A Phase 3 Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy with Supplemental Oxygen, with or without Concurrent RSR13 (efaproxiral), in Women with Brain Metastases from Breast Cancer - ENRICH study

Start Date14 Feb 2005

Sponsor / Collaborator

Allos Therapeutics, Inc.

NCT00083304 / CompletedPhase 3

A Phase 3 Randomized, Open-label Comparative Study of Standard Whole Brain Radiation Therapy With Supplemental Oxygen, With or Without Concurrent RSR13 (Efaproxiral), in Women With Brain Metastases From Breast Cancer

RSR13 (efaproxiral) is a radiation sensitizer that has shown positive results in a Phase 3, randomized clinical trial of patients with brain metastases. Of 111 eligible breast cancer patients with brain metastases in that trial, 59 patients who received RSR13 prior to radiation therapy had a median survival time that was twice as long as the 52 patients who did not receive RSR13 prior to radiation therapy.
RSR13 (efaproxiral) is an experimental drug that increases the amount of oxygen released from blood into the tissues. It is well known that certain types of cancer tumors, including those in brain metastases, lack oxygen. Lack of oxygen in a tumor can reduce the effect of radiation therapy (RT). RSR13 may increase the oxygen level in brain tumors so that radiation therapy works better.
This study will enroll up to 360 women with brain metastases from breast cancer, and will evaluate if whole brain radiation therapy given with RSR13 will have a better treatment effect than whole brain radiation therapy alone. RSR13 will be infused intravenously (IV) through a central catheter placed in a central vein. Women randomized (assigned) to receive RSR13, therefore, will need to have a central catheter placed for treatment unless one is already in place.

Start Date01 Feb 2004

Sponsor / Collaborator

Spectrum Pharmaceuticals, Inc.

NCT00055887 / WithdrawnPhase 3

A Phase III Randomized, Open-Label Comparative Study of Induction Chemotherapy Followed by Thoracic Radiation Therapy With Supplemental Oxygen, With or Without Concurrent RSR13 (Efaproxiral), in Patients With Locally Advanced Unresectable (Stage IIIA/IIIB) Non-Small Cell Lung Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Drugs such as efaproxiral may make the tumor cells more sensitive to radiation therapy. It is not yet known if chemotherapy combined with radiation therapy is more effective with or without efaproxiral in treating non-small cell lung cancer.
PURPOSE: Randomized phase III trial to compare the effectiveness of chemotherapy combined with radiation therapy with or without efaproxiral in treating patients who have stage III non-small cell lung cancer.

Start Date01 Nov 2002

Sponsor / Collaborator

Spectrum Pharmaceuticals, Inc.

100 Clinical Results associated with Efaproxiral

100 Translational Medicine associated with Efaproxiral

100 Patents (Medical) associated with Efaproxiral

Literatures (Medical) associated with Efaproxiral

15 Jan 2022·The Journal of experimental biologyQ2 · BIOLOGY

Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice

Q2 · BIOLOGY

Article

Author: Wearing, Oliver H. ; Ivy, Catherine M. ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Petersen, Elin E. ; Cheviron, Zachary A. ; Storz, Jay F. ; Natarajan, Chandrasekhar ; Scott, Graham R. ; Gutiérrez-Pinto, Natalia ; Schweizer, Rena M. ; Fago, Angela

ABSTRACT:

Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb–O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb–O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb–O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.

01 Jul 2021·World neurosurgeryQ4 · MEDICINE

Current Landscape and Future Prospects of Radiation Sensitizers for Malignant Brain Tumors: A Systematic Review

Q4 · MEDICINE

Review

Author: Tuanquin, Leonard C ; Kruser, Timothy J ; Mansouri, Alireza ; Connor, James ; Snyder, Brianna Michelle ; Madhani, Sarosh Irfan ; Beg, Usman ; Hamidi, Nima ; Padmanaban, Varun

BACKGROUND:

Radiation therapy (RT) is the cornerstone of management of malignant brain tumors, but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review, we provide an overview of radiosensitizers developed for malignant brain tumors, summarize their safety and efficacy, and evaluate areas for possible improvement.

METHODS:

Following PRISMA guidelines, PubMed, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT. Articles reporting clinical evidence of nonantineoplastic radiosensitizers with RT for malignant central nervous system tumors were included. Data of interest were presumed mechanism of action, median overall survival (OS), progression-free survival (PFS), and adverse events.

