SU 5416 - lek na raka ?

Liczba wypowiedzi w tym wątku: 2

1. Data: 2000-08-17 20:39:55

Temat: SU 5416 - lek na raka ?
Od: Grzegorz Szymanski <g...@c...com.pl> szukaj wiadomości tego autora

Czesc grupowicze !

Jestem pierwszy raz na tej grupie, wiec nie wiem czy ten temat byl juz
poruszany...

Czy ktos slyszal o leku SU5416?
Jak skonczyly sie testy kliniczne na ludziach?
W programie TV ( dzisiaj ok.15 ) mowili o 63-osobowej grupie poddanej
testowi,
z ktorej w 17 przypadkach efekty byly rewelacyjne ( badaniom poddane
byly osoby,
z zaawansowanym nowotworem, ktorym dawano nie wiecej niz 6 miesiecy
zycia..)
Czy ktos cos wie na ten temat, lub zna adres strony, z ktorej mozna sie
dowiedziec
czegos wiecej?
Dziekuje za info.

pozdrawiam - Grzegorz

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2. Data: 2000-08-17 23:48:55

Temat: Re: SU 5416 - lek na raka ?
Od: c...@p...wp.pl szukaj wiadomości tego autora

In article <3...@c...com.pl>,
Grzegorz Szymanski <g...@c...com.pl> wrote:
> Czesc grupowicze !
>
> Jestem pierwszy raz na tej grupie, wiec nie wiem czy ten temat byl juz
> poruszany...
>
> Czy ktos slyszal o leku SU5416?
> Jak skonczyly sie testy kliniczne na ludziach?
> W programie TV ( dzisiaj ok.15 ) mowili o 63-osobowej grupie poddanej
> testowi,
> z ktorej w 17 przypadkach efekty byly rewelacyjne ( badaniom poddane
> byly osoby,
> z zaawansowanym nowotworem, ktorym dawano nie wiecej niz 6 miesiecy
> zycia..)
> Czy ktos cos wie na ten temat, lub zna adres strony, z ktorej mozna sie
> dowiedziec
> czegos wiecej?
> Dziekuje za info.
>
> pozdrawiam - Grzegorz
>
Witaj na grupie.
Firma, ktora ma patent i prowadzi badania nazywa sie Sugen, link do ich
strony to www.sugen.com . Ponizej znajdziesz kilka abstraktow o wstepnych
badaniach. Wyglada to obiecujaco, ale jeszcze troche potrwa zanim lek
trafi do powszechnego leczenia. Z pewnoscia nie jest to uniwersalny lek
na raka.

Cien

[Proceedings of the 1999 AACR ˇ NCI ˇ EORTC International Conference]
Copyright Š 1999 by the American Association for Cancer Research

#13 A Phase I/II study of SU5416 in combination with 5-FU/leucovorin in
patients with metastatic colorectal cancer. L ROSEN1, P ROSEN1, R AMADO1,
D CHANG1, M MULAY1, M PARSON1, B LAXA1, P LANGECKER2, S GRACEY2, A SIEK2,
AND A HANNAH2 1UCLA Medical Center, Los Angeles, CA; 2SUGEN, Inc., S. San
Francisco, CA.

