Phase I/II Study of High Dose Interleukin 2, Aldesleukin, in Combination With the Histone Deacetylase Inhibitor Entinostat in Patients With Metastatic Renal Cell Carcinoma
I. To evaluate the safety and tolerability of high dose interleukin 2 (aldesleukin) in
combination with entinostat in patients with metastatic renal cell carcinoma (RCC). (Phase
I) II. To monitor toxicity and estimate the efficacy of high dose aldesleukin combined with
entinostat in patients with metastatic RCC. (Phase II)
I. To compare the time-to-tumor progression, progression-free survival and overall survival
of patients with metastatic RCC treated with high dose aldesleukin combined with entinostat
to the historical data of patients treated with high dose aldesleukin alone. (Phase II) II.
To assess the toxicity of high dose aldesleukin combined with entinostat. (Phase II) III. To
evaluate entinostat pharmacodynamics (PD) in blood and tumor samples. (Phase II) IV. To
measure the association between baseline laboratory parameters (e.g. cluster of
differentiation [CD]4+, CD8+, CD4+/forkhead box P3 [Foxp3]), tumor blood metabolism, and a
variety of response variables (e.g. toxicity, response and survival). (Phase II) V. To
explore the relationship between entinostat exposure with PD endpoints (e.g. toxicity and
histone acetylation in peripheral blood mononuclear cells or peripheral blood mononuclear
cells [PBMNCs] and changes in T cell subset population). (Phase II) VI. To evaluate the
modulation of tumor metabolism by fluorodeoxyglucose (FDG, fludeoxyglucose F 18) positron
emission tomography (PET)/computed tomography (CT) scan. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II
Patients receive entinostat orally (PO) every 2 weeks beginning on day -14 and high-dose
aldesleukin intravenously (IV) every 8 hours on days 1-5 and 15-19. Courses repeat every 84
days* in the absence of disease progression or unacceptable toxicity.
NOTE: *Patients with evidence of tumor shrinkage may receive up to 3 courses of high-dose
aldesleukin therapy. Patients with stable disease by Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.0 criteria, but without evidence of tumor shrinkage after two
courses will receive only entinostat until disease progression is documented.
After completion of study treatment, patients are followed up at 30 days and then every 3
A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-Experienced HIV-1 Infected Infants and Children, Aged 2 Months to < 6 Years (IMPAACT P1090, Version 5.0 dated, 03/10/2016)
Nevirapine (NVP) and Efavirenz, the two most widely used non nucleoside reverse transcriptase inhibitor (NNRTI) drugs, have a low genetic barrier for the development of drug resistance mutations, so that, a single amino acid substitution in the viral reverse transcriptase leads to profound reduction in viral susceptibility to both drugs. With the widespread use of first generation NNRTIs as components of combination antiretroviral therapy, and as a component of neonatal prevention of mother to child transmission (PMTCT) treatment regimens, and infant nevirapine during breastfeeding, the number of children harboring virus with one or two NNRTI-resistance mutations will continue to increase. Thus, there is an urgent need to develop alternative therapeutic options for newly diagnosed neonates and infants exposed to single dose NVP containing regimens, as well as for infants and children failing their present HAART regimens. Etravirine (ETR) is a second generation NNRTI and has a structure that allows more molecular flexibility relative to other NNRTIs, allowing ETR to maintain its binding affinity for HIV-1 reverse transcriptase despite binding site changes induced by the presence of common NNRTI resistance mutations. This is a Phase I/II, multicenter, open label 48 week study of the pharmacokinetics, safety and tolerability of ETR in combination with at least 2 active antiretrovirals (ARVs), including a boosted PI and NRTIs for treatment experienced HIV-1-infected infants and children 2 months to < 6 years cohorts. The study will, in a sequential manner, accrue subjects for an initial dose finding intensive PK component for age related cohorts. It is expected that up to 50 subjects will be accrued study wide, to yield at least 36 evaluable* subjects with a minimum of 12 subjects for each of the three cohorts (up to 18 subjects may be enrolled into Cohort 1), whose initial dose was that which was determined optimal for their age cohorts. 3 participants will be enrolled at this site. The total sample size will depend upon the number needed to complete the dose finding stage of the study, the number of subjects who discontinue the study and the number of subjects required for regulatory approval of ETR in these populations. The primary endpoints for this study will be toxicity and failure to meet PK targets. The analysis of dose finding data will consist of descriptive statistics summarizing the safety and PK data from the dose finding phase of the study.
