We fetch to your attention a new website where you can buy propecia australia at a low price with fast delivery to Australia.
ZIOPHARM Oncology, Inc.
1 First Avenue
Parris Building, #34
BETTER CANCER MEDICINE.
Navy Yard PlazaBoston, MA 02129Main 617-259-1970Fax 617-241-2855
Indibulin, a Novel Tubulin Targeting-Agent, in Combination with Capecitabine,
is Suitable for Mathematically-Optimized Dose-Scheduling
Jonathan J. Lewis1, Matthew D. Galsky2, 6, Luis H. Camacho3, David M. Loesch4, 6, Philip B. Komarnitsky1, Barbara Wallner1, Jan Stevens1, Larry Norton5.
1ZIOPHARM Oncology, New York, NY; 2Comprehensive Cancer Centers of Nevada, Las Vegas, NV; 3Oncology Consultants P.A., Houston, TX; 4Central Indiana Cancer Centers, Indianapolis, IN; 5Harmon Hill, New York, NY;
6US Oncology, Translational Oncology Program, Houston, TX.
Clinical: Key Inclusion Criteria
Preliminary Clinical Activity
Indibulin: Optimization of Dosing Schedules
Indibulin (IDB) is a novel, orally available tubulin-targeting
• Histologically confirmed solid tumors for whom treatment with
Median SD 6 Cycles
molecule that perturbs cancer cell migration and mitosis. It is active
capecitabine is considered medically acceptable
• Breast and colon cancer SD for 9 Cycles
Indibulin 22 kg/kg/day
against taxane-resistant cell lines and is synergistic with 5-FU in vitro
• No more than 2 prior chemotherapy regimens for metastatic disease
. Two translational studies have been conducted: a Phase IB study
of IDB in combination with capecitabine (CAP) in patients with advanced
• Adequate bone marrow, liver and renal function
solid tumors, and mathematical modeling applying Norton-Simon models
Daily Oral Therapy
to breast carcinoma MX-1 xenografts to further develop Phase II dose.
Breast and Colon Cancer
IDB is administered continuously starting at 400 mg BID. CAP
• ≥18 years of age. ECOG performance score ≤2; life expectancy ≥12 weeks
is administered for 2 weeks with 1 week rest, starting at 875 mg/m2
IDB and CAP are escalated to the highest planned dose level (not MTD):
Bladder and Prostate Cancer
IDB 600 mg BID & CAP 1000 mg/m2
BID. Efficacy is evaluated every 9 weeks
using RECIST. In the xenograft model indibulin is administered at dose levels
from 12 to 28.7 mg/kg/day to nude mice carrying MX-1 breast carcinoma.
0 5 10 15 20 25 30 35
Key Exclusion Criteria
Days of growth
Tumor growth is analyzed using a Gompertzian-type growth model to
determine via calculus of variations the optimal schedule to maximize the
• New York Heart Association (NYHA) functional class ≥3 or myocardial
AEs that are related and occurred in 2 or more pts (≥ 29%)
infarction ≤6 months, systemic infection
To date, 7 patients have been treated and are evaluable for safety.
Median age 62 yrs; ECOG ≤1; median prior therapies 3. Four patients are
• Severe renal impairment (creatinine clearance below 30 mL/min)
evaluable for efficacy and all have stable disease (3 for 6+ cycles, 1 for 3
Grade 1/2 AEs that Were Related
cycles). AEs include hand-and-foot syndrome (CAP), fatigue, vomiting,
• Known dihydropyrimidine dehydrogenase deficiency (DPD)
anorexia, and headache. DLTs have not been observed. In MX-1 xenografts,
• Radiotherapy ≤3 weeks. Any other anticancer, investigational drug, or
indibulin demonstrates linear dose-efficacy relationship over the range of
immunological therapy ≤4 weeks. Surgery ≤4 weeks excluding tumor
12 to 22 mg/kg. At all dose levels the first 5 days of administration are
associated with a rapid accumulation of anticancer effect with lesser
effects over the next 5 days to a peak of efficacy at day 10.
• History of invasive second primary malignancy diagnosed within 3 years
0 5 10 15 20 25 30 35
Days of growth
(except: Stage I endometrial/cervical carcinoma or prostate carcinoma
IDB + CAP is well tolerated. There is preliminary evidence
Grade 3/4 AEs that Were Related
treated surgically, or non-melanoma skin cancer)
of clinical activity even with this sub-optimal, continuous schedule of IDB.
Formal analyses suggest that an intermittent schedule could optimize
efficacy, minimize acquired resistance and allow for host recovery from drug-
induced toxicity. Pre-clinical evaluation in a breast cancer model supports
an intermittent dosing schedule to further increase the activity of IDB.
Clinical: Dosing Schedule
• Oral indibulin in combination with capecitabine is very well tolerated
with no neurotoxicity. Early activity in breast, colon, bladder, and
• Capecitabine (875 mg/m2
BID) given for 2 weeks followed by a 1-week
rest, and indibulin (400 mg BID, starting dose level) given every day
• Determine form and parameters of unperturbed growth curve*
continuously, until disease progression or unacceptable toxicity occurs
• Formal analyses of preclinical data utilizing Norton-Simon Modeling
• Assess degree of deviation (as differential equation) after growth
reveals that the major effect of therapy occurs in five days of exposure,
• To evaluate the combination of oral indibulin and capecitabine in subjects
• Three patients in each cohort. If a DLT occurs the cohort is expanded
perturbation by various schedules of therapy
which is not manifest on gross inspection until one week thereafter.
• Determine points of maximal change in rate of perturbation
Hence, an intermittent schedule based on five days of drug administration
preserves full activity while minimizing toxicity. This may also minimize
• Predict minimal exposure to create maximum effect
Dose Level Cohort
• To determine the most efficacious dosing strategy for oral indibulin using
• A Phase I-II study in breast cancer using this novel scheduling strategy
Artillery Projectiles, Fuzes and Propellants Royal Canadian Artillery School Table of Contents Introduction Main Topic Projectiles Propellants Conclusion Sources The weapon of the Artillery is often thought to be the cannon or howitzer. The weapon of the artillery is the projectile. I will give an overview of middle aged to modern era projectiles, fuzes and propell
REFERENCIAS BIBLIOGRÁFICAS “CÓMO USAR LOS ÁCIDOS GRASOS PARA EQUILIBRAR LOS PROCESOS INFLAMATORIOS Y CELULARES” 1. Wijendran V, Huang MC, and al. Efficacy of dietary 9. Maki KC, Bays HE and al. Effects of prescription arachidonic acid provided as triglyceride or phos-omega-3-acid ethyl esters, coadministered with pholipid as substrates for brain arachidonic acid atorvastatin,