A Phase II Study of Vorinostat and Capecitabine in Recurrent and/or Metastatic Squamous Cell Carcinoma of Head and Neck (SCCHN) and Nasopharyngeal Carcinoma (NPC)
PRIMARY OBJECTIVES:
I. To determine the objective response rate (complete and partial) and duration of response
of the combination of vorinostat and capecitabine in patients with recurrent and/or
metastatic squamous cell carcinoma of the head and neck (SCCHN). (SCCHN) II. To determine the
objective response rate (complete and partial) and duration of response of the combination of
vorinostat and capecitabine in patients with recurrent and/or metastatic nasopharyngeal
carcinoma (NPC). (NPC)
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of the combination of vorinostat and capecitabine
in patients with recurrent and/or metastatic SCCHN. (SCCHN) II. To determine the rate of
progression-free survival (PFS) at 6 months. (SCCHN) III. To determine the rate and duration
of stable disease (SD). (SCCHN) IV. To determine the median PFS, and the rate of PFS at 1
year. (SCCHN) V. To determine the median overall survival (OS), and rates of overall survival
at 6 months and at 1 year. (SCCHN) VI. To evaluate the safety and tolerability of the
combination of vorinostat and capecitabine in patients with recurrent and/or metastatic NPC.
(NPC) VII. To determine the duration of objective response. (NPC) VIII. To determine the rate
and duration of stable disease (SD). (NPC) IX. To determine the median PFS, and the rate of
PFS at 1 year. (NPC) X. To determine the median overall survival (OS), and rates of overall
survival at 6 months and at 1 year. (NPC)
OUTLINE: This is a non-randomized, open-label study of patients with SCCHN and NPC (Stage I),
followed by a randomized study of patients with NPC (Stage II).
STAGE I: Patients receive capecitabine orally (PO) twice daily (BID) and vorinostat PO daily
on days 1-14. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.
STAGE II: Patients with NPC are randomized to 1 of 2 treatment arms.
ARM I: Patients receive capecitabine PO BID and vorinostat PO daily on days 1-14. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive capecitabine PO BID on days 1-14. Courses repeat every 21 days in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients will be followed up at 3-4 weeks and then every
6 months for 1 year.
Randomized Phase II Study of AZD6244 MEK-Inhibitor With Erlotinib in KRAS Wild Type and KRAS Mutant Advanced Non-Small Cell Lung Cancer
Background:
Lung Cancer is the leading cause of death among both men and women. Of the approximately
172,000 patients that are diagnosed every year with non small cell lung cancer (NSCLC) in the
US, 55% present with advanced stage disease. The current treatment for advanced NSCLC is
first line chemotherapy with a platinum-based doublet. Second line treatment for recurrent or
progressive disease includes treatment with chemotherapy or treatment with an oral EGFR
(epidermal growth factor receptor) tyrosine kinase inhibitor. Several mechanisms of
resistance to EGFR tyrosine kinase inhibitors have been discovered. Presence of KRAS
mutations is one of them. AZD6244 (ARRY-142886) is an investigational drug that is orally
available and targets the critical kinase (MEK) in the mitogen-activated protein (MAP) kinase
signal transduction pathway which is activated in NSCLC and is downstream of EGFR.
Objectives:
- Determine the progression free survival (PFS) using the combination of AZD6244 and
erlotinib in patients with wild type KRAS advanced NSCLC
- Determine the clinical response rate (PR (partial response) + CR (complete response))
either monotherapy AZD6244 or the combination AZD6244 plus erlotinib in patients with
mutated KRAS advanced NSCLC
- Evaluate disease control rate (PR+CR+SD (stable disease)) and overall survival in both
patient groups.
- Determine a safety profile for use of AZD6244 in combination with erlotinib in patients
with advanced NSCLC.
- Measure serological markers to evaluate if these markers are correlated with tumor
response.
- Measure changes in a tumors MIB-1 (Ki-67) rate and pERK levels in response to treatment
with AZD6244.
