Phase I Study of MK-3475 (Pembrolizumab) in Patients With Human Immunodeficiency Virus (HIV) and Relapsed/Refractory or Disseminated Malignant Neoplasm
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 58
- 试验地点
- 12
- 主要终点
- Incidence of Immune-related Events of Clinical Interest (irECI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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
- 另有 11 项未显示
排除标准
- •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)
研究组 & 干预措施
Treatment (pembrolizumab and cART)
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.
干预措施: Antiretroviral Therapy (Drug)
Treatment (pembrolizumab and cART)
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.
干预措施: Biopsy (Procedure)
Treatment (pembrolizumab and cART)
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.
干预措施: Biospecimen Collection (Procedure)
Treatment (pembrolizumab and cART)
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.
干预措施: Computed Tomography (Procedure)
Treatment (pembrolizumab and cART)
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.
干预措施: Pembrolizumab (Biological)
Treatment (pembrolizumab and cART)
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.
干预措施: Positron Emission Tomography (Procedure)
结局指标
主要结局
Incidence of Immune-related Events of Clinical Interest (irECI)
时间窗: Up to 90 days after the last dose of trial treatment, up to 2 years or 35 cycles of trial treatment.
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.
Frequency of Observed Adverse Events (AEs)
时间窗: Up to 90 days after the last dose of trial treatment, up to 2 years or 35 cycles of trial treatment.
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.
Incidence of cART-related ECIs of Grade 2 or Higher AEs
时间窗: Up to 90 days after the last dose of trial treatment, up to 2 years or 35 cycles of trial treatment.
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.
次要结局
- Progression-free Survival (Cohorts 1-3)(From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 25 months)
- Objective Response Rate (Partial Response + Completion Response)(Kaposi Sarcoma Cohort)(Up to 2 years)
- Overall Survival (Kaposi Sarcoma Cohort)(From the first dose of study drug to death due to any cause, assessed up to 3 years)
- Duration of Response (Cohorts 1-3)(Interval between the date of first response (CR/PR) and the date of progression, assessed up to 2 years)
- Progression-free Survival (Kaposi Sarcoma Cohort)(From the first dose of study drug to progressive disease or death, whichever occurs earlier, assessed up to 3 years)
- Objective Response Rate (Cohorts 1-3)(Up to 2 years)
- Overall Survival (Cohorts 1-3)(From the first dose of study drug to death due to any cause, assessed up to 3 years)
- Duration of Response (Kaposi Sarcoma Cohort)(Interval between the date of first response (CR/PR) and the date of progression, assessed up to 2 years)