Adenocarcinoma of the large bowel affects more than 155,000
patients per year in the U.S.; 20-25% present with metastases or will
develop local recurrence or metastatic disease. Serum levels of vascular
endothelial growth factor (VEGF) in colorectal cancer patients correlate
positively with stage of disease, formation of liver metastases and rate
of disease progression. SU5416, a receptor tyrosine kinase, decreases
VEGF-stimulated Flk-1 phosphorylation.
Inhibiting VEGF-driven neovascularization in vivo by SU5416 reduces
or prevents tumor regrowth or metastasis proliferation. In preclinical
studies using a human colon cancer cell line, daily administration of
SU5416 in combination with 5-FU produced 55% tumor growth inhibition, an
additive effect over either agent used alone.
Up to 30 patients with untreated metastatic colorectal cancer are
treated with increasing doses of SU5416 administered twice weekly i.v.,
in combination with standard doses of 5-FU/LV therapy administered under
either the Mayo Clinic or Roswell Park regimens. Starting dose of SU5416
was 85 mg/m2, escalated to 145 mg/m2. The primary objective of the study
is to determine if these three agents can be safely combined for future
Phase II/III trials. Data regarding response rate, time to progression,
survival and pharmacokinetic interactions are being collected.
To date, 16 patients (ages from 33-76, KPS 70-100) have been
treated. On the Mayo Clinic regimen, 3 patients have been treated at 85
mg/m2 of SU5416; 7 at 145 mg/m2. On the Roswell Park regimen, 3 patients
have been treated at 85 mg/m2; 3 at 145 mg/m2.
As expected, 5-FU/LV-related toxicity predominates. To date, no dose-
limiting toxicity attributable to SU5416 has been observed. Both regimens
appear to be tolerable combined with full-dose SU5416. Individual
patients treated atthe higher doses reported mild headaches, which
decreased with continued therapy. Several patients observed transient
nausea. One patient with a central venous catheter experienced a
pulmonary embolism and DVT; the relationship to SU5416 is not known.
Other side effects reported are generally mild to moderate and responsive
tominimal supportive care. To date, no patient has experienced
progressive disease. Longest length of time on study is 5+ cycles (more
than 130 days on study).

A MULTICENTER, DOSE-ESCALATING STUDY IN PATIENTS WITHAIDS-RELATED
KAPOSI'S SARCOMA

Angiogenesis is one of the most important features of AIDS-associated
Kaposi's sarcoma (AIDS-KS). The strong expression of both Flk-1/KDR and
flt-1 in small stromal vessels in and around tumors suggests that
Vascular Endothelial Growth factor (VEGF) may be an important regulator
of the edema and angiogenesis seen in Kaposi's sarcoma. SU5416 is a
specific Flk-1 antagonist, decreasing VEGF-stimulated Flk-1
phosphorylation. Up to 30 patients with cutaneous AIDS-KS who are stable
or progressed under current therapy will be treated with escalating doses
of SU5416 administered twice weekly i.v. Starting dose was 65mg/m(2),
escalated to 85, 110 and 145 mg/m(2). Plasma levels of SU5416 and its
metabolites, protease inhibitor levels, viral load and t-cell subset
counts are being measured. Lesion size, extent of edema, as well as
investigator and patient global assessments are performed at 4-week
intervals. Response categorization is based on standard ACTG criteria.
Patients are maintained on stable anti-retroviral therapy.

To date, 16 HIV+ male patients with AIDS-related Kaposi's Sarcoma, ages
from 31-47 (m=36), with KPS of 70-100 have received doses of SU5416
ranging from 65-145 mg/m(2) for up to 4 cycles of therapy (a cycle is 29
days). Among the first 9 patients in whom outcome could be assessed, 5
patients have evidence of biological activity (flattening, shrinkage or
dissolution of lesions; reduction or dissolution of edema), 2 patients
had stable disease and 2 patients had progressive disease. Individual
patients showing response reported pain reduction and increased mobility.
At the current dose, no dose-limiting toxicity has been observed to date.
Individual patients treated at the higher doses reported mild headaches,
which decreased with continued therapy. Several patients observed
transient nausea. Two of the 16 patients discontinued treatment due to
local toxicity at the site of SU5416 administration (which may be
ameliorated by peripheral access device). SU5416 appears to have
biological activity in AIDS-KS patients, even those that have failed
multiple prior therapies. Side effects reported to date are mild to
moderate and responsive to supportive care.
Source:
Gill P, Arasteh K, Jacobs M et al: A multicenter, dose-escalating study
in patients with AIDS-related Kaposi's sarcoma (abstract 1160). Abstracts
of the 39th Interscience Conference on Antimicrobial Agents and
Chemotherapy, September 1999; p. 488.

Oncologist 5: 51-54 (2000) [20264300]

Clinical strategy for the development of angiogenesis inhibitors.

