Feasibility Study of Stereotactic Body Radiation Therapy Followed by Wedge Resection for Peripherally Located Early Stage Non-small Cell Lung Cancer
PRIMARY OBJECTIVES:
I. To assess the safety and feasibility of a wedge resection following stereotactic body
radiation therapy (SBRT) for early stage peripheral non-small cell lung cancer (NSCLC).
SECONDARY OBJECTIVES:
I. To assess pathologic response rates to SBRT as determined by pathologic examination of
resected tumors.
II. To prospectively assess patient quality of life when treated with SBRT and wedge
resection.
TERTIARY OBJECTIVES:
I. To describe the location of viable tumor and to correlate pathologic response rates with
radiation dose, size of tumor, and tumor histology.
II. To correlate pathologic response rates and functional imaging with pre- and
post-treatment dual-input perfusion (DP)-computed tomography (CT) and positron emission
tomography (PET)-CT.
III. To correlate changes in serum levels of deoxyribonucleic acid (DNA) methylation and
circulating tumor cells (CTC) with pathologic response rates.
OUTLINE:
Patients undergo stereotactic radiosurgery every other day for 3 or 5 fractions (depending on
the size tumor and proximity to the chest wall). Within 4-6 weeks after completion of
stereotactic radiosurgery, patients undergo wedge resection.
After completion of study treatment, patients are followed up at 1, 3, 6, and 12 months.
Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) Vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer
PRIMARY OBJECTIVES:
I. To assess overall survival (OS) in patients with refractory advanced biliary cancer
randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either
5-fluorouracil [fluorouracil] and leucovorin [leucovorin calcium] or capecitabine).
SECONDARY OBJECTIVES:
I. To determine the frequency and severity of adverse events of trametinib in this patient
population.
II. To assess response rate (RR) and progression-free survival (PFS) in patients randomized
to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil [5-FU] or
capecitabine in this patient population).
TERTIARY OBJECTIVES:
I. To determine if a 16-gene expression signature is predictive of mitogen-activated protein
kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.
II. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential
associations with response rate and survival.
III. To estimate lean soft tissue and fat mass weight gain as a result of treatment with
trametinib vs. capecitabine in patients with advanced refractory biliary cancer.
IV. To bank tissue samples for other future correlative studies including next generation
sequencing and whole genome methylation assays. NOTE: These potential future correlative
studies will not be performed until an amended protocol with relevant detailed information
including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat
every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.
ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil
IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
ARM IIB: Patients receive capecitabine PO twice daily (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 are followed up every 3 months for 2 years.
Pilot Study to Evaluate Melatonin Secretion as a Marker of Decreased Serotonin in Individuals With PKU: Evaluation of the CNS Effects of Tetrahydrobiopterin
Background: Phenylketonuria (PKU) is a genetic condition due to missing one of the key
enzymes of phenylalanine (Phe) degradation. The missing enzyme is phenylalanine hydroxylase
(PAH). Because of the deficiency of the enzyme, plasma Phe is highly elevated compared with
other plasma amino acids. This abnormal ratio i.e., Phe vs. each of the other large neutral
amino acids (LNAA) which are transported into the brain as precursors of neurotransmitters
through the common transporter LAT1, is likely to contribute to neurotransmitter deficiencies
in individuals with PKU. Patients who do not restrict Phe intake develop mental retardation
and neuropsychological disorders. Treatment of PKU has been historically limited to
restriction of Phe intake, meaning protein restriction.
