Clinical Trials /

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

NCT02595866

Description:

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.

Related Conditions:
  • AIDS-Related Lymphoma
  • Hepatocellular Carcinoma
  • Hodgkin Lymphoma
  • Kaposi Sarcoma
  • Melanoma
  • Non-Hodgkin Lymphoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01906
  • SECONDARY ID: NCI-2015-01906
  • SECONDARY ID: s16-01365
  • SECONDARY ID: CITN-12
  • SECONDARY ID: CITN-12
  • SECONDARY ID: P30CA015704
  • SECONDARY ID: U01CA154967
  • NCT ID: NCT02595866

Conditions

  • AIDS-Related Non-Hodgkin Lymphoma
  • HIV Infection
  • Locally Advanced Lung Non-Small Cell Carcinoma
  • Locally Advanced Malignant Neoplasm
  • Locally Advanced Malignant Solid Neoplasm
  • Metastatic Hepatocellular Carcinoma
  • Metastatic Lung Non-Small Cell Carcinoma
  • Metastatic Malignant Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • Metastatic Melanoma
  • Recurrent Cutaneous Melanoma
  • Recurrent Hepatocellular Carcinoma
  • Recurrent Hodgkin Lymphoma
  • Recurrent Kaposi Sarcoma
  • Recurrent Lung Non-Small Cell Carcinoma
  • Recurrent Malignant Neoplasm
  • Recurrent Non-Hodgkin Lymphoma
  • Refractory Classic Hodgkin Lymphoma
  • Refractory Hodgkin Lymphoma
  • Refractory Malignant Neoplasm
  • Refractory Malignant Solid Neoplasm
  • Stage IIIA Cutaneous Melanoma AJCC v7
  • Stage IIIA Hepatocellular Carcinoma AJCC v7
  • Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIB Hepatocellular Carcinoma AJCC v7
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IIIC Hepatocellular Carcinoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7
  • Stage IV Lung Non-Small Cell Cancer AJCC v7
  • Stage IVA Hepatocellular Carcinoma AJCC v7
  • Stage IVB Hepatocellular Carcinoma AJCC v7
  • Unresectable Melanoma

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab and cART)

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). 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

      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 treatment naive patients with 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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab and cART)ExperimentalPatients receive pembrolizumab 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.
  • Pembrolizumab

Eligibility 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) (following prior KS-specific therapy (Cohorts 1-3)

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

                    -  Stable KS 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 received a cumulative lifetime dose of anthracycline of >= 550
                       mg/m^2; or

                    -  Recurrent or progressive KS after completion of prior first line
                       chemotherapy or

                    -  Intolerant of or refuses further cytotoxic chemotherapy

                    -  No KSHV-associated multicentric Castleman disease in past 5 years

                    -  For KS patients, the following laboratory values supersede values below:

                         -  Platelets > lower limit of normal

                         -  Hemoglobin > 10 g/dL

          -  Treatment naive Kaposi sarcoma impacting physical and/or psychological wellbeing and
             not amenable to local therapy. (Cohort 4)

               -  On antiretroviral 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 prior systemic cancer chemotherapy

               -  No symptomatic pulmonary 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 >= 100 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 >= 100 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):

               -  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

          -  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-Guérin (BCG), and typhoid vaccine

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to MK-3475 (pembrolizumab)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency of observed adverse events (AEs)
Time Frame:Up to 90 days after the last dose of trial treatment
Safety Issue:
Description: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 (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.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Up to 1 year
Safety Issue:
Description:Defined as the proportion of patients who have achieved completer 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.
Measure:Progression-free survival
Time Frame:From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 1 year
Safety Issue:
Description:Assessed using RECIST 1.1, "Lugano Criteria" for Malignant Lymphoma or other tumor-specific criteria. Summarized statistically using Kaplan-Meier method.
Measure:Duration of response
Time Frame:Interval between the date of first response (CR/PR) and the date of progression, assessed up to 1 year
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:From the first dose of study drug to death due to any cause, assessed up to 1 year
Safety Issue:
Description:Summarized statistically using Kaplan-Meier method.
Measure:Best objective response rate (partial response + completion response)(Cohort 4)
Time Frame:Up to 1 year
Safety Issue:
Description:Determined by modified Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) criteria.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 27, 2020