Eligibility:
- Patients with pathologically confirmed NSCLC not amenable to potentially curative
therapy and having progressed after being treated with at least one prior platinum
containing chemotherapy regimen, or having refused cytotoxic chemotherapy.
- Progressive disease should be documented prior to enrollment on the study.
- Patient should not have more than 2 prior chemotherapy regimens.
- Measurable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.
- Adequate renal, cardiac, hepatic and hematopoietic functions
- No major surgery, radiotherapy, or chemotherapy within 28 days of enrollment.
Design:
- Patients will be stratified on the basis on their KRAS mutational status. Wild-Type KRAS
patients will be randomized to receive either single agent erlotinib 150 mg/day or the
combination of erlotinib 100 mg/day plus AZD6244 at 150 mg/day. KRAS mutant patients
will be randomized to receive AZD6244 monotherapy at a dose of 75 mg twice per day, or
the combination AZD6244 at 150 mg/day plus erlotinib 100 mg/day.
- Treatment will continue until disease progression.
- Toxicity will be assessed every cycle by the CTCAE (Common Terminology Criteria for
Adverse Events) Version 4.0.
- Tumor assessments by RECIST 1.1 criteria will be performed every 2 cycles (one cycle is
28 days).
- Correlative studies including initial tumor mutational analysis and tissue
immunohistochemistry (IHC) studies will be done on existing tumor blocks, or re-biopsied
tissue prior to enrollment.
- Patients will be evaluated for the potential to undergo repeat tumor biopsy after 1
cycle of therapy. Tumors will be assessed for MIB-1 (Ki-67) and pERK levels by IHC.
- The study will accrue up to 40 patients with wild-type KRAS NSCLC and up to 60 patients
with mutated KRAS NSCLC.
VX-770 Expanded Access Program (EAP)
VX-770, a compound being developed by Vertex Pharmaceuticals Incorporated (Vertex) for the
treatment of CF, is an orally bioavailable small molecule that targets the underlying defect
in CF, the dysfunctional CFTR protein. In Phase 3 studies of VX-770 in patients with CF and
a G551D CFTR mutation, improvements in CFTR function (measured by reduction in sweat
chloride concentration) and improvements in lung function were observed.
Patients who are interested in the VX-770 Expanded Access should contact their CF physician
about participation.
Physicians interested in participating as a site should contact 800-745-4484.
Approved for marketing | Cystic Fibrosis | Site Unknown
Phase III Trial of Dose Escalated Radiation Therapy and Standard Androgen Deprivation Therapy (ADT) With a GNRH Agonist vs. Dose Escalated Radiation Therapy and Enhanced ADT With a GNRH Agonist and TAK-700 For Men With High Risk Prostate Cancer
OBJECTIVES:
Primary
- To evaluate the difference in overall survival of patients with clinically localized
prostate cancer with unfavorable prognostic features between a) standard treatment
(androgen-deprivation therapy [ADT] + radiotherapy) and b) standard treatment with the
addition of 24 months of steroid 17alpha-monooxygenase TAK-700 (TAK-700).
Secondary
- To characterize differences between the treatment groups with respect to incidence of
unexpected grade ≥ 3 adverse events and/or clinically significant decrement in
patient-reported quality of life (QOL) among subjects treated with TAK-700.
- To compare rates and cumulative incidence of biochemical control (freedom from PSA
failure), local/regional progression, and distant metastases.
- To compare rate and cumulative incidence of clinical failure, defined as
prostate-specific antigen (PSA) > 25 ng/mL, documented local disease progression,
regional or distant metastasis, or initiation of ADT.
- To compare prostate cancer-specific survival and other-cause mortality.
- To compare the change in severity of fatigue as measured by the Patient-Reported Outcome
Measurement Information System (PROMIS) fatigue short form.
- To compare changes in patient-reported QOL as measured by Expanded Prostate Cancer Index
Composite (EPIC).
- To assess quality-adjusted survival using the EQ-5D.
