Try our beta test site
IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...

Pembrolizumab in Treating Patients With HIV and Relapsed, Refractory, or Disseminated Malignant Neoplasms

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2016 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02595866
First received: November 3, 2015
Last updated: April 17, 2017
Last verified: November 2016
  Purpose
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). Monoclonal antibodies, such as pembrolizumab, may block tumor or cancer growth in different ways by targeting certain cells. It may also help the immune system kill cancer cells.

Condition Intervention Phase
AIDS-Related Non-Hodgkin Lymphoma
Classical Hodgkin Lymphoma
HIV Infection
Locally Advanced Malignant Neoplasm
Metastatic Malignant Neoplasm
Recurrent Hepatocellular Carcinoma
Recurrent Hodgkin Lymphoma
Recurrent Kaposi Sarcoma
Recurrent Malignant Neoplasm
Recurrent Melanoma of the Skin
Recurrent Non-Hodgkin Lymphoma
Recurrent Non-Small Cell Lung Carcinoma
Refractory Hodgkin Lymphoma
Refractory Malignant Neoplasm
Solid Neoplasm
Stage IIIA Hepatocellular Carcinoma
Stage IIIA Non-Small Cell Lung Cancer
Stage IIIA Skin Melanoma
Stage IIIB Hepatocellular Carcinoma
Stage IIIB Non-Small Cell Lung Cancer
Stage IIIB Skin Melanoma
Stage IIIC Hepatocellular Carcinoma
Stage IIIC Skin Melanoma
Stage IV Non-Small Cell Lung Cancer
Stage IV Skin Melanoma
Stage IVA Hepatocellular Carcinoma
Stage IVB Hepatocellular Carcinoma
Other: Laboratory Biomarker Analysis
Biological: Pembrolizumab
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase I Study of MK-3475 (Pembrolizumab) in Patients With Human Immunodeficiency Virus (HIV) and Relapsed/Refractory or Disseminated Malignant Neoplasm

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Frequency of observed AEs graded using CTCAE version 4.0 [ Time Frame: Up to 90 days after the last dose of trial treatment ]
    Safety and tolerability will be assessed by summarizing all relevant parameters including AEs, serious AEs (SAEs), 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.

  • Incidence of cART-related ECIs of grade 2 or higher AEs using CTCAE version 4.0 [ Time Frame: Up to 90 days after the last dose of trial treatment ]
    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.

  • Incidence of immune-related events of clinical interest (ECIs), which include the occurrence of grade 2 or higher AEs using CTCAE version 4.0 [ Time Frame: Up to 90 days after the last dose of trial treatment ]
    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.


Secondary Outcome Measures:
  • Duration of response defined in participants experiencing CR or PR using RECIST 1.1, "Lugano Criteria" for malignant lymphoma or other tumor-specific criteria [ Time Frame: Interval between the date of first response (CR/PR) and the date of progression, assessed up to 1 year ]
    Summarized statistically using Kaplan-Meier method.

  • Objective response rate defined as the proportion of patients who have achieved completer response (CR) or partial response (PR) according to RECIST 1.1, "Lugano Criteria" for Malignant Lymphoma or other tumor-specific criteria [ Time Frame: Up to 1 year ]
    Analyzed using Clopper-Pearson 95% confidence intervals.

  • Overall survival [ Time Frame: From the first dose of study drug to death due to any cause, assessed up to 1 year ]
    Summarized statistically using Kaplan-Meier method.

  • Progression-free survival using RECIST 1.1, "Lugano Criteria" for Malignant Lymphoma or other tumor-specific criteria [ Time Frame: From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 1 year ]
    Summarized statistically using Kaplan-Meier method.


Estimated Enrollment: 39
Study Start Date: February 2016
Estimated Primary Completion Date: April 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (pembrolizumab and cART)
Patients receive pembrolizumab IV over 30 minutes on day 1. Patients continue receiving their recommended combination antiretroviral therapy orally daily. Courses repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Detailed Description:

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.

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.

