Clinical Trials /

Intra-lesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma

NCT03316274

Description:

There is no clear treatment for patients with limited cutaneous Kaposi sarcoma (KS). Radiation and injection of vinblastine both have side effects that may not be acceptable. Nivolumab has been used to treat more extensive KS when given intravenously. This is, to the investigators' knowledge, the first trial to see if nivolumab can be used as treatment in the form of an injection into KS lesion.

Related Conditions:
  • Kaposi Sarcoma
Recruiting Status:

Completed

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Intra-lesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma
  • Official Title: Phase 1 Study to Evaluate the Safety, Feasibility and Immunologic Correlatives of Intra-lesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 17872
  • SECONDARY ID: NCI-2018-02529
  • NCT ID: NCT03316274

Conditions

  • Kaposi Sarcoma
  • HIV/AIDS
  • Immunosuppression

Interventions

DrugSynonymsArms
Intra-lesional injection of nivolumabNivolumab, Nivolumab Injection, OpdivoNivolumab (Cohort A-Safety)

Purpose

There is no clear treatment for patients with limited cutaneous Kaposi sarcoma (KS). Radiation and injection of vinblastine both have side effects that may not be acceptable. Nivolumab has been used to treat more extensive KS when given intravenously. This is, to the investigators' knowledge, the first trial to see if nivolumab can be used as treatment in the form of an injection into KS lesion.

Detailed Description

      Infection with Kaposi sarcoma herpesvirus (KSHV, or human herpesvirus-8 (HHV-8)) causes
      Kaposi sarcoma (KS). These virally associated diseases occur more frequently in HIV-infected
      individuals, but can also be found in HIV-uninfected population. Evolution of
      immunosuppressive mechanisms presumably plays a permissive role in the development,
      progression and recurrence of these virus-associated cancers and pre-cancers. Currently,
      available treatment options for these lesions are imperfect.

      The goal of this study is to determine whether intra-lesional injections of nivolumab can
      enhance specific T cell responses in vitro and enhance activity against these
      virus-associated lesions. Chronic viral infections generate "exhausted" CD8+ T cells with a
      diminished capacity to produce cytokines and to lyse infected cells. The PD-1 (program
      death-1)/PD-L1 (program death ligand-1) pathway implicated in the balance between immune
      eradication and immune escape. This study will evaluate the safety, tolerability, and
      potential benefits of injecting nivolumab into KS in HIV-infected and HIV-uninfected
      individuals every 2 weeks for total of 4 doses. The investigators believe this mode of
      treatment is feasible and tolerable by avoiding the systemic autoimmune adverse events caused
      by systemic injection of nivolumab.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab (Cohort A-Safety)ExperimentalAll participants will receive 10mg in 1 mL injection into a single KS lesion in the skin, every 2 weeks for 4 doses.
  • Intra-lesional injection of nivolumab
Nivolumab (Cohort B-Expansion)ExperimentalAll participants will receive injection into up to two KS lesion in the skin, every 2 weeks for 4 doses. For participants in the expansion cohort whose injected lesion is improving as of week 26 and they also did not experience any serious adverse events (SAE), they can receive additional intra-lesional injections of nivolumab into up to 4 lesions every 2 weeks for up to 4 doses (for total up to 8 doses). The injected volume will not exceed 10 mg (or 1 mL) each time
  • Intra-lesional injection of nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. For screening: Patients must have histologically confirmed KS with active cutaneous
             disease and have less than 25 lesions.

             For enrollment: Patients must have histologically confirmed KS in the research skin
             biopsy performed during the screening visit.

          2. Patients must have measurable cutaneous KS disease, defined as: 1 or more marker
             lesion that is bi-dimensionally measureable, and >=0.5cm in shortest dimension. These
             measurable lesions must not have received previous local radiation, surgical, or
             intralesional cytotoxic therapy that would prevent response assessment.

             Note: Patients may eligible even if some of their KS lesions that have previously been
             treated with local therapy, as long as they have other untreated KS lesions that are
             measurable as defined in the protocol.

          3. For the initial safety cohort (cohort A), patients have to be treatment-experienced,
             i.e. at least one of their KS skin lesions has been persisted despite having been
             treated with:

               -  systemic chemotherapy; OR

               -  1 or more topical therapy, local radiation, surgery, or intra-lesional cytotoxic
                  therapy.