- To compare nadir and average serum testosterone at 12 and 24 months during treatment.
- To compare changes in hemoglobin A1C, fasting glucose, and fasting insulin during 24
months of systemic treatment and during the first three years of follow-up.
- To compare changes in fasting lipid levels during 24 months of treatment and during the
first three years of follow-up.
- To compare changes in body mass index (BMI) during 24 months of treatment and during the
first three years of follow-up.
- To compare the incidence of adverse events ascertained via CTCAE version 4.
- To compare the rate of recovery of testosterone to > 230 ng/dL (accepted threshold for
supplementation) after 12 and 24 months of follow-up.
- To compare the median time to recovery of testosterone to > 230 ng/dL during the first
five years of follow-up.
- To assess cumulative incidence of relevant clinical survivorship endpoints including new
diagnosis of type 2 diabetes, coronary artery disease, myocardial infarction, stroke,
pulmonary embolism, deep vein thrombosis, or osteoporotic fracture.
OUTLINE: This is a multicenter, randomized study. Patients are stratified according to risk
group (see Disease Characteristics) and type of radiation therapy (RT) boost
(intensity-modulated RT (IMRT) vs brachytherapy). Patients are randomized to 1 of 2 treatment
arms.
After completion of study therapy, patients are followed every 3 months for 2 years, every 6
months for 1 year, and then annually thereafter.
Beta Cell Restoration Through Fat Mitigation
BetaFat is a 2-arm, unblinded study to compare gastric banding to treatment with metformin
over a 24-month period in moderately obese adults with pre- or mild type 2 diabetes. The
primary outcome will be change in β-cell compensation for insulin resistance, which the
investigators will compare between groups. Secondary analyses will include other potential
markers of β-cell health and potential mediators of treatment-specific effects. The main
focus will be on mediators related to obesity. Clinically, the project will serve as a test
of concept for use of gastric banding relatively early in the spectrum of obesity and β-cell
disease. Biologically, the results will provide crucial information on potential mediators
of β-cell failure and its arrest or reversal in the context of obesity. Those mediators will
guide the development of more effective treatment and monitoring for the β-cell disease that
causes type 2 diabetes.
Phase II Study of Dose-Adjusted EPOCH+/-Rituximab in Adults With Untreated Burkitt Lymphoma, c-MYC Positive Diffuse Large B-Cell Lymphoma and Plasmablastic Lymphoma
Background:
- Burkitt lymphoma/leukemia (BL) is highly curable. Standard treatment employs dose
intense multi-agent chemotherapy and though effective is associated with high morbidity.
Therefore, novel approaches are needed that improve the therapeutic index of BL while
maintaining or improving efficacy. In human immunodeficiency virus (HIV)+ BL, outcome
has been poor, mainly due to the use of cyclophosphamide, doxorubicin hydrochloride
(hydroxydaunorubicin), vincristine sulfate (Oncovin), and prednisone (CHOP) based
regimens in this disease.
- Two National Cancer Institute (NCI) phase II trials have used etoposide, prednisone,
vincristine, cyclophosphamide, doxorubicin (EPOCH) chemotherapy with 1 or 2 doses of
rituximab (R) per cycle in untreated BL. (Dose-adjusted) etoposide, prednisone,
vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH)-Rituximab has been
used in16 HIV negative BL, and 8 HIV positive patients have received 3 to 4 cycles of
EPOCHRR to minimize toxicity and risk of opportunistic infections. All patients remain
in continuous remission. Treatment was very well tolerated and represents a novel
therapeutic strategy in BL.
- This trial seeks to assess the effectiveness of a risk adaptive approach with DA-EPOCHR
in untreated BL (HIV+/-). Because this treatment represents a major conceptual departure
from standard treatment, it is important to obtain additional Phase II results in
limited/advanced stage BL
- c-MYC positive Diffuse large B cell (DLBCL) is a rare variant of Diffuse Large B-Cell
Lymphoma (DLBCL). There is very little data on the biology of this disease and what the
optimal therapeutic approach should be has not been defined. Therefore, based on our
impression that this behaves aggressively and is likely characterized by a high tumor
proliferation rate, we plan to accrue patients with this disease in addition to BL
patients.