The FDA recently approved a new medication, Kuvan, a synthetic form of tetrahydrobiopterin
(BH4) manufactured by BioMarin Pharmaceutical Inc., for patients with PKU. Kuvan is a
cofactor for PAH, tyrosine hydroxylase, and tryptophan hydroxylase. Patients with PKU
typically undergo a month-long trial of Kuvan to determine if they are responders to the
drug, meaning blood phenylalanine drops by more than 30 percent. Those who are not responders
do not usually continue Kuvan, however our recent study (HS 08-00147) showed that classical
PKU patients who are not Kuvan responders demonstrated improvement in their maladaptive
behaviors, suggesting some effects of Kuvan in the CNS system without reducing blood
phenylalanine concentrations (Moseley et al, manuscript under preparation). Seven subjects
who did not respond to Kuvan with lower blood Phe levels had significant increases in blood
tyrosine after 6 months (p=0.015), along with improvement in the Vineland Internalizing and
Overall Maladaptive Behavior Indexes at 12 months (p=0.032 and 0.049, respectively). Kaufman
reported that Kuvan at dose of 20 mg/kg/day increased CSF BH4 levels (1). Based on these
observations, it is likely that Kuvan has some effects on neurotransmitter metabolism.
Supplementation of large neutral amino acids (LNAA) as a medical food has been used in Europe
for the past 25 years and it is believed to be effective in treating patients with PKU. In
the article by Shindeler et al. (2), 16 individuals (7 males and 9 females; age 11y to 45 y)
participated in the study which consisted 4 weeks wash-out and 4 two-weeks stages (on
phenylalanine restricted diet and with/without LNAA, and on no phenylalanine restricted diet
and with/without LNAA). No specific adverse effects are reported in the article. Large
neutral amino acid therapy for the treatment of PKU has been done in the past (3). LNAA is
used primarily for adolescents and adults who cannot adhere to the standard phe-restricted
diet. LNAA treatment has been approved for PKU patients just like other special formulas. Our
previous studies have demonstrated deficiency of serotonin in the brain, as evidenced by low
nocturnal melatonin secretion and reduced urine dopamine compared to controls, and that
supplementation with LNAA improves, but does not normalize these markers.
Rationale: Patients with PKU are thought to be deficient in tyrosine and tryptophan in the
brain tissue level because of the abnormal phe/tyrosine and phe/tryptophan ratios. Previous
studies showed low serotonin levels in cerebrospinal fluid in PKU individuals and some
improvement was observed after tryptophan supplementation (4). Our prior study suggested
deficiency of tryptophan in the brain tissue was demonstrated by low nocturnal melatonin
secretion and 6-sulfatoxymelatonin, which is a stable metabolite of melatonin (5). LNAA
supplementation resulted in some improvement in melatonin secretion, however, melatonin
secretion in patients with PKU on LNAA was still significantly lower than the control group.
Supplementation of Kuvan may activate the brain tyrosine and tryptophan hydroxylases (6),
resulting in improvement of nocturnal melatonin secretion and urine melatonin and dopamine
concentrations. By supplementing LNAA increased amount of neurotransmitter precursor amino
acids will be transported into the brain and activated brain tyrosine and tryptophan
hydroxylases by Kuvan will act on these precursors to produce neurotransmitters, i.e.,
serotonin and dopamine. These synergistic effects may increase melatonin and dopamine levels
to closer to the control levels.
Aims of the Study: To show scientific evidence of improvement in metabolism of
neurotransmitters including serotonin and dopamine in patients with PKU treated with LNAA
only, Kuvan only, and Kuvan and LNAA.
Objectives: This investigator initiated study has three objectives: (1) To evaluate if
tetrahydrobiopterin (Kuvan) supplementation has beneficial effects on melatonin secretion and
urine dopamine levels in individuals with PKU when they are and are not treated with large
neutral amino acids; (2) To demonstrate synergistic effects of LNAA supplementation and Kuvan
therapy in improvement of neurotransmitter metabolism in individuals with PKU; and (3) To
gather pilot information necessary to design a larger, multicenter trial of these
interventions, should results of these pilot studies indicate further study is warranted.
Study Methodology: This study will be conducted in adult patients with PKU in four 4-week
phases: phase I (large neutral amino acid/LNAA), phase II (Washout), phase III (Kuvan only)
and phase IV (Kuvan and LNAA). Kuvan supplementation will be adjusted to provide 20
mg/kg/day. LNAA therapy is adjusted to the manufacturer's instruction (total tablets of LNAA
is 1/2 X BW kg). On the last day of each phase, subjects will stay approximately 14 to 18
hours overnight at the CTU at USC University Hospital. Blood specimens will be collected
every 2 hours from 7:00 pm to 7:00 am. First void urine will be collected on the day of
discharge (patients will be asked to void urine at 11:00 pm and the first void urine will be
collected).
