Delving into the Latest Updates on Laromustine with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Cloretazine, Laromustine (USAN), Onrigin

+ [6]

Target

DNA

Mechanism

DNA inhibitors(DNA inhibitors), DNA alkylating agents

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesImmune System Diseases+ [3]

Active Indication-

Inactive Indication

Acute Myeloid LeukemiaAdvanced Malignant Solid NeoplasmChronic lymphocytic leukaemia refractory+ [11]

Originator Organization

Nanotherapeutics, Inc.

Active Organization-

Inactive Organization

Vion Pharmaceuticals, Inc.Viron Therapeutics, Inc.

Nanotherapeutics, Inc.

Drug Highest PhaseDiscontinuedPhase 3

First Approval Date-

RegulationOrphan Drug (US)

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Structure/Sequence

Molecular FormulaC6H14ClN3O5S2

InChIKeyPVCULFYROUOVGJ-UHFFFAOYSA-N

CAS Registry173424-77-6

RATIONALE: Drugs used in chemotherapy, such as laromustine, daunorubicin, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells.
PURPOSE: This phase I/II trial is studying the side effects and best dose of laromustine when given together with daunorubicin and cytarabine in treating patients with acute myeloid leukemia.

Start Date01 Jan 2009

Sponsor / Collaborator

Institut Jean Paoli & Irene Calmettes

NL-OMON26145

/ SuspendedNot ApplicableIIT

Randomized study to assess the added value of Laromustine in combination with standard remission-induction chemotherapy in patients aged 18-65 years with previously untreated acute myeloid leukemia (AML) or myelodysplasia (MDS) (RAEB with IPSS >= 1.5)

Start Date01 Oct 2008

Sponsor / Collaborator-

100 Clinical Results associated with Laromustine

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100 Translational Medicine associated with Laromustine

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100 Patents (Medical) associated with Laromustine

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91

Literatures (Medical) associated with Laromustine

01 Mar 2019·Journal of chromatographic science

Development and Validation of LC–MS-MS Assay for the Determination of the Emerging Alkylating Agent Laromustine and Its Active Metabolite in Human Plasma

Article

Author: Lam, Tukiet T ; Wisnewski, Adam V ; Nassar, Ala F ; King, Ivan ; Wu, Terence

The objective of this study was to validate a method for the determination of laromustine (VNP40101M) and short-lived its active metabolite (VNP4090CE) that has a half-life in human blood of <90 s in human plasma by liquid chromatography (LC) with tandem mass spectrometric (MS/MS) detection. We overcome the stability dilemma by acidified the human plasma with citric acid. Laromustine "breaks" down on the source of mass spectrometry to give m/z 249 which is the same m/z for VNP4090CE. Because VNP4090CE and laromustine elute at approximate retention time of 1.93 and 2.94 min, respectively, we were able to quantify both of them in one method. VNP40101M, VNP4090CE and the internal standards were extracted from human plasma by liquid-liquid extraction into ethyl ether. The ethyl ether layer was evaporated, reconstituted and analyzed using LC with MS/MS detection. Validation parameters such as selectivity, limit of quantitation, linearity, precision, accuracy, recovery, autosampler viability, freeze-thaw cycles and compounds stability are evaluated for this method. Results were calculated using peak area ratios, and calibration curves were generated using a weighted (1/x2) linear least-squares regression. Calibration curves for VNP40101M and VNP4090CE in human plasma ranged from 1.00 to 1,000 ng/mL. In this study, both intra- and inter-assay results demonstrated a relative standard deviation for calibration standards (inter-assay) and quality control samples (intra- and inter-assay) to be ≤15.0%. In this method, there is ~1.79% isotopic interference of VNP40101M to VNP40101M-IS, and ~3.76% isotopic interference of VNP4090CE to VNP4090CE-IS. It was concluded that there was no significant carryover.

01 Nov 2018·Drug metabolism and disposition: the biological fate of chemicalsQ2 · MEDICINE

Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds

Q2 · MEDICINE

Article

Author: Obach, R Scott ; Lombardo, Franco ; Berellini, Giuliano

We report a trend analysis of human intravenous pharmacokinetic data on a data set of 1352 drugs. The aim in building this data set and its detailed analysis was to provide, as in the previous case published in 2008, an extended, robust, and accurate resource that could be applied by drug metabolism, clinical pharmacology, and medicinal chemistry scientists to a variety of scaling approaches. All in vivo data were obtained or derived from original references, either through the literature or regulatory agency reports, exclusively from studies utilizing intravenous administration. Plasma protein binding data were collected from other available sources to supplement these pharmacokinetic data. These parameters were analyzed concurrently with a range of physicochemical properties, and resultant trends and patterns within the data are presented. In addition, the date of first disclosure of each molecule was reported and the potential "temporal" impact on data trends was analyzed. The findings reported here are consistent with earlier described trends between pharmacokinetic behavior and physicochemical properties. Furthermore, the availability of a large data set of pharmacokinetic data in humans will be important to further pursue analyses of physicochemical properties, trends, and modeling efforts and should propel our deeper understanding (especially in terms of clearance) of the absorption, distribution, metabolism, and excretion behavior of drug compounds.