Pediatric HIV/AIDS Cohort Study (PHACS): Surveillance Monitoring for ART Toxicities Study in HIV-uninfected Children Born to HIV-infected Women (SMARTT Study), Version 4.0, dated 08/10/2010
Many antiretroviral therapy (ART) medications given to a pregnant woman cross the placenta
and can be detected in the amniotic fluid and cord blood resulting in substantial fetal
exposure. Therefore, there is concern about toxicity of the drugs in the fetus and infant.
It is noteworthy that none of the currently approved ART medications for the prevention of
maternal to fetal transmission of HIV are in Food and Drug Administration (FDA) Pregnancy
Category A (no fetal risk ascertained in adequately controlled human studies). Thus, there
is continued need to examine the toxicity of ART in HIV transmission prevention for the
short-term toxicity of newer agents and combinations as well as the unanswered questions of
longer term toxicity and subtle adverse effects.
The study will use a registry approach to conduct active surveillance among children < 12
years of age at enrollment. Occurrences of abnormalities from ART exposure in utero and/or
in the first two months of life will be sought in multiple domains, including metabolic,
growth, cardiac, neurologic, neurodevelopmental, behavior, language, and hearing. Clinical
and laboratory data will be examined for abnormalities through a hierarchy of evaluations:
adverse events (AE) will be identified → selected AEs will trigger predefined additional
evaluations → significant observations will be defined as cases → a pattern of significant
study-wide cases will be defined as signals. The incidence of these events of interest will
be monitored over time and by ART regimen, and compared with historical data that may be
suggestive of a signal. Some signals may be testable using existing and/or previously
collected data, while other signals may indicate the need for additional hypothesis-driven
studies outside of SMARTT.
The objectives of SMARTT are:
1. To estimate the occurrence of potential ART-related toxicities through an ongoing
surveillance system among HIV-uninfected children born to mothers with HIV infection
with and without exposure to ART in utero and/or in the first two months of life and
compare the occurrences of these outcomes with other sources of data as well as by ART
2. To actively encourage hypothesis-driven studies to confirm that the signals are due to
ART exposure in utero and/or in the first two months of life. Note that the full design
and execution of these studies may be beyond the scope of the SMARTT study but will be
facilitated by SMARTT.
The specific aims of SMARTT are:
1. To create a Static Surveillance Cohort to extend domain-specific data collection in
children either 1) previously enrolled in any of the approved studies for enrollment
into SMARTT; 2) previously enrolled in another pediatric HIV/AIDS cohort study with
SMARTT Protocol Chair approval, or 3) not previously enrolled in an approved study but
with equivalent data available in the medical record;
2. To create a Dynamic Surveillance Cohort to examine domain-specific data of children
newly exposed to ART in utero and/or in the first two months of life;
3. To create a Young Adult Cohort to study long-term outcomes in SMARTT participants
formerly enrolled in the Static and Dynamic cohorts.
4. To identify a set of "triggers" for each domain that define a "signal" of possible ART
toxicity and compare the occurrence of these signals with previously collected data and
by ART exposure; and
5. To encourage and facilitate the development of hypothesis-driven studies to evaluate
whether a "signal" is the result of ART exposure in utero and/or in the first two
months of life.
Recruiting | Conditions and diagnoses potentially related to perinatal exposure to antiretroviral medications | Multisite
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission:A Phase I/II Proof of Concept Study (IMPAACT P1115 Version 1.0, dated March 12, 2014)
IMPAACT P1115 will explore the effects of early intensive ART on achieving HIV remission
(HIV RNA below the limit of detection of detection of the PCR assay) among infants infected
with HIV in utero. Infants in this study will initiate ART within 48 hours of birth and will
first be evaluated to determine whether HIV RNA can be detected in their blood while they
are on ART. Upon reaching two years of age, infants with undetectable HIV RNA will be
evaluated to determine if they meet study criteria to stop taking ART. Infants who meet
these criteria will stop taking ART and will be monitored closely to determine whether HIV
RNA remains undetectable while they are off ART. For any infant who stops ART and then has
HIV RNA detected, ART will be re-started.
The study will also assess the safety and pharmacokinetics of early intensive ART in