Blood will be collected in a red top tube (5 ml) through an IV line which is saline locked
during the study period. Avoid hemolysis by collecting blood through an IV line into a
reasonably large peripheral vein. Blood will be left to clot for 45 minutes at room
temperature (18-28 C) and protected from light (a dim flash light or a yellow light < 100
lux). Serum will be collected and stored at - 20 C until they are subjected to analysis for
plasma melatonin and plasma amino acids. Urine 20 ml first void sample will be collected into
two plain tubes (10 ml per each tube) and stored in a deep freezer (-20 C) until subjected to
be analyzed for dopamine and 6-sulfatoxymelatonin.
This is an open-labeled study. During all four 4-week phases, subjects will remain on their
protein-restricted diet. LNAA tablets are not considered a medicine, but are under the
category of medical foods; examples include low protein foods. LNAA tablets will be provided
by the LNAA manufacture (Applied Nutrition). Kuvan will be taken per orally with breakfast
and LNAA tablets will be taken with meals three times per day.
A Randomized Phase III Clinical Trial Evaluating Post-Mastectomy Chestwall and Regional Nodal XRT and Post-Lumpectomy Regional Nodal XRT in Patients With Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy
PRIMARY OBJECTIVES:
To evaluate whether the addition of chest wall + regional nodal radiation therapy (XRT) after
mastectomy or breast + regional nodal XRT after breast conserving surgery will significantly
reduce the rate of events for invasive breast cancer recurrence-free interval (IBC-RFI) in
patients who present with histologically positive axillary nodes but convert to
histologically negative axillary nodes following neoadjuvant chemotherapy.
SECONDARY OBJECTIVES:
I. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly prolong
overall survival (OS) in patients who present with histologically positive axillary nodes but
convert to histologically negative axillary nodes following neoadjuvant chemotherapy.
II. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly reduce the
rates of events for local-regional recurrence-free interval (LRRFI) in patients who present
with histologically positive axillary nodes but convert to histologically negative axillary
nodes following neoadjuvant chemotherapy.
III. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly reduce the
rate of events for distant recurrence-free interval (DRFI) in patients who present with
histologically positive axillary nodes but convert to histologically negative axillary nodes
following neoadjuvant chemotherapy.
IV. To compare the rates of disease-free survival (DFS)-ductal carcinoma in situ (DCIS) by
treatment arm.
V. To compare the rates of second primary cancer (SPC) by treatment arm.
VI. To compare the effect of adding XRT on the cosmetic outcomes in mastectomy patients who
have had reconstruction.
VII. To compare the effect of adding XRT on quality of life including arm problems,
lymphedema, pain, and fatigue.
VIII. To evaluate the toxicity associated with each of the radiation therapy regimens.
IX. To determine whether computed tomography (CT)-based conformal methods
(intensity-modulated radiation therapy [IMRT] and 3-dimensional conformal radiation therapy
[3DCRT]) for chestwall + regional nodal XRT post mastectomy and regional nodal XRT with
breast XRT following breast conserving surgery are feasible in a multi-institutional setting
and whether dose-volume analyses can be established to assess treatment adequacy and to
develop normal tissue complication probabilities (NTCP) for the likelihood of toxicity.
X. To compare the effect of XRT in patients receiving mastectomy and in patients receiving
lumpectomy.
XI. To examine the role of proliferation measures as a prognosticator for patients with
residual disease after neoadjuvant chemotherapy.
XII. To develop predictors of the degree of reduction in local regional recurrence (LRR).
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM 1: Patients are assigned to 1 of 2 treatment groups.
GROUP 1A: Lumpectomy patients undergo whole breast radiation therapy using IMRT or 3DCRT once
daily 5 days a week for 5 weeks followed by a radiation therapy boost to the lumpectomy
cavity once daily 5 days a week for 1-1/2 weeks.