RESULTS:

Twenty-two unique radiosensitizers were identified. Only 2/22 agents (fluosol with oxygen, and efaproxiral) showed improvement in OS in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. Improved PFS was reported with use of metronidazole, sodium glycididazole, and chloroquine. There was a wide range of toxicities, which prompted change of schedule or complete discontinuation of 9 agents.

CONCLUSIONS:

Progress in radiosensitizers for malignant CNS tumors has been limited. Only 2 radiosensitizers have shown limited improvement in survival. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Use of drug development strategies using new technologies to overcome past challenges is necessary.

01 Jan 2021·Journal of enzyme inhibition and medicinal chemistryQ2 · MEDICINE

Pharmacophore-guided repurposing of fibrates and retinoids as GPR40 allosteric ligands with activity on insulin release

Q2 · MEDICINE

ArticleOA

Author: Cione, Erika ; Manetti, Fabrizio ; Caroleo, Maria Cristina ; Kagechika, Hiroyuki

A classical drug repurposing approach was applied to find new putative GPR40 allosteric binders. A two-step computational protocol was set up, based on an initial pharmacophoric-based virtual screening of the DrugBank database of known drugs, followed by docking simulations to confirm the interactions between the prioritised compounds and GPR40. The best-ranked entries showed binding poses comparable to that of TAK-875, a known allosteric agonist of GPR40. Three of them (tazarotenic acid, bezafibrate, and efaproxiral) affect insulin secretion in pancreatic INS-1 832/13 β-cells with EC₅₀ in the nanomolar concentration (5.73, 14.2, and 13.5 nM, respectively). Given the involvement of GPR40 in type 2 diabetes, the new GPR40 modulators represent a promising tool for therapeutic intervention towards this disease. The ability to affect GPR40 was further assessed in human breast cancer MCF-7 cells in which this receptor positively regulates growth activities (EC₅₀ values were 5.6, 21, and 14 nM, respectively).

