Phase I Study of MK-3475 (Pembrolizumab) in Patients With Human Immunodeficiency Virus (HIV) and Relapsed/Refractory or Disseminated Malignant Neoplasm

  • End date
    Nov 1, 2024
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 27 October 2022
monoclonal antibodies
serum pregnancy test
human immunodeficiency virus
measurable disease
HIV Infection
hiv viral load
direct bilirubin
lung cancer
glomerular filtration rate
liver transplant
neutrophil count
tumor cells
epidermal growth factor receptor
monoclonal antibody therapy
solid tumors
wbc count
b-cell lymphoma
solid tumor
stem cell transplant
targeted therapy
solid neoplasm
antibody therapy
HIV Vaccine
hcv viral load
metastatic cancer
immune globulin
hiv protease inhibitors
kaposi's sarcoma


This phase I trial studies the side effects of pembrolizumab in treating patients with human immunodeficiency virus (HIV) and malignant neoplasms that have come back (relapsed), do not respond to treatment (refractory), or have distributed over a large area in the body (disseminated). Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.



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.


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.


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.


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 up to 1 year.

Condition AIDS-Related Non-Hodgkin Lymphoma, Classic Hodgkin Lymphoma, Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Hepatocellular Carcinoma, HIV Infection, Locally Advanced Lung Non-Small Cell Carcinoma, Locally Advanced Malignant Neoplasm, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Melanoma, Metastatic Neoplasm, Pathologic Stage III Cutaneous Melanoma AJCC v8, Pathologic Stage IIIA Cutaneous Melanoma AJCC v8, Pathologic Stage IIIB Cutaneous Melanoma AJCC v8, Pathologic Stage IIIC Cutaneous Melanoma AJCC v8, Pathologic Stage IIID Cutaneous Melanoma AJCC v8, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Recurrent Classic Hodgkin Lymphoma, Recurrent Kaposi Sarcoma, Refractory Classic Hodgkin Lymphoma, Refractory Kaposi Sarcoma, Refractory Neoplasm, Stage III Lung Cancer AJCC v8, Stage IIIA Lung Cancer AJCC v8, Stage IIIB Lung Cancer AJCC v8, Stage IIIC Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8, Unresectable Melanoma
Treatment laboratory biomarker analysis, Pembrolizumab
Clinical Study IdentifierNCT02595866
SponsorNational Cancer Institute (NCI)
Last Modified on27 October 2022


Yes No Not Sure

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 naive 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
Disease evaluable by AIDS Clinical Trial Group (ACTG) Kaposi sarcoma (KS) response criteria
patients are both potentially eligible to participate
CD4+ T-cell count >= 50 cells/uL
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)
For KS patients, the following laboratory values supersede values below
No human herpesvirus 8 (KSHV)-associated multicentric Castleman disease in past 5 years
Platelets > lower limit of normal
No symptomatic pulmonary Kapsoi sarcoma (KS) or chest X-rays positive for un-evaluated abnormalities
Hemoglobin > 10 g/dL
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
Unresectable or metastatic disease progression following a BRAF inhibitor if BRAF V600 positive
Patients must be on cART >= 4 weeks; and
Note: Prior therapy with ipilimumab not required
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
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
Thyroid stimulating hormone (TSH) within institutional limits (ie: normal); if TSH is
At least 2 weeks from end of radiation therapy
greater or less than institutional limits patients may participate if their T4
At least 4 weeks from end of monoclonal antibody therapy
is within normal limits (WNL); patients may be on a stable dose of replacement
At least 2 weeks from end of targeted therapy
thyroid medication; dose adjustments are allowed if needed
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
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
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

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)
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
Note: the following will NOT be exclusionary
Grade 3 or 4 immune related toxicity associated with prior ipilimumab therapy that has
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
not resolved to grade 0 or 1
Patients with chronic HBV suppressed by appropriate antiretroviral therapy with activity against HBV, as outlined in DHHS guidelines
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
Uncontrolled hepatitis B virus (HBV) infection, defined as acute liver failure or protracted, severe course, as indicated by total bilirubin > 3 mg/dL (or direct bilirubin > 1.5 mg/dL), international normalized ratio > 1.5, encephalopathy, or ascites
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
Uncontrolled hepatitis C virus (HCV) infection, defined as plasma HCV RNA detectable
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
by PCR
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)
History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 (pembrolizumab)
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
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