GROUP 1B: Mastectomy patients do not undergo radiation therapy.
ARM 2: Patients are assigned to 1 of 2 treatment groups.
GROUP 2A: Lumpectomy patients undergo regional nodal radiation therapy with whole breast
radiation therapy using IMRT or 3DCRT once daily 5 days a week for 5 weeks followed by a
radiation therapy boost to the lumpectomy cavity once daily 5 days a week for 1-1/2 weeks.
GROUP 2B: Mastectomy patients undergo regional nodal radiation therapy and chestwall XRT
using IMRT or 3DCRT once daily 5 days a week for 5 weeks.
All patients also receive systemic therapy as planned (hormonal therapy for patients with
hormone-receptor positive breast cancer and trastuzumab or other anti-human epidermal growth
factor receptor 2 [HER2] therapy for patients with breast cancer that is HER2-positive).
After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months and
then yearly for 8 years.
Pragmatic, Randomized Optimal Platelet and Plasma Ratios
Background: Multiple observational studies have reported that blood product component ratios
(i.e., plasma:platelets:RBCs) that approach the 1:1:1 ratio, found in fresh whole blood, are
associated with significant decreases in truncal hemorrhagic death and in overall 24-hour and
30-day mortality among injured patients. The rationale for the 1:1:1 ratio is that the closer
a transfusion regimen approximates whole blood, the faster hemostasis will be achieved with
minimum risk of coagulopathy. The current DoD guideline specifies the use of 1:1:1, and this
practice is followed on almost all combat casualties. In other observational studies, leading
centers have reported good outcomes across a range of different blood product ratios. For
example, a 1:2 plasma:RBC ratio is used with little guidance regarding platelets. The
proposed randomized trial is intended to resolve debate and uncertainty regarding optimum
blood product ratios.
Study Design: Randomized, two-group, controlled Phase III trial with a Vanguard stage. Equal
random allocation to treatment using stratified, permuted blocks with randomly chosen block
sizes and stratification by site.
Objective: To conduct a Phase III multi-site, randomized trial in subjects predicted to have
a massive transfusion, comparing the efficacy and safety of 1:1:1 transfusion ratios of
plasma and platelets to red blood cells (the closest approximation to reconstituted whole
blood) with the 1:1:2 ratio. The co-primary outcomes will be 24-hour and 30-day mortality.
The PROPPR Trial will be conducted with exception from informed consent (EFIC). Additionally,
laboratory data from the trial will add to the understanding of trauma induced coagulopathy
(TIC) and inflammation.
A Randomized, Phase IIB/III Study of Ganetespib (STA-9090) in Combination With Docetaxel Versus Docetaxel Alone in Subjects With Stage IIIb or IV Non-Small-Cell Lung Cancer
Preliminary signals of clinical activity of ganetespib as a single agent have been observed
in NSCLC. A novel approach to treatment of NSCLC is the combination of Hsp90 inhibitors, such
as ganetespib, and taxanes. Such combinations have shown potential for synergy in preclinical
and clinical evaluations with other Hsp90 inhibitors. Preclinical studies with ganetespib and
taxanes have indicated that the combination of these drugs was more effective than either
drug alone at inducing cell death, and an ongoing phase 1 study indicates that the
combination is well tolerated and warrants systematic evaluation in a larger study.
A Phase III Trial Evaluating the Addition of Trastuzumab to Trimodality Treatment of HER2-Overexpressing Esophageal Adenocarcinoma
PRIMARY OBJECTIVES:
l. To determine if trastuzumab increases disease-free survival when combined with trimodality
treatment (radiation plus chemotherapy followed by surgery) for patients with human epidermal
growth factor receptor 2 (HER2)-overexpressing esophageal adenocarcinoma.
SECONDARY OBJECTIVES:
I. To evaluate if the addition of trastuzumab to trimodality treatment increases the
pathologic complete response rate and overall survival for patients with HER2-overexpressing
esophageal adenocarcinoma.
