Delving into the Latest Updates on OSI-7904L with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

+ [7]

Target

TYMS

Mechanism

TYMS inhibitors(Thymidylate synthase inhibitors)

Therapeutic Areas

NeoplasmsDigestive System DisordersInfectious Diseases

Active Indication-

Inactive Indication

adenocarcinoma of biliary tractAdvanced Malignant Solid NeoplasmBiliary Tract Neoplasms+ [8]

Originator Organization

Gilead Sciences, Inc.

Active Organization-

Inactive Organization

OncoVista Innovative Therapies, Inc.

OSI Pharmaceuticals, Inc.OncoVista, Inc.

+ [1]

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC27H24N4O6

InChIKeyBRVFNEZMTRVUGW-QFIPXVFZSA-N

CAS Registry139987-54-5

RATIONALE: OSI-7904L may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining OSI-7904L with oxaliplatin may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of OSI-7904L and oxaliplatin in treating patients with refractory or recurrent advanced colorectal cancer.

Start Date01 Feb 2004

Sponsor / Collaborator

Eortc

100 Clinical Results associated with OSI-7904L

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100 Translational Medicine associated with OSI-7904L

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100 Patents (Medical) associated with OSI-7904L

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62

Literatures (Medical) associated with OSI-7904L

01 Nov 2009·Molecular and Biochemical ParasitologyQ4 · MEDICINE

Catalytic and ligand-binding characteristics of Plasmodium falciparum serine hydroxymethyltransferase

Q4 · MEDICINE

Article

Author: Pradipsinh K. Rathod ; Cullen Kt T. Pang ; Julie Bowman ; Joshua H. Hunter ; Ramulu Podutoori ; Ramesh Gujjar ; Devaraja G. Mudeppa

The plant-like, bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) from malaria parasites has been a good target for drug development. Dihydrofolate reductase (DHFR) is inhibited by clinically established antimalarials, pyrimethamine and cycloguanil. Thymidylate synthase (TS) is the target of potent experimental antimalarials such as 5-fluoroorotate and 1843U89. Another enzyme in folate recycling, serine hydroxymethyltransferase (SHMT), produces 5,10-methylenetetrahydrofolate which, in many cells, is required for the de novo, biosynthesis of thymidine and methionine. Thus, the biochemical characterization of malarial SHMT was of interest. The principle, active Plasmodium falciparum SHMT (PfSHMT) was expressed in E. coli and purified using an N-terminal histidine tag. Unlike the plant enzyme, but like the host enzyme, PfSHMT requires the cofactor pyridoxal 5'-phosphate for enzymatic activity. The substrate specificities for serine, tetrahydrofolate, and pyridoxal 5'-phosphate were comparable to those for SHMT from other organisms. Antifolates developed for DHFR and TS inhibited SHMT in the mid-micromolar range, offering insights into the binding preferences of SHMT but clearly leaving room for improved new inhibitors. As previously seen with P. falciparum DHFR-TS, PfSHMT bound its cognate mRNA but not control RNA for actin. RNA binding was not reversed with enzyme substrates. Unlike DHFR-TS, the SHMT RNA-protein interaction was not tight enough to inhibit translation. Another gene PF14_0534, previously proposed to code for an alternate mitochondrial SHMT, was also expressed in E. coli but found to be inactive. This protein, nor DHFR-TS, enhanced the catalytic activity of PfSHMT. The present results set the stage for developing specific, potent inhibitors of SHMT from P. falciparum.

01 Dec 2008·Clinical Cancer ResearchQ1 · MEDICINE

Phase I, Pharmacokinetic and Biological Correlative Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor, and Cisplatin in Patients with Solid Tumors

Q1 · MEDICINE

Article

Author: Syed, Samira ; Horan, Julie ; Berlin, Jordan D. ; Ricart, Alejandro D. ; Drolet, Daniel W. ; Tolcher, Anthony W. ; Papadopoulos, Kyriakos P. ; Chick, Jon ; Vermeulen, Wendy ; Rothenberg, Mace L. ; Rowinsky, Eric K. ; Quaratino-Baker, Charlotte