- Plasmablastic lymphoma, another variant of DLBCL is frequently characterized by the
activation of MYC and has had a poor outcome historically with standard treatment. We
plan to include these patients in the study also. As they are cluster of differentiation
20 (CD20) negative, they will receive DA-EPOCH without Rituximab.
Objectives:
- Determine progression free survival (PFS), event free survival (EFS) and overall
survival (OS) of risk adaptive DA-EPOCH-R in untreated BL and c-MYC + DLBCL and DA-EPOCH
in c-MYC+ plasmablastic lymphoma.
- Assess predictive value of early fluorodeoxyglucose (FDG)-positron emission tomography
(PET)/computed tomography (CT) scans on PFS.
- Obtain pilot comparative molecular profiling in HIV negative and positive BL and c- MYC
+ DLBCL, including c-MYC+ plasmablastic lymphoma.
Eligibility:
- Burkitt lymphoma, c-MYC + DLBCL and c-MYC + plasmablastic lymphoma age greater than or
equal to 18 years.
- No prior treatment except limited-field radiotherapy, short course of glucocorticoids
and/or cyclophosphamide for an urgent problem at diagnosis.
- Adequate major organ function unless impairment due to lymphoma.
Study Design:
- Phase II Study of risk adapted DA-EPOCH-R in BL, c-MYC + DLBCL and DA-EPOCH in c-MYC+
plasmablastic lymphoma
- Low risk: DA-EPOCH-RR x 3 cycles.
- High risk , c-MYC + DLBCL and c-MYC+ plasmablastic lymphoma : DA-EPOCH (+/-) R x 6
cycles or 8 cycles in select patients.
- Cerebrospinal fluid (CSF) cytology and flow cytometry for analysis of BL.
- High Risk CSF negative - Prophylactic intrathecal treatment
- CSF positive - Active intrathecal treatment
- FDG-PET/CT pre- and post-cycle 2 in all patients.
- A total of 194 patients will be enrolled in the protocol.
An Extension Protocol for Subjects Who Were Previously Enrolled in Other Tivantinib (ARQ 197) Protocols
This open label extension protocol enrolls participants who were treated in previous phase 1
(NCT01149720, NCT01517399, NCT01699061, NCT00612703, NCT00827177, and NCT00874042) and phase
2 (NCT00777309, NCT00557609, NCT00988741, NCT01395758 , and NCT01055067) tivantinib studies
that have reached their designated end-dates. Participants enrolled in this extension
protocol will provide further safety and tolerability information about tivantinib
monotherapy or in combination with other drug(s) at the same dose(s), and same schedule(s) in
which they were originally enrolled.
Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs
There is a compelling need for prospective, properly controlled studies in women with
epilepsy (WWE) during pregnancy to improve maternal and child outcomes. The proposed
investigations are pertinent to the National Institute of Neurological Disorders and Stroke
Epilepsy Research Benchmarks and will address multiple gaps in our knowledge noted by the
recent American Academy of Neurology guidelines. This multicenter investigation will employ a
prospective, observational, parallel-group, cohort design with an established research team.
The specific aims are to:
1. Determine if women with epilepsy have increased seizures during pregnancy and delineate
the contributing factors;
2. Determine if C-section rate is increased in women with epilepsy and delineate
contributing factors;
3. Determine if women with epilepsy have an increased risk for depression during pregnancy
and post-partum period and characterize risks factors;
4. Determine the long-term effects of in utero antiepileptic drug exposure on verbal
intellectual abilities and other neurobehavioral outcomes in the children of women with
epilepsy;
5. Determine if small for gestation age and other adverse neonatal outcomes are increased
in children of women with epilepsy;
6. Determine if breastfeeding when taking antiepileptic drugs impairs the child's verbal
intellectual and other cognitive abilities.