II. To develop a tissue bank of tumor tissue from patients with non-metastatic esophageal
adenocarcinoma.
III. To determine molecular correlates of complete pathologic response, disease-free
survival, and overall survival for patients with HER2-overexpressing esophageal
adenocarcinoma treated with neoadjuvant and maintenance trastuzumab.
IV. To evaluate predictors of cardiotoxicity in patients with esophageal cancer treated with
trastuzumab and chemoradiation.
V. To evaluate adverse events associated with the addition of trastuzumab to trimodality
treatment for patients with non-metastatic esophageal adenocarcinoma.
PATIENT-REPORTED QUALITY OF LIFE OBJECTIVES:
I. To determine if the addition of trastuzumab to trimodality treatment improves the
patient-reported Functional Assessment of Cancer Therapy for Esophageal Cancer (FACT-E)
Esophageal Cancer Subscale (ECS) score.
II. To determine if an improvement in the FACT-E ECS score at 6-8 weeks post completion of
neoadjuvant chemoradiation correlates with pathologic complete response.
III. To determine if pathologic complete response correlates with the FACT-E ECS score at 1
year and/or 2 years from the start of chemoradiation.
IV. To determine if the addition of trastuzumab to trimodality treatment improves the Swallow
Index and Eating Index Subscale scores of the FACT-E.
V. To determine if the addition of trastuzumab to paclitaxel, carboplatin, and radiation
impacts quality-adjusted survival.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also
receive trastuzumab intravenously (IV) over 30-90 minutes on days 1, 8, 15, 22, 29, 36, and
57 and paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15,
22, 29, and 36. Beginning 21-56 days after surgery, patients receive trastuzumab IV over
30-90 minutes. Treatment repeats every 21 days for 13 courses in the absence of disease
progression or unacceptable toxicity.
ARM II: Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks. Patients also
receive paclitaxel IV over 60 minutes and carboplatin IV over 30-60 minutes on days 1, 8, 15,
22, 29, and 36.
Within 5-8 weeks after completion of radiotherapy, all patients undergo surgery.
After completion of study therapy, patients are followed up every 4 months for 2 years and
then yearly thereafter.
A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor (VEGF) Therapy in Patients With Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib
PRIMARY OBJECTIVE:
I. To evaluate the overall response rate (complete response [CR] + partial response [PR]) of
trebananib (AMG 386) alone and in combination with continuation of previously administered
bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or
sunitinib malate (sunitinib) in advanced renal cell carcinoma.
SECONDARY OBJECTIVES:
I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and
toxicity of AMG 386 alone and in combination with continuation of the prior VEGF targeted
agent.
CORRELATIVE OBJECTIVES:
I. To evaluate the association between pretreatment tumor gene expression levels and response
to AMG 386 in combination with continuation of the prior VEGF targeted agent.
II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic
genes and response to AMG 386 in combination with continuation of the prior VEGF targeted
agent.
III. To compare changes in circulating angiogenic factors in patients treated with AMG 386
monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.
IV. To compare expression of angiogenic genes from archival tumor specimens to the expression
in biopsy specimens obtained after progression on anti-VEGF therapy.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15,
22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or
unacceptable toxicity.
ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes
on days 1, 15, and 29, pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42,
sorafenib tosylate PO twice daily (BID) on days 1-42, or sunitinib malate PO QD on days 1-28.
Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4-8 weeks.
A Phase I Study of Ipilimumab in Combination With Rituximab in Patients With Relapsed/Refractory CD20+ B-Cell Lymphoma
PRIMARY OBJECTIVES:
I. To determine a recommended phase II dose for ipilimumab in combination with rituximab.
SECONDARY OBJECTIVES:
I. To obtain preliminary information on the effect of adding ipilimumab to rituximab in
regard to: immune response; clinical anti-tumor response/overall remission rate (ORR)
(complete remission + partial remission); progression free survival (PFS).
OUTLINE: This is a dose-escalation study of ipilimumab followed by a randomized study.