             For the expansion cohort (cohort B), patients can be either treatment-experienced or
             treatment-naïve.

             For the extension cohort (cohort B-plus), patients are from the expansion cohort above
             (cohort B) who have achieved partial response (PR) or complete response (CR) in their
             injected KS lesion at week 26 or later.

          4. Age >= 18 years.

          5. If human immunodeficiency virus (HIV)-infected, patients must have:

               -  HIV-1 infection, documented by any federally approved, licensed HIV rapid test
                  performed in conjunction with screening (or ELISA, test kit, and confirmed by
                  Western blot or other approved test). Alternatively, this documentation may
                  include a record demonstrating that another physician has documented the
                  participant's HIV status based on either: 1) approved diagnostic tests, or 2) the
                  referring physician's written record that HIV infection was documented, with
                  supporting information on the participant's relevant medical history and/or
                  current management of HIV infection

               -  CD4 >= 350 cells/mm3

               -  HIV-1 viral load below the limit of detection by commercial assays (<75
                  copies/mL).

               -  Participants MUST receive appropriate care and treatment for HIV infection,
                  including antiretroviral medications when clinically indicated, and should be
                  under the care of a physician experienced in HIV management. Participants should
                  be documented to be on an effective combination anti-retroviral (ART) regimen,
                  generally a 3-drug regimen based on Department of Health and Human Services
                  (DHHS) treatment guidelines by a licensed health care provider. Participants will
                  be eligible regardless of antiretroviral medication (including no antiretroviral
                  medication) provided there is no intention to initiate therapy or the regimen has
                  been stable for at least 4 weeks with no intention to change the regimen within
                  12 weeks following enrollment.

          6. If HIV-uninfected, patients must have documentation of a negative HIV result by any
             federally approved, licensed HIV test within the last 12 months.

          7. Adequate organ function defined as follows:

             Adequate bone marrow function:

             leukocytes > 3,000/microliter (mcL) absolute neutrophil count > 1,000/mcL Hemoglobin >
             10 g/dL platelets > 100,000/mcL

             Adequate hepatic function:

             total bilirubin within normal institutional limits aspartate aminotransferase
             (AST)/serum glutamic-oxaloacetic transaminase (SGOT) < 2.5 X institutional upper limit
             of normal (ULN) alanine aminotransferase (ALT)/ serum glutamic-pyruvic transaminase
             (SGPT) < 2.5 X institutional ULN

             Adequate renal function:

             creatinine < 1.5 X institutional ULN

          8. Participants must be purified protein derivative (PPD) negative. Alternatively, the
             QuantiFERON-TB Gold In-Tube (QFT-GIT) assay (Cellestis Limited, Carnegie, Australia)
             can be used. An individual is considered positive for M. tuberculosis (TB) infection
             if the Interferon (IFN)-gamma response to TB antigens is above the test cut-off (after
             subtracting the background IFN-gamma response in the negative control). The result
             must be obtained within 12 months prior to enrollment. PPD positive (or QuantiFERON
             assay positive) participants are permitted if prophylaxis has been completed prior to
             enrollment.

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status of <=1 (Karnofsky >=
             70%).

         10. The effects of nivolumab on the developing fetus are unknown. Therefore, only the
             following patients should be enrolled:

               -  Woman of child-bearing potential (WOCBP, defined as a sexually mature woman who
                  has not undergone a hysterectomy (the surgical removal of the uterus) or
                  bilateral oophorectomy (the surgical removal of both ovaries) or, has not been
                  naturally postmenopausal for at least 24 consecutive months (i.e., has had menses
                  at any time during the preceding 24 consecutive months} must have negative serum
                  pregnancy test within 7 days before starting study treatment in WOCBP and
                  willingness to adhere to acceptable forms or birth control (a physician-approved
                  contraceptive method (oral, injectable, or implantable hormonal contraceptive;
                  tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or
                  vasectomized partner).

        WOCBP receiving nivolumab will be instructed to adhere to contraception for a period of 6
        months after the last dose.