News (Medical) associated with Efaproxiral

09 Nov 2005

·www.biospace.com

Allos Therapeutics, Inc. Reports Third Quarter 2005 Financial Results

WESTMINSTER, Colo., Nov. 9 /PRNewswire-FirstCall/ -- Allos Therapeutics, Inc. today reported financial results for the third quarter of 2005. For the three months ended September 30, 2005, the Company reported a net loss of $4.8 million, or $0.09 per share. This compares to a net loss of $4.6 million, or $0.15 per share, for the three months ended September 30, 2004. For the nine months ended September 30, 2005, the Company reported a net loss of $15.5 million, or $0.36 per share, compared to a net loss of $16.9 million, or $0.54 per share, for the same period last year. Cash, cash equivalents, and investments in marketable securities as of September 30, 2005 amounted to $59.4 million. Product Portfolio Update: EFAPROXYN(TM) (efaproxiral): * ENRICH, the Company's Phase 3 study of the radiation sensitizer EFAPROXYN in patients with brain metastases originating from breast cancer, continues to progress in line with Company expectations. The Company expects to complete patient enrollment in this trial during the second half of 2006 and report preliminary results approximately six months thereafter. * In September 2005, the Company announced the publication of results from its Phase 2 multi-center study of EFAPROXYN in patients with unresectable non-small cell lung cancer (NSCLC) receiving sequential chemoradiotherapy (S-CRT). Results from the study, which were reported in the September 1st edition of the Journal of Clinical Oncology, suggest that the addition of EFAPROXYN to S-CRT may improve survival over S-CRT alone without increasing radiation toxicity rates. * In October 2005, the Company withdrew its European Marketing Authorization Application (MAA) for its investigational radiation sensitizer REVAPROXYN(TM) (efaproxiral, EFAPROXYN(TM) in the United States) for use as an adjunct to whole brain radiation therapy for the treatment of patients with brain metastases originating from breast cancer. The Company believes that the ongoing ENRICH trial, if positive, together with other supporting data, should provide the additional data necessary to support the filing of a new MAA and the future approval of EFAPROXYN for the treatment of brain metastases originating from breast cancer in Europe. * Charles Scott, Ph.D., CBS Squared, is scheduled to present a quality adjusted survival analysis of the Phase 3 REACH study of EFAPROXYN in patients with brain metastases in a poster presentation titled "Improved survival, quality of life and quality-adjusted survival in breast cancer patients treated with efaproxiral + whole brain radiation therapy for brain metastases" at the San Antonio Breast Cancer Symposium on December 10, 2005. PDX (pralatrexate): * Enrollment in a Phase 1/2 study of PDX in patients with relapsed or refractory aggressive lymphoproliferative malignancies continues to progress in line with Company expectations. The Company expects to complete patient enrollment in the Phase 1 portion of this trial in the fourth quarter of 2005. * In January 2005, the Company initiated a Phase 1 dose escalation study of PDX with vitamin B12 and folic acid supplementation in patients with previously treated advanced NSCLC. The Company currently expects to complete patient enrollment in this trial in 2006. RH1: * Enrollment in a Phase 1 dose escalation study of RH1 in patients with advanced solid tumors continues to progress in line with Company expectations. The Company currently expects to complete enrollment in this trial in the fourth quarter of 2005. Sarah Danson, M.D., Department of Medical Oncology, Christie Hospital, is scheduled to report updated clinical and PK/PD data from an on-going Phase 1 study of RH1 in patients with advanced solid tumors in a poster presentation titled "Phase 1 Pharmacokinetic (PD) trial of the bioreductive drug RH1" at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics on November 17, 2005. Corporate Highlights: * In October 2005, the only remaining securities class action lawsuit that had been brought against the Company and one of its officers in May 2004 was dismissed with prejudice. In an opinion dated October 20, 2005, the United States District Court for the District of Colorado concluded that the plaintiff's complaint failed to meet the legal pleading requirements applicable to its alleged claims. The plaintiff has until November 19, 2005 to determine whether it will appeal the decision to the U.S. Court of Appeals for the Tenth Circuit. * In July 2005, a shareholder of the Company commenced a stockholder's derivative action in the United States District Court for the District of Colorado against several current and former directors of the Company, naming the Company as a nominal defendant. The factual allegations in the derivative action were substantially the same as the factual allegations in the purported securities class action lawsuit filed in May 2004. On November 2, 2005, the court granted the parties joint motion for voluntary dismissal and dismissed the case without prejudice. Conference Call The Company will host a conference call to review its third quarter results on Wednesday, November 9, 2005, at 11 AM ET. The dial in number for U.S. residents to participate is 877-407-8031. International callers should dial 201-689-8031. Participants should reference the Allos Therapeutics conference call. Conference Call Replay An audio replay of the conference call will be available from 5:30 PM ET on Wednesday, November 9, 2005, until 11:59 PM ET on Wednesday, November 16, 2005. To access the replay, please dial 877-660-6853 (domestic) or 201-612-7415 (international); Replay pass codes (both required for playback): account # 286; conference ID # 175174. Webcast Allos Therapeutics will hold a live webcast of the conference call. The webcast will be available from the homepage and the investors/media section of the Company's web site at and will be archived for 30 days. About Allos Therapeutics, Inc. Allos Therapeutics, Inc. is a biopharmaceutical company focused on developing and commercializing innovative small molecule therapeutics for the treatment of cancer. The Company's lead product candidate, EFAPROXYN(TM) (efaproxiral), is a synthetic small molecule designed to sensitize hypoxic, or oxygen-deprived, tumor tissue during radiation therapy. EFAPROXYN is currently being evaluated as an adjunct to whole brain radiation therapy in a pivotal Phase 3 trial in women with brain metastases originating from breast cancer. The Company's other product candidates are: PDX (pralatrexate), a small molecule chemotherapeutic agent (DHFR inhibitor) currently under investigation as both a single agent and in combination therapy regimens in patients with non-small cell lung cancer and Non-Hodgkin's lymphoma; and RH1, a small molecule chemotherapeutic agent bioactivated by the enzyme DT-diaphorase currently under evaluation in patients with advanced solid tumors. For more information, please visit the Company's web site at: . Safe Harbor Statement This press release contains forward-looking statements that are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements concerning our projected timelines for completion of enrollment and announcement of the results of our clinical trials, the potential safety and efficacy of EFAPROXYN for the treatment of patients with NSCLC receiving S-CRT or any other type of cancer, and other statements which are other than statements of historical facts. In some cases, you can identify forward- looking statements by terminology such as "may," "will," "should," "expects," "intends," "plans," anticipates," "believes," "estimates," "predicts," "projects," "potential," "continue," and other similar terminology or the negative of these terms, but their absence does not mean that a particular statement is not forward-looking. Such forward-looking statements are not guarantees of future performance and are subject to risks and uncertainties that may cause actual results to differ materially from those anticipated by the forward-looking statements. These risks and uncertainties include, among others: that we may experience difficulties or delays in our clinical trials, whether caused by adverse events, investigative site initiation rates, patient enrollment rates, regulatory issues or other factors; and that clinical trials may not demonstrate the safety and efficacy of our product candidates in their target indications. Additional information concerning these and other factors that may cause actual results to differ materially from those anticipated in the forward-looking statements is contained in the "Risk Factors" section of the Company's Annual Report on Form 10-K for the year ended December 31, 2004, and in the Company's other periodic reports and filings with the Securities and Exchange Commission. The Company cautions investors not to place undue reliance on the forward-looking statements contained in this press release. All forward-looking statements are based on information currently available to the Company on the date hereof, and the Company undertakes no obligation to revise or update these forward-looking statements to reflect events or circumstances after the date of this presentation, except as required by law. ALLOS THERAPEUTICS, INC. CONDENSED STATEMENTS OF OPERATIONS (in thousands ~ except share and per share information) (unaudited) Three-months ended Nine-months ended September 30, September 30, 2004 2005 2004 2005 Operating expenses: Research and development $2,203 $3,001 $7,638 $7,970 Clinical manufacturing 432 307 2,589 934 Marketing, general and administrative 2,035 2,005 6,989 6,813 Restructuring costs -- -- -- 380 Total operating expenses 4,670 5,313 17,216 16,097 Loss from operations (4,670) (5,313) (17,216) (16,097) Interest and other income, net 116 522 365 1,238 Net loss (4,554) (4,791) (16,851) (14,859) Dividend related to beneficial conversion feature of preferred stock -- -- -- (624) Net loss attributable to common stockholders $(4,554) $(4,791) $(16,851) $(15,483) Basic and diluted net loss per share $(0.15) $(0.09) $(0.54) $(0.36) Weighted average common shares: basic and diluted 31,153,489 55,015,757 31,134,311 43,045,637 ALLOS THERAPEUTICS, INC. CONDENSED BALANCE SHEETS (in thousands) (unaudited) December 31, September 30, 2004 2005 ASSETS Cash, cash equivalents and investments in marketable securities $23,849 $59,426 Other assets 1,344 1,512 Equipment and leasehold improvements, net 980 748 Total assets $26,173 $61,686 Liabilities and Stockholders' Equity Liabilities $2,310 $3,212 Stockholders' equity 23,863 58,474 Total liabilities and stockholders' equity $26,173 $61,686 Allos Therapeutics, Inc. CONTACT: Jennifer Neiman, Manager, Corporate Communications of AllosTherapeutics, Inc., +1-720-540-5227, jneiman@allos.com Web site:

Financial StatementRadiation TherapySmall molecular drugAACR

100 Deals associated with Efaproxiral

External Link

KEGG	Wiki	ATC	Drug Bank
-	Efaproxiral	L01XD06	DB08486

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Brain metastases	Phase 3	US	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	AR	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	AT	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	BR	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	CA	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	CL	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	HR	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	FR	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	GR	Spectrum Pharmaceuticals, Inc.	01 Feb 2004
Brain metastases	Phase 3	HU	Spectrum Pharmaceuticals, Inc.	01 Feb 2004

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


RTOG-94-10 (ASTRO2006)	Phase 2	Locally Advanced Lung Non-Small Cell Carcinoma	402	Efaproxiral + Radiotherapy	bepukesgiu(zwuattfvcg) = gseubiuksz zrvsqvnjch (ryhsbnpdmf ) View more	Positive	01 Nov 2006
				Efaproxiral (Sequential arm (STD50))	bepukesgiu(zwuattfvcg) = ydvxfyjqnv zrvsqvnjch (ryhsbnpdmf ) View more
NCT00005887 (Pubmed \| J Urol)	Phase 3	Brain metastases	515	Efaproxiral at 75 or 100 mg/kg	rokyjnkzog(inqosxbbgx) = The most common severe adverse event in patients treated with efaproxiral was hypoxemia, which was reversible and effectively managed with supplemental oxygen in most patients. trmovfzrfu (fbdornhgkr )	-	01 Jan 2006
				No efaproxiral
RT-009 (ASTRO2004)	Phase 3	Brain metastases	538	RSR13 plus WBRT and supplemental O2	bccdemjlyf(nkayrkqpvr) = bdqkgzphfc iyrjkfjzfl (mrlbwvcfpk )	Positive	01 Sep 2004
ASTRO	Not Applicable	Locally Advanced Lung Non-Small Cell Carcinoma	-	RSR13	qcfvooxyca(lidinozvnu) = 19% of patients experienced transient RSR-13 induced hypoxemia mzefnvocyx (resblvwcoj ) View more	-	01 Nov 2001

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