S. K. Carter

SUGEN, Inc., South San Francisco, California, USA. s...@s...com

Angiogenesis inhibitors differ from conventional cytotoxic chemotherapy
agents by targeting normal cells rather than tumor cells, which may
contain multiple mutations. Because of this, the traditional strategy
used in clinical development of cytotoxic agents may not be appropriate
for these novel agents. Many clinical studies are now evaluating these
agents with a new approach, referred to as the cytostatic paradigm. The
cornerstone of the cytostatic paradigm is the use of time to progression
(TTP) of disease as the decision-making criterion for "go/no go" in the
early phases of clinical development. However, the use of TTP as the main
criterion for clinical trials is complicated for a variety of reasons,
including: A) the lack of standardized criteria accepted by regulatory
authorities; B) the heterogeneity of the historical database, and C) the
larger number of patients needed for the "go/no go" decision-making
process. In addition, clinical trials of cytotoxic agents have
traditionally used objective response (despite the controversy regarding
objective response as a surrogate for clinical activity) as the main
criterion for determining whether the results of phase II studies justify
the pivotal phase III studies. Another aspect of the clinical development
strategy is combining angiogenesis inhibitors with cytotoxic
chemotherapy. The rationale for combination of angiogenesis inhibitors
with cytotoxic agents is based on: A) different targets for these agents;
B) lack of cross-resistance patterns; C) lack of myelosuppression with
angiogenesis inhibitors allows administration of full doses of all
agents, and D) the assumption that combining these agents will result in
additive antitumor activity. Combination therapy with angiogenesis
inhibitors may be attractive to both clinicians and their patients
because it allows cytostatic agents to be used upfront in treatment while
contributing to drug registration strategy (cytostatic/cytotoxic
combination therapy versus cytotoxic therapy). The clinical development
of the angiogenesis inhibitor SU5416, a small molecule inhibitor of
vascular endothelial growth factor, is currently ongoing. In phase I
trials, SU5416 demonstrated activity in both colorectal and non-small-
cell lung cancer patients. Based on these encouraging results, phase III
studies to evaluate combination of SU5416 with established cytotoxic
therapy are planned. These studies will include an interim analysis, the
equivalent of a phase II evaluation of clinical activity. If successful,
this strategic approach will save significant time in the clinical
development process.

Oncologist 5: 45-50 (2000) [20264299]

Targeting vascular endothelial growth factor blockade: ascites and
pleural effusion formation.

H. M. Verheul, K. Hoekman, A. S. Jorna, E. F. Smit & H. M. Pinedo

Department of Medical Oncology, University Hospital Vrije Universiteit,
Amsterdam, The Netherlands.

PRIMARY PURPOSE: Formation of ascites and pleural effusion (PE) is a
common problem for patients with advanced-stage cancer. These fluid
accumulations cause severe symptoms such as abdominal distention,
shortness of breath, cachexia, anorexia, and fatigue. Preclinical models
have demonstrated that vascular endothelial growth factor (VEGF) plays a
pivotal role in the accumulation of malignant PE or ascites. This study
investigated whether blockade of VEGF activity would reduce biological
activity of PE and ascites on endothelial cells of cancer patients.
PATIENTS AND METHODS: The activity of VEGF in PE and ascites of 58
patients (39 with PE and 19 with ascites) was measured. An endothelial
cell proliferation assay with human umbilical vein endothelial cells was
used to determine the biological activity of ascites and PE. RESULTS:
VEGF concentrations ranged from 67-6,245 pg/ml. A significantly higher
concentration of VEGF was detected in the ascites and PE of patients
with cancer (median, 1,290 pg/ml) than in patients with nonmalignant
disease (median, 250 pg/ml; p = 0.02). Of the 58 PE and ascites samples,
41 were biologically active, based on a two- to fourfold stimulation of
endothelial cell proliferation in 72 hours. VEGF concentrations were
significantly higher in the biologically active samples compared with the
17 nonactive samples (2,056 pg/ml versus 771 pg/ml; p = 0.02).
Coincubation of the samples with either a neutralizing polyclonal
antibody against VEGF or SU5416, a small molecule inhibitor of the VEGF
receptor Flk-1/KDR, inhibited endothelial cell proliferation by 66% and
100%, respectively. The inhibition caused by the antibody and that caused
by SU5416 correlated significantly (r = 0.8, p<0.001).
CONCLUSION: We conclude that malignant ascites and PE contain high levels
of biologically active VEGF. This study strongly supports the hypothesis
that blockade of VEGF, such as that afforded by SU5416, may benefit
cancer patients with recurrent ascites or PE formation.

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