PART I:
INDUCTION: Patients receive ipilimumab intravenously (IV) over 90 minutes once every 3 weeks
for 12 weeks and rituximab IV over 2-6 hours once weekly for 4 weeks.
MAINTENANCE: Patients receive ipilimumab IV over 90 minutes and rituximab IV over 2-6 hours
once every 12 weeks for up to 1 year.
PART II: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab
IV over 90 minutes once weekly in weeks 1, 4, 7, and 10. Patients then receive ipilimumab IV
over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the
absence of disease progression or unacceptable toxicity.
ARM B: Patients receive rituximab IV over 2-6 hours once weekly in weeks 1-4 and ipilimumab
IV over 90 minutes once weekly in weeks 3, 6, 9, and 12. Patients then receive ipilimumab IV
over 90 minutes and rituximab IV over 2-6 hours once every 12 weeks for up to 1 year in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 12 months.
Real Time Contrast Enhanced Ultrasound and Ultrasound-Based Elastography: Novel Techniques in Assessment of Treatment Response to Neoadjuvant Chemotherapy for Breast Cancer
PRIMARY OBJECTIVES:
I. To establish a quantitative prediction rule for accurate and early prediction of the
pathologic tumor response assessed post-surgery, using the change of contrast enhanced
ultrasound (CEUS) assessed tumor size and perfusion characteristics before (baseline) and 2-3
weeks following initiation of neoadjuvant chemotherapy (NAC).
II. To assess the agreement between CEUS based classification rule and pathologically
determined treatment response (baseline versus pre-surgical scan).
III. To establish a quantitative prediction rule for accurate and early prediction of the
pathologic tumor response assessed post-surgery, using the change in propagation velocity of
a shear mechanical wave in tissue before (baseline) and 2-3 weeks following initiation of
NAC.
IV. To assess the agreement between shear wave elastography (SWE) based classification rule
and pathologically determined treatment response (baseline versus pre-surgical scan).
SECONDARY OBJECTIVES:
I. To explore the role of combined CEUS + SWE features obtained at early treatment phase (2-3
weeks following initiation of NAC), in accurately predicting the pathologically determined
tumor response.
II. To investigate the agreement in assessment of therapy response to NAC between CEUS versus
contrast enhanced magnetic resonance imaging (CE MRI) and SWE versus CE MRI for baseline
versus pre-surgery scan and to identify discordant cases using scatter plot and contingency
tables.
OUTLINE:
Patients undergo dynamic contrast-enhanced ultrasound imaging and shear wave elastography at
baseline, 2-3 weeks after initiation of chemotherapy, and before surgery.
Phase I Study of the Aurora Kinase a Inhibitor MLN8237 in Combination With the Histone Deacetylase Inhibitor Vorinostat in Lymphoid Malignancies
PRIMARY OBJECTIVES:
I. To determine the maximum-tolerated dose (MTD) of MLN8237 (alisertib) when given in
combination with vorinostat and to select a dose and schedule for further testing
(recommended Phase 2 dose: RP2D) in patients with lymphoid malignancies.
II. To describe the toxicities of MLN8237 when given in combination with vorinostat on a
21-day schedule.
III. To determine any clinical responses with MLN8237 in combination with vorinostat.
IV. To compare the plasma pharmacokinetics of MLN8237 when given alone and in combination
with vorinostat.
V. To perform immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH)
analysis to determine aurora kinase A (AURKA) expression in archival formalin-fixed
paraffin-embedded sections from the most recent available tumor specimens of patients.
VI. To perform correlative studies for apoptosis and proliferation on bone marrow and lymph
node specimens, where available, obtained from patients in the expanded cohort at RP2D.
OUTLINE: This is a dose-escalation study of alisertib.
Patients receive alisertib orally (PO) twice daily (BID) on days 1-7 or days 1-3 and 8-10,
and vorinostat PO BID on days 1-14 or days 1-5 and 8-12. Courses repeat every 21 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for at least 30 days.
Powered by
SC CTSI