AbstractPurpose: To evaluate the safety and describe the pharmacokinetic profile of OSI-7904L, a novel liposomal thymidylate synthase inhibitor, in combination with cisplatin (CDDP) in adults with advanced solid tumors.Experimental Design: CDDP was administered as a 2-h intravenous infusion followed by OSI-7904L intravenously over 30 min, both given every 3 weeks. Doses of each drug were escalated in separate cohorts of patients. Five dose levels of CDDP/OSI-7904L were explored: 60/6, 60/9, 60/12, 60/7.5, and 75/7.5 mg/m2. Pharmacokinetic samples, baseline plasma homocysteine, and genotype polymorphisms were evaluated.Results: Twenty-seven patients were treated with 101 total courses of CDDP/OSI-7904L. Dose-limiting toxicity was observed in 2 patients in the CDDP/OSI-7904L 60/12 mg/m2 cohort. One patient experienced rash, stomatitis, dehydration, renal failure, hyperbilirubinemia, and fatal neutropenic sepsis, whereas the other patient experienced grade 3 nausea, vomiting, and ileus. Therefore, the CDDP/OSI-7904L 60/9 mg/m2 cohort was expanded, with 2 of 6 patients reporting significant fatigue. Other toxicities were mild or moderate. Intermediate dose levels of 60/7.5 and 75/7.5 mg/m2 were evaluated, and the latter was identified as the recommended dose for phase II studies. No major pharmacokinetic interactions between CDDP and OSI-7904L were observed. Three patients had partial responses (gastric adenocarcinoma and heavily pretreated breast cancer). There was no significant relationship between baseline homocysteine and toxicity.Conclusions: The recommended doses for CDDP and OSI-7904L administered once every 3 weeks are 75 and 7.5 mg/m2, respectively. Pharmacokinetic interaction between the agents was not apparent. Preliminary clinical activity was observed in breast and gastric cancer.

01 Apr 2008·Cancer Chemotherapy and PharmacologyQ4 · MEDICINE

A phase I and pharmacokinetic study of OSI-7904L, a liposomal thymidylate synthase inhibitor in combination with oxaliplatin in patients with advanced colorectal cancer

Q4 · MEDICINE

Article

Author: Sandrine Marreaud ; Juan W Valle ; J Chick ; C Twelves ; A-S Govaerts ; Andrew R Clamp ; Gordon C Jayson ; M Debois ; D Lacombe ; Patrick Schöffski ; R Wilson

PURPOSEOSI-7904L is a liposomal formulation of a potent thymidylate synthase (TS) inhibitor. This phase I study evaluated the safety, tolerability and pharmacokinetics (PK) of OSI-7904L administered in combination with oxaliplatin every 21 days in patients with advanced colorectal carcinoma.METHODA 3+3 study design was utilized at predefined dose levels. Polymorphisms in the TS enhancer region and XPD enzyme were investigated as potential predictors of efficacy and toxicity.RESULTSFourteen patients received 76 cycles of treatment. At the highest dose level (OSI-7904L 9 mg/m(2), oxaliplatin 130 mg/m(2)) investigated, one of nine patients experienced dose-limiting toxicity of grade 3 oral mucositis with cycle 1 and five further patients required dose reductions. The toxicity profile of stomatitis, diarrhea, nausea, fatigue, sensory neuropathy and skin rash was consistent with that expected for a TS inhibitor/oxaliplatin combination regimen. PK analysis showed high interpatient variability with no detectable interaction between OSI-7904L and oxaliplatin. Partial radiological responses were documented in two patients.CONCLUSIONSThe recommended regimen for further investigation is OSI-7904L 9 mg/m(2) and oxaliplatin 130 mg/m(2).

100 Deals associated with OSI-7904L

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External Link

KEGG	Wiki	ATC	Drug Bank
-	OSI-7904L	-	DB05457

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Gastrooesophageal junction cancer	Phase 2	US	OSI Pharmaceuticals, Inc.	01 Oct 2003
Gastrooesophageal junction cancer	Phase 2	GB	OSI Pharmaceuticals, Inc.	01 Oct 2003
Biliary Tract Neoplasms	Phase 2	-	Gilead Sciences, Inc.	-
Biliary Tract Neoplasms	Phase 2	-	OncoVista Innovative Therapies, Inc.	-
Colorectal Cancer	Phase 2	-	Gilead Sciences, Inc.	-
Colorectal Cancer	Phase 2	-	OncoVista Innovative Therapies, Inc.	-
Esophageal Carcinoma	Phase 2	US	OSI Pharmaceuticals, Inc.	-
Esophageal Carcinoma	Phase 2	GB	OSI Pharmaceuticals, Inc.	-
Esophageal Carcinoma	Phase 2	BE	OSI Pharmaceuticals, Inc.	-
Neoplasms	Phase 2	US	OncoVista, Inc.	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASCO2009	Phase 2	Recurrent Squamous Cell Carcinoma of the Head and Neck	41	OSI-7904L	(pxltmokplj) = mfwrhalpyk pufwimwcsx (hlhnthsuex )	Negative	20 May 2009
ASCO2005	Phase 2	Neoplasms	53	OSI-7904L	(tzquvgguok) = pscbwzfpkx agdzmrojbx (hogfwsrfxs, 6.2 - 28.3) View more	-	01 Jun 2005