3 augustus 2012: Onderaan hebben we het abstract van dit volledige studierapport: The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics toegevoegd. Ook efaproxiral behoort tot de niet toxische middelen die worden besproken.  

5 april 2006: J Clin Oncol. 2005 Sep 1;23(25):5918-28.

Zie onderaan een overzichtsstudie met de aanpak met Efaproxiral - RSR 13. In de derde helft van 2006 worden resultaten uit een 5 jarige fase III studie verwacht met deze aanpak.

Het bedrijf Allos Therapeutics meldt opnieuw een goed behandelingsresultaat, zonder ernstige bijwerkingen, in een fase II trial bij niet-kleincellige-longkanker als hun het middel RSR13 ( efaproxiral) aanvullend wordt gegeven tijdens de bestraling en daarop aansluitend chemotherapie. Al eerder berichtte dit bedrijf over goede resultaten hiermee, zie onder dit nieuwe artikel een artikel uit 2002.

RSR 13 - efaproxiral - is volgens dit bedrijf een synthetische molecuul die het zuurstofniveau in de kankercellen verhoogt waardoor het effect van de bestraling wordt vergroot. De nieuwe studie is uitgevoerd bij 51 patiënten met niet operabele en gevorderde niet-kleincellige-longkanker in 13 verschillende ziekenhuizen. De resultaten zijn nagenoeg hetzelfde als eerdere studie: Met RSR 13 - efaproxiral - als toevoeging aan de bestraling bleken de behandelde patiënten een mediane overlevingsduur te hebben van 20,6 maanden (95% CI, 14.0 to 24.2) tegenover 15,1 maanden en 17,9 maanden in controlegroepen; Overall overleving na 1- en 2 jaar was 67% en 37%, respectievelijk. Ook het bijwerkingsprofiel was significant minder dan zonder RSR13.

Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer.

Choy H, Nabid A, Stea B, Scott C, Roa W, Kleinberg L, Ayoub J, Smith C, Souhami L, Hamburg S, Spanos W, Kreisman H, Boyd AP, Cagnoni PJ, Curran WJ.
Vanderbilt University Medical Center, Nashville, TN, USA. hak.choy@utsouthwestern.edu

PURPOSE: Efaproxiral (RSR13) reduces hemoglobin oxygen-binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS: Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10.

RESULTS: Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%).

CONCLUSION: Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.

Publication Types:
Clinical Trial
Clinical Trial, Phase II
Multicenter Study

PMID: 16135463 [PubMed - indexed for MEDLINE]

19 september 2002: Bron: Alos Therapeutics

Het bedrijf Allos Therapeutics meldt een goed behandelingsresultaat, zonder ernstige bijwerkingen, in een fase II trial bij niet-kleincellige-longkanker als hun het middel RSR13 ( efaproxiral) aanvullend wordt gegeven tijdens de bestraling en daarop aansluitend chemotherapie van de niet-kleincellige-longkankertumoren.
RSR 13 - efaproxiral - is volgens dit bedrijf een synthetische molecuul die het zuurstofniveau in de kankercellen verhoogt waardoor het effect van de bestraling wordt vergroot. De studie is uitgevoerd bij 52 patiënten met niet operabele en gevorderde niet-kleincellige-longkanker. De resultaten zijn bemoedigend. Met RSR 13 - efaproxiral - als toevoeging aan de bestraling bleken de behandelde patiënten met een niet operabele gevorderde niet-kleincellige-longkanker graad IIIa en IIIB (zie verder onder longkanker algemeen op deze pagina wat dit betekent) een gemiddelde overlevingsduur te hebben van 20,6 maanden tegenover 13,0 en 14,6 maanden in vergelijkbare controlegroepen die de bestraling kregen zonder de RSR 13 - efaproxiral - toevoeging. De 1 jaarsoverleving in de groep van RSR 13 - efaproxiral - was 67 procent en de twee jaarsoverleving 37 procent. Deze resultaten zijn significant te noemen en vrijgegeven en gepubliceerd op ESTRO - het grote Europese congres over longkanker en actuele behandelingen d.d. 19 september 2002.

