PRIMARY OBJECTIVES:
I. To assess the safety and tolerability of MK-3475 (pembrolizumab) in HIV-infected patients
on effective antiretroviral therapy and with relapsed/refractory or disseminated acquired
immune deficiency syndrome (AIDS)-defining or non-AIDS defining malignancy.
II. To assess the safety and feasibility of MK-3475 (pembrolizumab) administration as first
systemic therapy for HIV associated Kaposi sarcoma in patients on effective antiretroviral
therapy.
SECONDARY OBJECTIVES:
I. To obtain preliminary insights into clinical benefit (e.g., tumor shrinkage or
stabilization >= 24 weeks) across a variety of tumors in patients infected with HIV and on
effective antiretroviral therapy.
II. To evaluate the response rate in Kaposi sarcoma impacting physical and/or psychological
wellbeing and not amenable to local therapy.
EXPLORATORY OBJECTIVES:
I. To assess the correlation of pre-therapy tumor programmed death-ligand 1 (PD-L1)
expression and T-cell infiltration on clinical benefit.
II. To assess the effect of MK-3475 (pembrolizumab) on circulating HIV and the HIV viral
reservoir in patients on effective combination anti-retroviral therapy (cART), as measured by
plasma HIV single copy ribonucleic acid (RNA), cluster of differentiation (CD)4+ T-cell
associated HIV unspliced RNA, CD4+ T-cell associated integrated HIV deoxyribonucleic acid
(DNA) provirus, ratio of HIV unspliced RNA/DNA, "Tat/Rev induced limiting dilution assay"
(TILDA), and phylogenetic analysis of HIV-1 molecular evolution.
III. To evaluate the effect of MK-3475 (pembrolizumab) on host gene expression in circulating
blood cells.
IV. To evaluate the effect of MK-3475 (pembrolizumab) on circulating HIV-specific CD8+ T-cell
cytotoxicity against autologous HIV infected CD4+ T-cells in patients on effective
antiretroviral therapy.
V. To evaluate the effect of MK-3475 (pembrolizumab) on circulating lymphocyte and monocyte
numbers and phenotypes.
VI. To assess biopsied tumors from participants that progress by immunohistochemistry arrays
and gene expression analysis to evaluate potential reasons for the lack of response to
MK-3475 (pembrolizumab) or progression such as a lack of T cells within or around tumor.
VII. To evaluate the effect of pembrolizumab on Kaposi sarcoma-associated herpesvirus (KSHV)
viral load in the blood, KSHV seroreactivity and KSHV specific CD8+ T-cell activity.
OUTLINE:
Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients continue
receiving their recommended combination antiretroviral therapy orally daily. Cycles repeat
every 21 days for up to 2 years in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up 30 days and then every 12
weeks.
Inclusion Criteria:
- Histologically or cytologically proven metastatic or locally advanced tumors for which
no standard therapy exists, or where standard therapy has failed, or in patients
otherwise ineligible for standard therapy, or for an indication that anti-programmed
cell death protein 1 (PD-1) therapy has been shown to be effective in studies in
HIV-uninfected participants; disease-specific criteria will be applied for certain
common cancers and cancers strongly associated with HIV; however, enrollment will not
be confined to these tumors
- Non-small cell lung cancer (NSCLC)
- Metastatic or locally advanced disease that progressed after at least one prior
therapy
- Note: patients who have actionable molecular targets (e.g., epidermal growth
factor receptor [EGFR], anaplastic lymphoma kinase [ALK], c-ros oncogene 1[ROS1]
mutations) must have received (when indicated) prior appropriate targeted therapy
using Food and Drug Administration (FDA)-approved agents
- AIDS-related non-Hodgkin lymphoma and other non-Hodgkin lymphoma
- Failed standard first-line therapy; and
- Failed autologous stem cell transplant if indicated for histology (i.e diffuse
large B-cell lymphoma) or autologous stem cell transplant is not feasible
- Classical Hodgkin lymphoma
- Relapsed or refractory de novo classical Hodgkin lymphoma having failed standard
first-line therapy; and
- May have failed to achieve a response or progressed after treatment with
brentuximab vedotin or may be brentuximab vedotin naïve but is ineligible or
unable to receive brentuximab vedotin; and
- May have failed to achieve a response to, progressed after, or is ineligible for
autologous stem cell transplant (auto-SCT)
- Hepatocellular carcinoma (HCC)
- Not eligible for curative attempt resection or liver transplant
- Kaposi sarcoma impacting physical and/or psychological wellbeing and not amenable to
local therapy. Patients who have received prior therapy and treatment naive patients
are both potentially eligible to participate.
