Parallel (Randomized) Phase II Evaluation of ARQ 197 and ARQ 197 in Combination With Erlotinib in Papillary Renal Cell Carcinoma
PRIMARY OBJECTIVES:
I. To assess the response rate (confirmed complete and partial response) of patients with
locally advanced or metastatic papillary renal cell carcinoma treated with either ARQ 197
(tivantinib) or ARQ 197 combined with erlotinib (erlotinib hydrochloride).
SECONDARY OBJECTIVES:
I. To assess the progression free survival (PFS) of patients with locally advanced or
metastatic papillary renal cell carcinoma treated with either ARQ 197 or ARQ 197 combined
with erlotinib.
II. To assess the safety and tolerability of ARQ 197 therapy and ARQ 197 combined with
erlotinib.
III. To descriptively assess the role of prior treatment on outcome.
TERTIARY OBJECTIVES:
I. To bank tissue specimens for future use and once funding is obtained to evaluate the
expression of tissue correlative biomarkers such as hepatocyte growth factor receptor (c-MET)
and epidermal growth factor receptor (EGFR), and to perform exploratory correlation with
clinical outcomes.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive tivantinib orally (PO) twice daily (BID) on days 1-28.
ARM II: Patients receive tivantinib PO BID and erlotinib hydrochloride PO once daily (QD) on
days 1-28.
In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months for up to 2 years.
Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals With Latent Tuberculosis Infection
The World Health Organization (WHO) estimated that in 2017 there were 10 million new cases of
TB, and 1.6 million people died as a result of TB. Among new TB cases, it is estimated that
920,000 occurred in people who were HIV-coinfected, and 23% of TB deaths were among
HIV-coinfected individuals. In Africa, TB is the leading AIDS-related opportunistic
infection. Latent TB infection occurs when people are infected with the bacteria that cause
TB, but they do not have any symptoms of TB infection. Latent TB can develop into active TB,
and HIV-infected people have an increased risk of progressing from latent TB to active TB.
INH is a medication that is prescribed for people with latent TB to help prevent active TB
from developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment
regimen of 3 months of once-weekly RPT plus INH has proven to be as effective and improved
adherence. The purpose of this study was to compare the safety and effectiveness of a 4-week
daily regimen of RPT plus INH to a standard 9-month daily INH regimen for TB prevention in
HIV-infected individuals.
This study enrolled HIV-infected people who did not have evidence of active TB but who were
at high risk of developing active TB. Participants were randomly assigned to receive RPT and
INH once a day for 4 weeks or INH once a day for 9 months. All participants received
pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study
visits occurred at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study
visits, participants had a physical exam, clinical assessment, blood collection, and a chest
radiograph or chest computed tomography (CT) scan (if needed). Some participants had their
blood stored for future testing. Follow-up study visits occurred every 12 weeks starting at
Week 48 and continued for 3 years after the last participant enrolled.
A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Weekly Low-dose Methotrexate (LDM) in the Prevention of Cardiovascular Events Among Stable Coronary Artery Disease Patients With Type 2 Diabetes or Metabolic Syndrome
While inflammation contributes crucially to atherothrombosis, it is unknown whether
inhibition of inflammation per se will lower vascular event rates. The primary aim of the
Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory
hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will
reduce rates of myocardial infarction, stroke, and cardiovascular death among stable coronary
artery disease patients with type 2 diabetes or metabolic syndrome, conditions associated
with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind,
placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women
from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8
weeks), eligible participants who have either suffered documented myocardial infarction in
the past or have angiographically demonstrated multivessel coronary artery disease in the
past will be randomly allocated over a three to four year period to usual care plus placebo
or usual care plus LDM. The target methotrexate dose among those allocated to active therapy
is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment
of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate
to be taken daily six days per week. LDM complications will be minimized through education
programs for all investigators and coordinators, through enhanced communication with study
participants, by limiting enrollment to those with no evidence of malignancy, hepatitis,
renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity;
by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to
eliminate individuals who are either intolerant of or unable to adhere to treatment before
randomization; and through regular monitoring of liver function and hematologic indices using
a centralized methodology designed to ensure participant safety, allow for dose adjustments
while maintaining the study blind, and provide an efficient method to address issues of
compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is
the rate of myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary
endpoints include all-cause mortality, coronary revascularization, incident congestive heart
failure, incident peripheral artery disease, incident venous thrombosis, clinically
significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with
metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among
those with diabetes at study entry. The trial is event driven such that in the absence of
extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an
effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction.