An overall goal of the proposed research is to establish the relationship between
antiepileptic drug exposure and outcomes in the mother and child as well as describe and
explain the variability in antiepileptic drug exposure and response.
Anticonvulsant blood levels (ABLs) and area-under-the-concentration-time-curves (AUCs) will
be used as direct measures of drug exposure. The results will enable clinicians to
prospectively calculate individual dosing regimens for the mother in order to optimize dosing
and limit unnecessary drug exposure to the child. In addition, genetic samples will be
collected, which will provide a valuable resource for future pharmacogenetics studies to
further delineate individual variability across patients.
FACTORS ASSESSED IN MONEAD.
Maternal factors: IQ, age, education, employment, ethnic group, maternal and family medical
history including prior pregnancies and psychiatric disorders, socioeconomic status, site,
periconception and pregnancy folate, concomitant medications, alcohol use, tobacco use, or
other drug use during pregnancy, unwanted pregnancy, pregnancy complications, medical
diseases and serious adverse events, McMaster Family Assessment Device (FAD), Block Food
Frequency, and for WWE: types and frequency of seizures or epilepsy, antiepileptic drug
dosages & blood levels, and compliance.
Depression during pregnancy and post-partum as determined by the screening instrument (Beck
Depression Inventory-II; BDI-II), the EPDS (Edinburgh Postnatal Depression Scale) and
confirmed by the Structured Clinical Interview for DSM-IV (SCID), Beck Anxiety Inventory
(BAI), Pittsburgh Sleep Index, and Perceived Stress Scale in mothers, Parental Stress Index,
and Neurological Disorders Depression Inventory in Epilepsy (NDDI-E).
Maternal hormones (estradiol, progesterone) and Vit D will be drawn at Visit 1, 2, 3, 4, 5, 6
and 7. Maternal continine Levels will be collected via urine sample at Visit 3 on all
non-smoking mothers. If the continine result is positive for tobacco smoke exposure, an LC/MS
(liquid chromatography/mass spectrometry test.
Paternal & relative factors: In fathers and a primary maternal relative, the following were
collected: head circumference, IQ estimates, socioeconomic status, dob, race, ethnicity,
family history, and medical history. For the father, marital status, total household income,
employment status. weight, height, and handedness were also collected.
Adult IQ Assessments:
Peabody Picture Vocabulary Test (PPVT), Wechsler's Adult Intelligence Scale (WAIS).
Child factors: enrollment & birth gestational ages, birthweight, breastfeeding, AED levels
when breastfeeding, physical examinations, childhood medical diseases (including congenital
malformations), head circumference, weight, serious adverse events, developmental delays, and
special education. Also, obtained premature delivery, APGARs (1 & 5 minutes), Neonatal
Intensive Care Unit admissions and all admissions >12hrs, hypoglycemia (<45), need for
resuscitation, and neonatal death. Child Hgb, Hct, PKU, TSH, and T4 at delivery from med
records if collected.
Child Cognitive/Behavioral Assessments:
Denver II, Behavior Assessment System for Children - Parent (BASCP-2) and Teacher (BASCT-2),
Behavior Rating Inventory of Executive Functioning Preschool (BRIEFP) and version 2
(BRIEF-2), Adaptive Behavior Assessment Scale 3 (ABAS-3), Modified Checklist for Autism in
Toddlers (M-CHAT), Modified Edinburgh Handedness Inventory, Gilliam Autism Rating Scale 3
(GARS-3), Bayley Scales of Infant and Toddler Development-3 (BSID-III), Differential
Abilities Scale-II (DAS-II), Preschool Language Scale-5 (PLS-5), Peabody Picture Vocabulary
Test-4 (PPVT-4), Beery-Buktenica Developmental Test of Visual-Motor Integration-6 (VMI-6),
Torrance Test of Creative Thinking- Figural (TTCT-F), NEuroPSYchological Assessment 2nd
edition (NEPSY2), Expressive One Word Picture Vocabulary Test-4 (EOWPVT4), Wechsler's
Intelligence Scale for Children 5 (WISC5) Coding subtest, Children's Memory Scale (CMS),
Lafayette Grooved Pegboard (GPB), Wide Range Achievement Test 5th edition (WRAT5), and Social
Responsiveness Scale 2
Verbal intellectual ability at age 6 years is the ultimate primary outcome. It is determined
by Verbal Index which is average of Word Definitions and Verbal Similarities subtests from
the Differential Ability Scales-2nd ed. (DAS-II),50 -School Age Level, Expressive One-Word
Picture Vocabulary Test-4,51 the Phonological Processing, Comprehension of Instructions and
Sentence Repetition subscales from the NEPSY-2 57 and the Peabody Picture Vocabulary Test-4th
ed. (PPVT-4).52 Children will not reach age 6 in this initial grant period, so primary
outcome at age 2 will be the Language Scale from the Bayley Scales of Infant & Toddler
Development-III.
