Testing the Addition of an Experimental Medication MK-3475 (Pembrolizumab) to Usual Anti-Retroviral Medications in Patients With HIV and Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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 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), CD4+ 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 human herpesvirus 8 (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 (PO) once daily (QD). Cycles repeat every 21 days for up to 2 years or 35 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) or positron emission tomography (PET)/CT and blood sample collection throughout the trial. Patients may also undergo biopsies during screening and on study. After completion of study treatment, patients are followed up 30 days and then every 12 weeks up to 1 year.

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

Conditions
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AIDS-Related Non-Hodgkin Lymphoma, Clinical Stage III Cutaneous Melanoma AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Hepatocellular Carcinoma, HIV Infection, Kaposi Sarcoma, Locally Advanced Lung Non-Small Cell Carcinoma, Locally Advanced Malignant Solid Neoplasm, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Non-Hodgkin Lymphoma, Recurrent Classic Hodgkin Lymphoma, Recurrent Malignant Neoplasm, Refractory Classic Hodgkin Lymphoma, Refractory Malignant Neoplasm, Stage III Lung Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Unresectable Melanoma

Intervention / Treatment
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* Drug: Antiretroviral Therapy
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Biological: Pembrolizumab
* Procedure: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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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-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 that 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 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) No KSHV-associated multicentric Castleman disease in past 5 years No symptomatic pulmonary Kapsoi sarcoma (KS) or chest X-rays positive for un-evaluated abnormalities Disease evaluable by AIDS Clinical Trial Group (ACTG) 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 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 (PI) 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 Age >= 18 years Because no dosing or adverse event data are currently available on the use of MK-3475 (pembrolizumab) in combination with cART in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials 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 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 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 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 infection 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pembrolizumab and cART)<br>Patients receive pembrolizumab IV over 30 minutes on day 1. Patients continue receiving their recommended combination antiretroviral therapy PO QD. Cycles repeat every 21 days for up to 2 years or 35 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or PET/CT and blood sample collection throughout the trial. Patients may also undergo biopsies during screening and on study. | Drug: Antiretroviral Therapy<br>* Given PO<br>* Other names: ART;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo blood sample collection<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Biological: Pembrolizumab<br>* Given IV<br>* Other names: SCH 900475;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of observed adverse events (AEs) | Will be graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (version 5.0 beginning April 1, 2018). Safety and tolerability will be assessed by summarizing all relevant parameters including AEs, serious AEs, laboratory tests, vital signs, and electrocardiogram measurements. All summaries will be presented for each cohort and overall. If the numbers are sufficient, the results may additionally be stratified by tumor type. | Up to 90 days after the last dose of trial treatment | 
| Incidence of immune-related events of clinical interest (ECIs) | This includes the occurrence of grade 2 or higher AEs. Will be graded using CTCAE version 4.0 (version 5.0 beginning April 1, 2018). Any AE of unknown etiology associated with study therapy will be evaluated to determine if it is possibly an ECI of a potentially immunologic etiology or related to combination antiretroviral therapy (cART). All summaries will be presented for each cohort and overall. If the numbers are sufficient, the results may additionally be stratified by tumor type. | Up to 90 days after the last dose of trial treatment | 
| Incidence of cART-related ECIs of grade 2 or higher AEs | Will be graded using CTCAE version 4.0 (version 5.0 beginning April 1, 2018). Any AE of unknown etiology associated with study therapy will be evaluated to determine if it is possibly an ECI of a potentially immunologic etiology or related to cART. All summaries will be presented for each cohort and overall. If the numbers are sufficient, the results may additionally be stratified by tumor type. | Up to 90 days after the last dose of trial treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (Cohorts 1-3) | Defined as the proportion of patients who have achieved complete response (CR) or partial response (PR). Assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, Lugano Criteria for Malignant Lymphoma or other tumor-specific criteria. Analyzed using Clopper-Pearson 95% confidence intervals. | Up to 2 years | 
| Progression-free survival (Cohorts 1-3) | Assessed using RECIST 1.1, Lugano Criteria for Malignant Lymphoma or other tumor-specific criteria. Summarized statistically using Kaplan-Meier method. | From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 3 years | 
| Duration of response (Cohorts 1-3) | Defined in participants experiencing CR or PR using RECIST 1.1, Lugano Criteria for malignant lymphoma or other tumor-specific criteria. Summarized statistically using Kaplan-Meier method. | Interval between the date of first response (CR/PR) and the date of progression, assessed up to 3 years | 
| Overall survival (Cohorts 1-3) | Summarized statistically using Kaplan-Meier method. | From the first dose of study drug to death due to any cause, assessed up to 3 years | 
| Best objective response rate (partial response + completion response)(Cohort 4) | Determined by modified Acquired Immunodeficiency Syndrome Clinical Trials Group (ACTG) criteria. | Up to 2 years | 
| Progression-free survival (Cohort 4) | Assessed using ACTG criteria. Summarized statistically using Kaplan-Meier method. | From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 3 years | 
| Duration of response (Cohort 4) | Assessed using ACTG criteria. Summarized statistically using Kaplan-Meier method. | Interval between the date of first response (CR/PR) and the date of progression, assessed up to 3 years | 
| Overall survival (Cohort 4) | Summarized statistically using Kaplan-Meier method. | From the first dose of study drug to death due to any cause, assessed up to 3 years |