The potential clinical impact of CIRT is broad as it has sufficient power to directly address
core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will
open major new directions for cardiovascular treatment.
Phase II Study of Azacitidine and Entinostat (SNDX-275) in Patients With Advanced Breast Cancer
PRIMARY OBJECTIVES:
I. To evaluate objective response rate by Response Evaluation Criteria In Solid Tumors
(RECIST) criteria of the combination of azacitidine (5-AZA) and entinostat in women with
advanced breast cancer; triple-negative and hormone-refractory.
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of the combination of 5-AZA and entinostat in
women with advanced breast cancer.
II. To determine progression-free survival, overall survival, and clinical benefit rate of
the combination of 5-AZA and entinostat.
TERTIARY OBJECTIVES:
I. To collect safety and toxicity data as well as the feasibility and response rate where
hormonal therapy is added to the combination under investigation at the time of progressive
disease. (Exploratory) II. To determine the pharmacokinetic profile of 5-AZA (full profile)
and entinostat (trough concentrations) in patients with advanced breast cancer. (Exploratory)
III. To assess serum cytidine deaminase pharmacogenetics and phenotypic activity as a
potential biomarker of response to 5-AZA. (Exploratory) IV. To evaluate baseline and change
in candidate gene re-expression (e.g., estrogen receptor [ER] alpha, retinoic acid receptor
[RAR] beta) in malignant tissue obtained from selected patients through fine-needle
aspiration (FNA) and core biopsy, prior to and following combination therapy. (Exploratory)
V. To evaluate baseline and change in gene methylation silencing in circulating
deoxyribonucleic acid (DNA) obtained prior to and following combination therapy.
(Exploratory) VI. To evaluate baseline and change in gene methylation in malignant tissue
obtained through FNA and core biopsy. (Exploratory)
OUTLINE: This is a multicenter study.
Patients receive azacitidine subcutaneously (SC) on days 1-5 and 8-10, and entinostat orally
(PO) on days 3 and 10. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity. Patients with progressive disease may continue azacitidine and
entinostat in combination with hormonal therapy, at treating physician discretion, or undergo
event monitoring.
After completion of study therapy, patients are followed up every 3-6 months for up to 3
years.
Magnetic Resonance Imaging in Obstructive Sleep Apnea
This project examines the role of magnetic resonance imaging (MRI) in patients who are undergoing obstructive sleep apnea surgery at Keck Medical Center of USC. One part of the study will compare findings from MRI to those of drug-induced sleep endoscopy (DISE). Another will examine the association between MRI and surgical outcomes.
An Open-Labeled, Multicenter Phase II Study of Cabazitaxel in Refractory Metastatic Gastric or Gastroesophageal Adenocarcinoma
Prior to initiating protocol therapy, patients will undergo screening evaluations, to be done
within 30 days of protocol initiation unless otherwise noted.
Patients who are taxane naïve will be assigned to arm A and patients who have had prior
taxane therapy will be assigned to Arm B. Each arm will be analyzed separately for the
primary study endpoint of 3 month progression free survival rate (PFS), as defined as the
time from the start of treatment to the date of disease progression or death. Cabazitaxel
will be administered 20 mg/m2 IV over 1 hour every 3 weeks.
In the absence of treatment delays due to adverse event(s), treatment may continue until
disease progression; intercurrent illness that prevents further administration of treatment;
unacceptable adverse event(s); patient decides to withdraw; general or specific changes in
the patient's condition render the patient unacceptable for further treatment in the judgment
of the investigator.
Patients will be followed for 6 months after removal from study or until death, whichever
occurs first. Patients removed from study for unacceptable adverse events will be followed
until resolution or stabilization of the adverse event.
A Phase III Surgical Trial to Evaluate the Benefit of a Standard Versus an Extended Pelvic Lymphadenectomy Performed at Time of Radical Cystectomy for Muscle Invasive Urothelial Cancer
OBJECTIVES:
Primary
- To compare disease-free survival (DFS) of patients with muscle-invasive urothelial
carcinoma of the bladder undergoing radical cystectomy with extended pelvic lymph node
dissection (PLND) or standard pelvic lymphadenectomy.