TERTIARY OBJECTIVES:

I. To assess the effect 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 by biopsy 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.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients continue receiving their recommended combination antiretroviral therapy orally daily. Courses 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 for 1 year.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 (KS) impacting physical and/or psychological wellbeing and not amenable to local therapy and one or more of the following:

    • Stable KS by despite 6 or more cycles of liposomal doxorubicin or paclitaxel or other active cytotoxic agents (i.e. etoposide, bleomycin, anthracyclines, vincristine [vincristine sulfate], vinblastine); or
    • Progressive disease despite 3 or more cycles of liposomal doxorubicin or paclitaxel or other active cytotoxic agents (i.e. etoposide, bleomycin, anthracyclines, vincristine, vinblastine); or
    • Patient who has received a cumulative lifetime dose of anthracycline of >= 550 mg/m^2; or
    • Recurrent or progressive KS after completion of prior first line chemotherapy
    • Intolerant of or refuse further cytotoxic chemotherapy
  • Melanoma

    • Unresectable or metastatic and 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 AE if resolvable 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 >= 100 cells/uL; for CD4+ T-cell count < 200 cells/uL, requires CD4+/CD8+ T-cell ratio greater than 0.4
  • Patients must have marrow function and organ function as defined below; abnormal lab values will not be considered exclusions IF the abnormal values are:

    • Probably or definitely attributed to the cancer; or
    • If non-hematologic, are equal to or less than grade 2; or
    • If hematologic are equal to or less than grade 3; and
    • Only after discussion with the principal investigator (PI)

      • 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 grade of any abnormal laboratory (lab) value allowed by the protocol P.I. at enrollment will be considered the patient's baseline when off treatment criteria are applied for potentially resuming therapy after modification/holding of therapy
  • 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: 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 the 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):

    • Patients who are undergoing first month of therapy (RIPE or equivalent) for active TB
    • Patients with TB immune reconstitution syndrome (IRIS) requiring corticosteroids

      • Note: patients who are receiving therapy beyond month one of initial therapy with no evidence of TB IRIS requiring corticosteroid therapy, or those receiving treatment for latent tuberculosis (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
  • 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-Guérin (BCG), and typhoid vaccine
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-3475 (pembrolizumab)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02595866

Locations
United States, Connecticut
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Mario Sznol    203-785-5702      
Principal Investigator: Mario Sznol         
United States, Louisiana
Louisiana State University Health Science Center Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Thomas M. Reske    504-568-2428    emede1@lsuhsc.edu   
Principal Investigator: Thomas M. Reske         
United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: Thomas S. Uldrick    800-411-1222      
Principal Investigator: Thomas S. Uldrick         
United States, New York
Roswell Park Cancer Institute Suspended
Buffalo, New York, United States, 14263
Laura and Isaac Perlmutter Cancer Center at NYU Langone Recruiting
New York, New York, United States, 10016
Contact: Mohammad M. Abdul-Hay    212-263-4434    prmc.coordinator@nyumc.org   
Principal Investigator: Mohammad M. Abdul-Hay         
United States, Washington
Cancer Immunotherapy Trials Network Recruiting
Seattle, Washington, United States, 98109
Contact: Thomas S. Uldrick    301-402-6296    uldrickts@mail.nih.gov   
Principal Investigator: Thomas S. Uldrick         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Thomas Uldrick Cancer Immunotherapy Trials Network
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02595866     History of Changes
Other Study ID Numbers: NCI-2015-01906
NCI-2015-01906 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CITN-12 ( Other Identifier: Cancer Immunotherapy Trials Network )
CITN-12 ( Other Identifier: CTEP )
U01CA154967 ( US NIH Grant/Contract Award Number )
Study First Received: November 3, 2015
Last Updated: April 17, 2017

Additional relevant MeSH terms:
Lymphoma
Carcinoma
Lung Neoplasms
Neoplasms
Carcinoma, Non-Small-Cell Lung
Melanoma
Carcinoma, Hepatocellular
HIV Infections
Lymphoma, Non-Hodgkin
Hodgkin Disease
Sarcoma, Kaposi
Neoplasms, Second Primary
Recurrence
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Glandular and Epithelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue

ClinicalTrials.gov processed this record on April 26, 2017