01 Jan 2018·Chemical biology & drug designQ4 · MEDICINE

pH‐dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2‐bis(methylsulfonyl)‐1‐(2‐chloroethyl)hydrazine prodrugs

Q4 · MEDICINE

Article

Author: Ratner, Elena S. ; Penketh, Philip G. ; Baumann, Raymond P. ; Shyam, Krishnamurthy ; Finch, Richard A. ; Sauro, Rachel

Laromustine (also known as cloretazine, onrigin, VNP40101M, 101M) is a prodrug of 90CE, a short‐lived chloroethylating agent with anticancer activity. The short half‐life of 90CE necessitates the use of latentiated prodrug forms for in vivo treatments. Alkylaminocarbonyl‐based prodrugs such as laromustine exhibit significantly superior in vivo activity in several murine tumor models compared to analogs utilizing acyl, and alkoxycarbonyl latentiating groups. The alkylaminocarbonyl prodrugs possess two exclusive characteristics: (i) They are primarily unmasked by spontaneous base catalyzed elimination; and (ii) they liberate a reactive carbamoylating species. Previous speculations as to the therapeutic superiority of laromustine have focused upon the inhibition of enzymes by carbamoylation. We have investigated the therapeutic interactions of analogs with segregated chloroethylating and carbamoylating activities (singly and in combination) in the in vivo murine L1210 leukemia model. The combined treatment with chloroethylating and carbamoylating prodrugs failed to result in any synergism and produced a reduction in the therapeutic efficacy compared to the chloroethylating prodrug alone. Evidence supporting an alternative explanation for the superior tumor selectivity of laromustine is presented that is centered upon the high pH sensitivity of its base catalyzed activation, and the more alkaline intracellular pH values commonly found within tumor cells.

100 Deals associated with Laromustine

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External Link

KEGG	Wiki	ATC	Drug Bank
D08939	-	-	DB05817

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Relapsing acute myeloid leukemia	Phase 3	US	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	BE	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	CA	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	FR	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	DE	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	GR	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	NL	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	PL	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	RS	Vion Pharmaceuticals, Inc.	01 Mar 2005
Relapsing acute myeloid leukemia	Phase 3	GB	Vion Pharmaceuticals, Inc.	01 Mar 2005

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2014	Not Applicable	Leukemia	-	Laromustine	yvtvpuawll(ksgsxaildh) = vfvkbhrqyy ypgcldlyhx (wlzgpuuvez ) View more	-	01 Oct 2014
				Vehicle	joeofthlpp(hasmrzxjjm) = qlffipyzsp jwcnbbssqq (tgcawygjkq ) View more
NCT00112554 (Pubmed \| Blood)	Phase 3	Relapsing acute myeloid leukemia	-	Laromustine and high-dose cytarabine (HDAC)	zqdglaqgcn(eljbpmdjqt) = hkamsgidnb xcnfcaxjot (knxgqnrdhl ) View more	-	05 Nov 2009
				HDAC/placebo	zqdglaqgcn(eljbpmdjqt) = djeoudylwf xcnfcaxjot (knxgqnrdhl ) View more
ASCO2009	Phase 1	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	-	Laromustine 300 mg/m2	mymzjhgzme(rgbhkuesfs) = zsmfkwlcrt qfargvcqpv (syfmpvxceb )	-	20 May 2009
ASCO2008	Phase 2	Acute Myeloid Leukemia	85	VNP40101M	wdunlheoqd(mbpvrmtahg) = 32 VNP40101M-related serious adverse events (SAEs) have been reported in 28 of 85 pts. The most common SAEs were related to myelosuppression or infection. Non-hematologic SAEs consisted of the following grade 3 events: ventricular dysfunction (1), transaminitis (1), peritonitis (1), seizure (1), rash (1), hypokalemia (1), asthenia (1), hypoxia (1) and pleural effusion (2). 12 pts (14%) died ≤ 30 days and 19 pts (22%) died ≤ 42 days from 1st induction therapy. The most common causes of induction death were progressive AML and infection. vbuugufxlu (smmxxlafky )	-	20 May 2008
ASCO2008	Phase 3	Relapsing acute myeloid leukemia	420	araC + 101M	jrtsitaeog(pkzodjdmxh) = dwuvjjjawi bzqqjjlkfz (ltvgighfxx ) View more	-	20 May 2008
				araC + placebo	jrtsitaeog(pkzodjdmxh) = dpxqjntxpr bzqqjjlkfz (ltvgighfxx ) View more
ASCO2007	Phase 1	Brain Cancer	41	VNP40101M	leggwuunwu(gpppydhqbg) = 1 case ftdmsukbhg (nqwvbrllyf ) View more	-	20 Jun 2007
ASCO2006	Phase 2	Acute Myeloid Leukemia \| Myelodysplastic Syndromes	105	Cloretazine	jrqcngxjiw(ldmfedmzjn) = koglnoyasz hmgoqhiwkf (ynhstwjhna )	-	20 Jun 2006
ASCO2006	Not Applicable	Acute Myeloid Leukemia	105	Cloretazine	jnamaxtcvt(lmwycgxulc) = xkcpnxncsk ptjetqmymn (zglfjjplya ) View more	Positive	20 Jun 2006
ASCO2005	Phase 1/2	Hematologic Neoplasms	-	VNP40101M	tdgbjuvbuo(hceqbmrvpn) = qnkvcsrcfc dljxmgpsux (pjlvrndnht )	-	01 Jun 2005
				araC	tdgbjuvbuo(hceqbmrvpn) = ndudibdsqs dljxmgpsux (pjlvrndnht )
ASCO2005	Phase 2	High Risk Myelodysplastic Syndrome	101	VNP40101M (Group A)	imkhnejruk(azizydyava) = with minimal extramedullary toxicity ctqvenkbyk (dosqpideif ) View more	-	01 Jun 2005
				VNP40101M (Group B)