Secondary
- To compare overall survival (OS) of patients randomized to extended PLND versus those
randomized to standard pelvic lymphadenectomy.
- To evaluate operative time; whether or not nerve sparing was performed, intraoperative,
peri-operative and 90-day morbidity and mortality; length of hospital stay; histology
(pure urothelial versus mixed); lymph node counts and lymph node density; adjuvant
chemotherapy received; and local and retroperitoneal soft tissue recurrence in patients
randomized to extended PLND versus those randomized to standard pelvic lymphadenectomy.
- To collect peripheral blood and two paraffin-embedded blocks of the primary tumor for
translational medicine studies, including circulating tumor cells (CTCs) and markers of
epithelial and mesenchymal transition, and correlate these findings with pathologic T
stage and node metastasis as well as DFS and OS.
OUTLINE: This is a multicenter study. Patients are stratified according to prior neoadjuvant
therapy (yes vs no), clinical stage (T2 vs T3 vs T4a), and Zubrod performance status (0-1 vs
2). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients undergo radical cystectomy and standard pelvic lymphadenectomy.
- Arm II: Patients undergo radical cystectomy and extended pelvic lymphadenectomy.
Blood and tumor specimens may be collected periodically for translational studies.
After completion of study therapy, patients are followed up periodically for 6 years.
A Randomized, Open-Label, Phase 2 Trial Examining the Sequencing of Sipuleucel-T and Androgen Deprivation Therapy in Men With Non-metastatic Prostate Cancer and a Rising Serum Prostate Specific Antigen After Primary Therapy
Multicenter, randomized, open-label study, with subjects allocated (1:1) to 1 of 2 study
arms, using a stratified randomization based on:
• Prostate-specific antigen doubling time (PSADT): ≤ 3 months or > 3 months and ≤ 12 months.
• Primary therapy: radical prostatectomy (RP) or radiation, including brachytherapy, (XRT) or
RP + XRT.
Arm 1: Subjects received one infusion of sipuleucel-T every two weeks for a total of three
infusions. Two weeks after the third sipuleucel-T infusion, subjects started ADT with 45 mg
leuprolide acetate depot injection (Eligard® 45 mg). An additional leuprolide acetate
injection was administered at 6 months after the first injection for a total of 2 injections
and 12 months of ADT.
Arm 2: Subjects started ADT with 45 mg leuprolide acetate depot injection (Eligard® 45 mg) 12
weeks before infusion 1 of sipuleucel-T. An additional leuprolide acetate injection was
administered at 6 months after the first injection for a total of 2 injections and 12 months
of ADT. Twelve weeks after the initial leuprolide 45 mg depot injection, subjects began one
infusion of sipuleucel-T every two weeks for a total of three infusions.
Cellular and humoral immune responses were assessed for Arm 2 subjects at 12, 8, and 4 weeks
pre infusion 1, and in all subjects (both arms) at pre-leukapheresis 1, 2, and 3, and
post-infusion 1, 2 and 3, and at the following time points after the third infusion: Weeks 2,
6, and 12 and Months 6, 9, 12, 15, 18, 21, and 24.
Safety assessments included adverse event (AE) monitoring, laboratory tests (complete blood
count (CBC) and serum chemistry), vital signs, Eastern Cooperative Oncology Group (ECOG)
performance status, physical examination, as well PSA and testosterone monitoring. The study
was complete at the 27-Month visit for Arm 1 and the 24-Month visit for Arm 2.
A Phase III Study of Postoperative Radiation Therapy (IMRT) +/- Cetuximab for Locally-Advanced Resected Head and Neck Cancer
OBJECTIVES:
Primary
- Determine whether the addition of cetuximab to postoperative intensity-modulated
radiotherapy (IMRT) will improve overall survival (OS) in patients with locally advanced
squamous cell carcinoma of the head and neck at intermediate risk following surgery.
Secondary
- Assess the impact of the addition of cetuximab to postoperative IMRT on disease-free
survival (DFS) of these patients.
- Assess the impact of the addition of cetuximab to postoperative IMRT on acute and late
dysphagia, xerostomia, skin toxicity, and other toxicities according to common Toxicity
Criteria for Adverse Effects (CTCAE), v. 4 and their relationships with patient-reported
outcomes at 3, 12, and 24 months.