Cerebral Lateralization will be assessed as verbal minus non-verbal difference scores and
proportion of dextrals in PWWE vs. HPW and in their children as assessed by the Edinburgh
Handedness Inventory.
Phase I Trial of Oral 5-Fluoro-2'-Deoxycytidine With Oral Tetrahydrouridine in Patients With Advanced Solid Tumors
Background:
- 5-Fluoro-2'-deoxycytidine (FdCyd), a fluoropyrimidine nucleoside analog, has a short
(10-minute) half-life and is rapidly degraded in vivo by cytidine deaminase. However,
co-administration with tetrahydrouridine (THU), an inhibitor of cytidine/deoxycytidine
deaminase, has been shown to increase the AUC of the parent compound more than 4-fold.
Increased FdCyd exposure allows it to be taken up intracellularly and converted to its
triphosphate, which is incorporated into DNA and inhibits the action of the enzyme DNA
methyltransferase (DNMT). Inhibition of DNMT, and in turn DNA methylation, can result in
the re-expression of tumor suppressor genes.
- Intravenous FdCyd with THU has been evaluated in a Phase I clinical trial with some
preliminary evidence of activity. This trial will investigate oral administration of the
drugs, which was shown to be feasible in an expansion cohort of the previous trial.
Primary objectives:
-Establish the safety and tolerability of oral FdCyd in combination with oral THU
administered on an intermittent schedule in 21-day cycles to patients with refractory solid
tumors
Exploratory objectives:
- Determine the pharmacokinetics of oral FdCyd and oral THU
- Document preliminary evidence of activity of oral FdCyd and oral THU
- Determine the clinical benefit rate (CR+PR+SD at 4 months) in patients treated with
study drug combination at the MTD
- Determine effect of study treatment on re-expression of p16 and other select genes
silenced by methylation in circulating tumor cells and tumor biopsies
- Evaluate the effect of study treatment on DNA (cytosine-5)-methyltransferase 1 and 3
(DNMT1 and DNMT3) expression in tumor biopsies
Eligibility:
-Adults with histologically documented solid tumors whose disease has progressed after at
least one line of standard therapy.
Design:
- This is a multicenter trial with NCI as the coordinating center.
- FdCyd and THU will be administered on an intermittent schedule in 21-day cycles. THU
will be administered orally 30 minutes prior to FdCyd.
- The trial will follow a standard Phase I dose escalation design (3-6 patients per
cohort).
- Consideration will be given to increasing the days of administration of FdCyd with THU
after a target maximum plasma concentration of FdCyd is reached.
- Blood and urine for pharmacokinetic studies will be obtained from all patients. Blood
for pharmacodynamic studies will be obtained after we achieve a target Cmax of 1microM.
- Up to 25 patients will be enrolled in the expansion cohort, from which mandatory pre-
and post-dose tumor biopsies will be collected for the assessment of pharmacodynamic
endpoints, at dose level 8 (160 mg FdCyd + 3000 mg THU 1x daily days 1-6 week 1, days
8-13 week 2, in 21-day cycles).
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