- On antiretrovival therapy (ART) with suppressed HIV viral load for > 3 months
(Note: an extended washout period is needed to avoid treatment during the period
of risk for the highly toxic and often fatal "Immune Reconstitution Inflammatory
Syndrome (IRIS)" abnormalities
- Disease evaluable by AIDS Clinical Trial Group (ACTG) Kaposi sarcoma (KS)
response criteria
- CD4+ T-cell count >= 50 cells/uL
- For KS patients, the following laboratory values supersede values below:
- Platelets > lower limit of normal
- Hemoglobin > 10 g/dL
- Melanoma
- Unresectable or metastatic disease progression following a B-Raf proto-oncogene,
serine/threonine kinase (BRAF) inhibitor if BRAF V600 positive
- Note: prior therapy with ipilimumab not required
- Available pretreatment biopsy, either fresh (optimal) or archival (acceptable)
- Resolution of any adverse events (AEs) from prior treatments must be resolved to
baseline or grade =< 1 at enrollment (with the exception of alopecia), neuropathy, and
ototoxicity (i.e., AEs that are not expected to improve within the washout period)
- On an effective combination cART regimen, generally a 3-drug regimen based on
Department of Health and Human Services (DHHS) treatment guidelines
- Patients must be on cART >= 4 weeks; and
- Evidence of viral suppression defined as HIV viral load < 200 copies/mL; and
- No symptomatic AEs > grade 1 by Common Terminology Criteria for Adverse Events
(CTCAE) criteria probably or definitely attributed to cART; and
- No laboratory AEs noted on protocol defined screening laboratories > grade 1 by
CTCAE criteria probably or definitely attributed to cART, with exceptions noted
below
- Note: if cART is modified during the screening period, patients must be on an
effective new regimen for >= 2 weeks and otherwise meet eligibility criteria
- Most patients have viral loads that are suppressible to < 50 copies/mL, but about
25% of patients will occasionally have blips up to 400-500 copies/mL, which do
not appear to correlate with lack of viral suppression in most studies; thus, an
HIV viral load of =< 400 copies/mL for an occasional "blip" will be allowed, if
there is documentation of an HIV viral load < 200 on the same regimen and no
significant treatment interruption
- CD4+ T-cell count >= 50 cells/uL
- Patients must have marrow function and organ function as defined below
- Note: to remain on treatment, any abnormal lab values allowed by the PI must
remain stable or improve during treatment; similar off treatment rules will be
applied to all patients, except the following: the grade of any abnormal
laboratory (lab) value allowed by the protocol principal investigator (P.I.) at
enrollment will be considered the patient's baseline for potentially resuming
therapy after modification/holding of therapy when off treatment criteria are
applied
- Leukocytes no lower limit
- Absolute neutrophil count > 500/mcL
- Platelets > 50,000/mcL
- Hemoglobin > 9 g/dL
- Total bilirubin < 1.5 X upper limit of normal (ULN); or < 3 x institutional ULN for
Gilbert's syndrome or HIV protease inhibitors; or < 5 x ULN and direct bilirubin < 0.7
mg/dL for patients on atazanavir containing HIV regimen
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 2.5 X institutional ULN
- Creatine kinase < 5 X institutional ULN
- Serum creatinine < 2.5 X institutional ULN OR measured or calculated* creatinine
clearance (CrCl) (glomerular filtration rate [GFR] can also be used in place of
creatinine or CrCl) >= 30 mL/min for subject with creatinine levels > 2.5 X
institutional ULN
- Creatinine clearance should be calculated per institutional standard
- Thyroid stimulating hormone (TSH) within institutional limits (ie: normal); if TSH is
greater or less than institutional limits patients may participate if their T4 is
within normal limits (WNL); patients may be on a stable dose of replacement thyroid
medication; dose adjustments are allowed if needed
- Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1
- At least 2 weeks from end of chemotherapy with resolution of neutropenia to above
level
- At least 2 weeks from end of radiation therapy
- At least 4 weeks from end of monoclonal antibody therapy
- At least 2 weeks from end of targeted therapy
- Female patients of childbearing potential must have a negative urine or serum
pregnancy within 72 hours before receiving the first dose of study medication; if the
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will
be required
- Note: the effects of MK-3475 on the developing human fetus are unknown; for this
reason and because anti-PD-1 agents may be teratogenic, women of child-bearing
potential must agree to use 2 methods of birth control, or be surgically sterile,
or abstain from heterosexual activity beginning with the screening visit and for
the duration of study participation, through 120 days beyond last dose of MK-3475
administration; patients of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year
- Should a woman become pregnant or suspect she is pregnant while she or her
partner is participating in this study, she should inform her treating physician
immediately
- Men treated or enrolled on this protocol must agree to use 2 adequate methods of
