Intra-lesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Kaposi Sarcoma, HIV/AIDS, Immunosuppression

Intervention / Treatment
-----------------
* Drug: Intra-lesional injection of nivolumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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. 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. 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. Age >= 18 years. 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. If HIV-uninfected, patients must have documentation of a negative HIV result by any federally approved, licensed HIV test within the last 12 months. 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 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. Eastern Cooperative Oncology Group (ECOG) Performance Status of <=1 (Karnofsky >= 70%). 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: 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. 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. Hypersensitivity to nivolumab or any of its excipients 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. Opportunistic infection within the last 3 months. 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. 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). Active systemic immunosuppressive therapy. 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. Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in place. Unstable angina, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure. Major surgery ≤ 2 weeks prior to starting a study drug or who have not recovered from side effects of such therapy. Any significant medical condition, laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. Any condition that confounds the ability to interpret data from the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Standard 3+ 3 design during the initial safety cohort, then expansion cohort
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nivolumab (Cohort A-Safety)<br>All participants will receive 10mg in 1 mL injection into a single KS lesion in the skin, every 2 weeks for 4 doses. | Drug: Intra-lesional injection of nivolumab<br>* 10mg in 1 mL injection into a KS lesion in the skin, every 2 weeks<br>* Other names: Opdivo;|
| Experimental: Nivolumab (Cohort B-Expansion)<br>All 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 | Drug: Intra-lesional injection of nivolumab<br>* 10mg in 1 mL injection into a KS lesion in the skin, every 2 weeks<br>* Other names: Opdivo;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Dose Limiting Toxicity (DLT) | 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 | 6 months | 
| Maximun Tolerated Dose (MTD) | The MTD is defined as the dose at which no more than 1/6 patients experience a DLT | 6 months | 

Secondary Outcome Measures

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