Durante mucho tiempo no había principios uniformes para la Atribución de nombres a los antibióticos https://antibioticos-wiki.es . Más a menudo se les llama por el nombre genérico o especie del producto, con menos frecuencia-de acuerdo con la estructura química. Algunos antibióticos se nombran de acuerdo con el lugar donde se asignó el producto.
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
DOLECTRAN DOCETAXEL 80 mg/ 2ml DOCETAXEL 20 mg/ 0,5ml INJECTABLE CONCENTRATE FOR INTRAVENOUS INFUSION Made In Argentina - Under Prescription Only CUALIQUANTITATIVE FORMULA Each 0,5 ml DOLECTRAN vial of 20 mg contains: Docetaxel.20,0 Polysorbate 80 csp.0,5 mg Each sterile diluent vial contains: Ethanol (95% v/v) .……….13% Sterile Distillate water.……….87% For
EXEMPLOS DE PROGRAMAS COM ESTRUTURAS DE REPETIÇÃO Exemplo 1 Criar um programa em fluxograma convencional e Linguagem C que realiza a soma dos 100 primeiros números inteiros positivos. Solução: O problema dado resume-se à expressão: Para que o programa computacional seja eficiente e para que não seja necessário escrever um código onde os números inteiros sejam digitados