that have been apparently cured such as basal or squamous cell skin
                  cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast or
                  low risk Gleason 6 prostate cancer

               -  Known history of testing positive for human immunodeficiency virus (HIV) or known
                  acquired immunodeficiency syndrome (AIDS); Any positive test for hepatitis B or
                  hepatitis C virus indicating acute or chronic infection

               -  Known medical condition (e.g., a condition associated with diarrhea or acute
                  diverticulitis) that, in the investigator's opinion, would increase the risk
                  associated with study participation or study drug administration or interfere
                  with the interpretation of safety results

               -  Major surgery (i.e., nephrectomy) less than 28 days prior to the first dose of
                  study drug

               -  Anti-cancer therapy less than 14 days prior to the first dose of study drug or
                  palliative, focal radiation therapy less than 14 days prior to the first dose of
                  study drug

               -  Presence of any toxicities attributed to prior immunotherapy, other than
                  alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before
                  administration of study drug

          -  Physical and Laboratory Test Findings: Any of the following laboratory test findings:

               -  WBC < 2,000/mm3

               -  Neutrophils < 1,500/mm3

               -  Platelets < 100,000/mm3

               -  AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)

               -  Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
                  total bilirubin < 3.0 mg/dL)

               -  Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40
                  mL/min (measured or calculated by Cockroft-Gault formula)

          -  Allergies and Adverse Drug Reaction: History of severe hypersensitivity reaction to
             any monoclonal antibody or study drug components

          -  Other Exclusion Criteria

               -  Prisoners or subject who are involuntarily incarcerated

               -  Not suitable for SBRT treatment

               -  Subjects who are compulsorily detained for treatment of either a psychiatric or
                  physical illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety of SBRT in the presence of immune checkpoint blockade (ICB) as measured by number of participants experiencing adverse events
Time Frame:12 weeks
Safety Issue:
Description:Number of participants with advanced unresectable melanoma, receiving SBRT in the presence of ICB who experience metabolic or hematological, or non-hematological adverse events Grade 3 or higher, as defined by CTCAE v4.0

Secondary Outcome Measures

Measure:Clinical abscopal effect as assessed by number of unradiated lesions with response per RECIST 1.1.
Time Frame:12 weeks
Safety Issue:
Description:Number of lesions that are not targeted by SBRT with any response as defined by RECIST 1.1 criteria. Complete response (CR) = disappearance of all target lesions and normalization of tumor marker levels; Partial response (PR) = decrease from baseline >= 30% in the sum of the longest diameter of all target lesions.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

  • immune checkpoint blockade
  • SBRT
  • Nivolumab

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