- Analyze tumor for epidermal growth factor receptor (EGFR), specifically the extent of
EGFR overexpression by immuno-histochemistry (IHC) and FISH analysis, EGFRvIII
expression, as well as the association of these assay data with OS and DFS.
- Analyze tumor for human papillomavirus (HPV) infection (as defined by in situ
hybridization), specifically, within the cohort of patients with oropharynx cancer, to
perform an exploratory analysis of the impact of HPV on DFS and OS of this patient
subset.
- Analyze tumor DNA for TP53 mutations as a predictor of response to cetuximab and
prognosis.
- Analyze germline DNA of polymorphic variants in EGFR intron repeats as a predictor of
response to cetuximab.
Tertiary
- Assess the impact of the addition of cetuximab to postoperative IMRT on loco-regional
control.
- Assess the impact of the addition of cetuximab to postoperative IMRT on patient-reported
quality of life, swallowing, xerostomia, and skin toxicity based on head and neck
specific instruments, including the Performance Status Scale for Head and Neck Cancer
(PSS-HN), the Functional Assessment of Cancer Therapy-Head & Neck (FACT-H&N), the
University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS), and the
Dermatology Life Quality Index (DLQI).
- Assess the impact of the addition of cetuximab to postoperative IMRT on cost-utility
analysis using the EuroQol (EQ-5D).
- Evaluate the utility of image-guided radiotherapy (IGRT) as a means of enhancing the
efficacy (i.e., loco-regional control) of IMRT while reducing the acute and/or late
toxicity (particularly xerostomia) and improving patient-reported outcomes (particularly
XeQOLS scores).
- Retrospectively compare the loco-regional control rate in patients treated with IMRT
alone (no IGRT or cetuximab) with similar patients treated with external beam
radiotherapy alone in the postoperative clinical trial Radiation Therapy Oncology Group
(RTOG)-95 01.
OUTLINE: This is a multicenter study. Patients are stratified according to clinical stage
(T2-3 vs T4a), EGFR expression (high [≥ 80% of cells staining positive] vs low [< 80% of
cells staining positive] vs not evaluable), primary site of disease (oral cavity vs larynx vs
oropharynx p16+ vs oropharynx p16- vs oropharynx, p16 not evaluable), and use of image-guided
radiotherapy (yes vs no). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients undergo intensity-modulated radiotherapy (IMRT) once daily 5 days a week
for 6 weeks in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients undergo IMRT as in arm I. Patients also receive cetuximab IV over 1-2
hours once weekly beginning at least 5 days prior to the start of IMRT and continuing
for 4 weeks after the completion of IMRT (for a total of 11 doses) in the absence of
disease progression or unacceptable toxicity.
Quality of life is assessed at baseline and at 3, 12, and 24 months.
Tissue samples are collected periodically for further laboratory analysis.
After completion of study treatment, patients are followed up at 1 and 3 months, every 3
months for 2 years, every 6 months for 3 years, and then annually thereafter.
Allopregnanolone Regenerative Therapeutic for MCI/AD: Dose Finding Phase 1
1) Each dose group will be comprised of 8 participants (6 randomized to allopregnanolone; 2
randomized to placebo) administered one dose of allopregnanolone or placebo once per week for
12 weeks. A higher dose will be administered to the next group of participants when the lower
dose is shown to be safe and tolerable. 2) Pharmacokinetic analyses will be conducted on
blood samples taken from participants at the beginning and end of the trial. 3) The trial
will assess safety including via MRI brain imaging.
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
Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing,
especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as
part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for
prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic
barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and
efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in
the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose
of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV
regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or
who have failed their current antiretroviral (ARV) regimens. In this study, the
second-generation NNRTI ETR was tested for safety, tolerability, and appropriate dosing.
Children were assigned to one of three cohorts based on age:
- Cohort I: At least 2 but younger than 6 years of age
- Cohort II: At least 1 but younger than 2 years of age
- Cohort III: At least 2 months but younger than 1 year of age
Children in all three cohorts were treatment experienced, defined as being on a failing
combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a
treatment interruption of at least 4 weeks with a history of virologic failure while on a
combination ARV regimen (containing at least 3 ARVs).