contraception starting with the screening visit, for the duration of study
participation, and through 120 days after the last dose of MK-3475 administration
- No prior treatment with anti-PD-1 or anti-PD-L1
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version
(v) 1.1 or other tumor-specific criteria or disease assessable by physical exam or
other methods if not measurable by RECIST
- Baseline tumor tissue, either fresh (preferred) or from paraffin block/unstained
slides if contemporary biopsy is unsafe or not otherwise obtainable from the primary
tumor site or metastatic site to be available for use on correlative studies
- Ability to understand and willingness to sign a written informed consent document
Exclusion Criteria:
- Active systemic immunosuppressive therapy
- Systemic steroid therapy or steroid therapy that cannot be discontinued with more than
7 consecutive days of steroids within the prior 2 weeks
- Note: the use of prednisone or equivalent < 0.125 mg/kg/day (absolute maximum of
15 mg/day) as replacement therapy is permitted; inhaled or topical
corticosteroids are permitted
- Current or history of systemic autoimmune disease requiring systemic therapy
- Note: the following will NOT be exclusionary:
- The presence of laboratory evidence of autoimmune disease (e.g., positive
antinuclear antibody [ANA] titer or lupus anticoagulant) without associated
symptoms
- Clinical evidence of vitiligo or other forms of depigmenting illness
- Mild autoimmunity not impacting the function of major organs (e.g., limited
psoriasis)
- Grade 3 or 4 immune related toxicity associated with prior ipilimumab therapy that has
not resolved to grade 0 or 1
- Cardiovascular disease that meets one of the following: congestive heart failure (New
York Heart Association class III or IV), active angina pectoris, or recent myocardial
infarction (within the last 6 months)
- Active tuberculosis (TB) or atypical mycobacterial infection:
- Patients who are undergoing undergoing systemic antibiotics for active
mycobacterial infection
- Patients with TB immune reconstitution syndrome (IRIS) requiring corticosteroids
- Note: patients who are receiving treatment for latent tuberculosis
(isonicotinylhydrazide [INH] or alternative) may be eligible after
discussion with the protocol P.I.
- Cirrhosis with Child-Pugh score of B or C
- Uncontrolled hepatitis B virus (HBV) infection, defined as plasma HBV DNA detectable
by polymerase chain reaction (PCR)
- Note: the following will NOT be exclusionary:
- A positive hepatitis B serology indicative of previous immunization (i.e.,
hepatitis B surface antibody [HBsAb] positive and hepatitis B core antibody
[HBcAb] negative), or a fully resolved acute HBV infection
- Patients with chronic HBV suppressed by appropriate antiretroviral therapy
with activity against HBV, as outlined in DHHS guidelines
- Uncontrolled hepatitis C virus (HCV) infection, defined as plasma HCV RNA detectable
by PCR
- Note: the following will NOT be exclusionary:
- Positive HCV serology but no detectable HCV RNA, indicative of spontaneously
cleared HCV infection
- Patients who have been successfully treated for HCV as long as therapy for
HCV has been completed
- Patients who are receiving any other investigational agents for cancer
- Extensive active brain disease including symptomatic brain metastases or the presence
of leptomeningeal disease, and all patients with infratentorial tumors
- Note: patients with brain metastasis after definitive therapy with surgery or
stereotactic radiation and stable off steroids for > 4 weeks are eligible as are
patients with asymptomatic brain metastasis as long as less than 1 cm and thus
deemed as not requiring therapy by the primary physician and the lesions(s) are
not infratentorial
- Pregnancy or nursing or unwilling to take adequate birth control during therapy
- Prior organ allograft or allogeneic transplantation, if the transplanted tissue is
still in place
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia
- Medical or psychiatric illness or social situations that would, in the opinion of the
investigator, preclude participation in the study or the ability of patients to
provide informed consent for themselves
- Clinically significant lung disease including known history or evidence of
interstitial lung disease or chronic obstructive pulmonary disease (COPD) that
requires oxygen therapy
- Active non-infectious pneumonitis >= grade 2 or history of grade 3 non-infectious
pneumonitis requiring steroids within the past 12 months; or any history of grade 4
non-infectious pneumonitis
- Grade 3-4 ascites or pleural effusion
- Note: The following will NOT be exclusionary: A participant who is clinically
stable following treatment for ascites or pleural effusion (including therapeutic
thoracentesis or paracentesis)
- Receipt of live vaccines within 30 days before the first dose of trial treatment and
while participating in the trial; examples of live vaccines include, but are not
limited to, the following: measles, mumps, rubella, chicken pox, yellow fever,
seasonal flu, H1N1 flu, rabies, bacillus Calmette-Guerin (BCG), and typhoid vaccine
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475 (pembrolizumab)
