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.
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.