Children received ETR together with an optimized background regimen (OBR) consisting of at
least 2 active agents (a boosted protease inhibitor [PI] and at least 1 additional active ARV
drug). OBR were based on clinical status, treatment history, resistance data, and
availability of appropriate pediatric dosing and formulations. The children received an oral
dose of ETR twice daily.
Most children had 11 visits: at screening, entry (Day 0), Day 14 (intensive pharmacokinetic
[PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits included a physical
exam, giving a medical history, discussion of adherence, and blood and urine collection. The
screening and intensive PK visits also included an electrocardiogram (ECG). During the
intensive PK visit, the child had blood drawn approximately 7 times over 12 hours. After the
Week 48 visit, children entered the long-term follow-up phase of the study and have a visit
every 12 weeks for up to 5 years. These follow-up visits included giving a medical history
and undergoing a physical exam and blood draw.
A Dose Finding Study Followed by Phase II Randomized, Placebo-Controlled Study of Veliparib (ABT-888) Added to Chemoradiotherapy With Carboplatin and Paclitaxel for Unresectable Stage III Non-small Cell Lung Cancer (NSCLC), (NCI Study Number 8811)
PRIMARY OBJECTIVES:
I. To establish the maximum tolerated dose (MTD) and the recommended phase II dose of ABT-888
(veliparib) when given concurrently with standard carboplatin/paclitaxel and radiotherapy in
patients with unresectable stage III non-small cell lung cancer (NSCLC). (Phase I) II. To
assess whether carboplatin/paclitaxel plus ABT-888 compared with carboplatin/paclitaxel plus
placebo improves progression-free survival (PFS) in patients with unresectable stage III
NSCLC. (Phase II) III. To compare overall survival (OS) in patients treated with
carboplatin/paclitaxel and radiotherapy plus ABT-888 to those treated with carboplatin,
paclitaxel and radiotherapy plus placebo. (Phase II) IV. To assess the response rate
(confirmed and unconfirmed, complete and partial responses) and disease control rate in the
subset of patients with measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) criteria. (Phase II) V. To assess the safety and toxicity profile of the regimen.
(Phase II)
SECONDARY OBJECTIVES:
I. To collect tumor tissue from pretreatment biopsies (archival samples) for biomarker
studies, including poly (ADP-ribose) polymerase 1 (PARP) activity by measuring the levels of
poly-ADP-ribose, gamma-H2A histone family, member X (gamma-H2AX), and messenger ribonucleic
acid (mRNA) expression levels of deoxyribonucleic acid (DNA) repair enzymes such as excision
repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1)/x-ray
repair complementing defective repair in Chinese hamster cells 1 (XRCC1).
II. To collect blood samples for evaluation of gamma-H2AX (circulating tumor cells) and other
relevant future studies.
OUTLINE: This is a phase I, dose-escalation study of veliparib followed by a randomized phase
II study.
PHASE I:
INDUCTION THERAPY: Patients undergo 3-dimensional conformal radiation therapy (3D-CRT) once
daily (QD), 5 days a week, for 6 weeks. Patients also receive veliparib orally (PO) twice
daily (BID) on days 1-43 and carboplatin intravenously (IV) over 30 minutes and paclitaxel IV
over 1 hour on days 1, 8, 15, 22, 36, and 43 in the absence of disease progression or
unacceptable toxicity. Patients without disease progression after completion of
chemoradiotherapy undergo consolidation therapy.
CONSOLIDATION THERAPY: Beginning within 4-6 weeks of chemotherapy and radiation therapy,
patients receive veliparib PO BID on days 1-7 (course 1) and 22-28 (course 2) and carboplatin
IV over 30 minutes and paclitaxel IV over 3 hours on day 1 and on day 22 of course 2.
Treatment repeats every 21 days for 2 courses in the absence of disease progression or
unacceptable toxicity.
PHASE II: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo 3D-CRT and receive veliparib, carboplatin, and paclitaxel as in Phase
I induction and consolidation therapy.
ARM II: Patients undergo 3D-CRT as in arm I. Patients also receive placebo PO BID on days
1-43 and carboplatin and paclitaxel as in Phase I. Within 4-6 weeks after completion of
chemotherapy and radiation therapy, patients receive placebo on days 1-7 and carboplatin and
paclitaxel as in Phase I.
After completion of study treatment, patients are followed up every 4 months for first 2
years and then every 6 months until 5 years.
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