        Should a woman become pregnant or suspect she is pregnant while she or her partner is
        participating in this study (including the time after last dose previously mentioned), she
        (or the participating partner) should inform the treating physician immediately.

        o Men receiving nivolumab and who are sexually active with WOCBP will be instructed to
        adhere to contraception for a period of 7 months after the last dose of investigational
        product.

        Exclusion Criteria:

          1. Prior systemic KS-directed treatments or investigational modalities <= 5 half-lives or
             4 weeks, whichever is shorter, prior to starting study drug or who have not recovered
             from side effects of such therapy to grade 1 or less.

          2. Presence of any visceral KS (including KS-associated lymphedema) requiring systemic
             chemotherapy. This includes, but not limited to, any symptomatic visceral KS or
             asymptomatic pulmonary KS.

          3. Hypersensitivity to nivolumab or any of its excipients

          4. Has a known additional malignancy that is progressing or requires active treatment.

             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
             skin that has undergone potentially curative therapy or in situ cervical cancer.

          5. Opportunistic infection within the last 3 months.

          6. Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          7. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. This
             does not apply to participants in the extension cohort (cohort B-plus).

          8. Active systemic immunosuppressive therapy.

          9. The use of prednisone or equivalent 10mg or greater a day that cannot be discontinued
             with more than 7 consecutive days of steroids within the prior 2 weeks.

         10. Prior organ allograft or allogeneic transplantation, if the transplanted tissue is
             still in place.

         11. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA)
             class 3 or 4 congestive heart failure.

         12. Major surgery ≤ 2 weeks prior to starting a study drug or who have not recovered from
             side effects of such therapy.

         13. Any significant medical condition, laboratory abnormalities, which places the subject
             at unacceptable risk if he/she were to participate in the study.

         14. Any condition that confounds the ability to interpret data from the study.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of Dose Limiting Toxicity (DLT)
Time Frame:6 months
Safety Issue:
Description:Safety will be defined based on the rate of drug-related grade 3-5 adverse events. These will be assessed using the NCI CTCAE v5.0

Secondary Outcome Measures

Measure:Changes in CD3+/CD4+ cells
Time Frame:6 months
Safety Issue:
Description:Treatment induced, tumor infiltrating immune cells will be evaluated in pre-treatment and post-treatment tissue via immunohistochemistry (IHC).
Measure:Changes in CD8+/Granzyme+ T cytotoxic T cells
Time Frame:6 months
Safety Issue:
Description:Treatment induced, tumor infiltrating immune cells will be evaluated in pre-treatment and post-treatment tissue via immunohistochemistry (IHC).
Measure:Changes in CD56+ natural killer (NK) cells
Time Frame:6 months
Safety Issue:
Description:Treatment induced, tumor infiltrating immune cells will be evaluated in pre-treatment and post-treatment tissue via immunohistochemistry (IHC).
Measure:Changes in CD4+FOXP3-effector T cells
Time Frame:6 months
Safety Issue:
Description:Treatment induced, tumor infiltrating immune cells will be evaluated in pre-treatment and post-treatment tissue via immunohistochemistry (IHC).
Measure:Changes in CD4+FOXP3+regulatory T cells
Time Frame:6 months
Safety Issue:
Description:Treatment induced, tumor infiltrating immune cells will be evaluated in pre-treatment and post-treatment tissue via immunohistochemistry (IHC).
Measure:Changes in Circulating plasma cytokines
Time Frame:6 months
Safety Issue:
Description:Circulating plasma cytokines will be evaluated in pre-treatment and post-treatment
Measure:Changes in frequency of circulating activated T cells in the peripheral blood
Time Frame:6 months
Safety Issue:
Description:Frequency of circulating activated T cells in the peripheral blood induced by intra-lesional nivolumab therapy will be assessed via flow cytometry
Measure:Changes in number of circulating activated T cells in the peripheral blood
Time Frame:6 months
Safety Issue:
Description:Changes in number of circulating activated T cells in the peripheral blood induced by intra-lesional nivolumab therapy will be assessed via flow cytometry
Measure:Changes in PD-1 expression as determined by immunohistochemistry in lesions
Time Frame:6 months
Safety Issue:
Description:Changes in PD-L1 expression induced by intra-lesional nivolumab therapy will be assessed via IHC, using commercially available PD-1 antibody.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:University of California, San Francisco

Last Updated

August 9, 2021