Het bedrijf Allos gaat een grotere fase III studie doen in het vierde kwartaal van 2002 met RSR 13 - efaproxiral - en dezelfde uitgangspunten. Ook worden er trials voorbereid voor RSR 13 - efaproxiral - bij hersentumoren. Voor wie is geïnteresseerd in nadere informatie kan met haar/zijn oncoloog contact opnemen met Allos.

Hieronder het originele persbericht van het bedrijf Allos.

-- PRESS RELEASE: Allos Updates RSR13 Phase 2 Study Results --

Allos Updates RSR13 Phase 2 Study Results in Non-Small Cell Lung Cancer
At European Radiation Therapy Conference

- Updated 2-Year Follow Up Results Continue to Show Significant Improvement
In Median Survival Time Over Like Studies With Addition of RSR13 -

PRAGUE, Sept. 19 /PRNewswire-FirstCall/ -- Allos Therapeutics, Inc. (Nasdaq:
ALTH) today announced updated positive survival results from a Phase 2 clinical
trial evaluating the use of RSR13 (efaproxiral) in patients with locally
advanced, unresectable, non-small cell lung cancer receiving thoracic radiation
therapy following induction chemotherapy. At the time of the analysis,
approximately 96 percent of evaluable patients had been followed for at least 2
years. The updated results showed a median survival of 20.6 months, 1-year
survival rate of 67 percent and a 2-year survival rate of 37 percent. There
were no cases of moderate to severe esophagitis Data from this study were presented today at the European Society for Therapeutics Radiology and Oncology (ESTRO), Abstract
896.
RSR13 is a synthetic small molecule that enhances the diffusion of oxygen to
hypoxic (oxygen deprived) tumor tissue and has the potential to enhance the
effectiveness of standard radiation therapy.
"The fact that the median survival of 20.6 months remains constant with a
median follow up of over two years is very encouraging for patients with this
aggressive and difficult-to-treat disease," said Pablo J. Cagnoni, M.D., senior
director, clinical development at Allos Therapeutics, Inc. "The results of this
study compare favorably to the sequential chemoradiotherapy arm of the LAMP
study (ASCO 2002 Abstract #1160, Arm 1) which showed a median survival of 13.0
months for the identical treatment, minus RSR13; and the sequential
chemoradiotherapy arm of the RTOG 94-10, which reported a median survival time
of 14.6 months."
The study was conducted in 52 patients with locally advanced, unresectable,
stage IIIA/IIIB non-small cell lung cancer. Response rate data was obtained in
44 patients that reached the 2-month follow-up. The objectives of this study
were to evaluate overall survival, progression-free interval in the chest,
complete and partial response rates in the chest (radiation portal) and time to
disease progression outside of the radiation portal. The patients received two
courses of induction chemotherapy with paclitaxel and carboplatin followed by
daily RSR13 combined with thoracic radiation therapy for 32 doses.



SOURCE Allos Therapeutics, Inc

Geplaatst 6 april 2006:

Drugs R D. 2005;6(3):178-85.

Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13.

[No authors listed]

Efaproxiral [RSR 13, GSJ 61, JP 4, KDD 86, RS 4] is a synthetic, small-molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. This first-of-its-class compound is particularly applicable for the treatment of certain tumour types that lack oxygen, such as brain metastases. In contrast to conventional chemotherapeutic agents or radiation sensitisers, there is no requirement for efaproxiral to be administered directly into tumours or to cross the blood-brain barrier for it to display efficacy.

Efaproxiral is under review for approval in the US and EU as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases originating from breast cancer. It is also under clinical evaluation for a variety of other cancers, including glioblastoma, non-small cell lung cancer (NSCLC) and cervical cancer.Allos is seeking partnership opportunities for efaproxiral's development and marketing. The company has indicated that the development of efaproxiral would be in cooperation with a corporate partner, according to its 2003 Annual Report.

In 1994, Allos Therapeutics acquired exclusive worldwide rights to intellectual property relating to efaproxiral from the Center for Innovative Technology (CIT).Allos has entered into arrangements with two contract manufacturers for the supply of efaproxiral, and a third manufacturer for the supply of the formulated drug product. Hovione FarmaCiencia is the primary supplier of efaproxiral, and is contracted to manufacture sufficient quantities on a commercial scale. In addition, a second manufacturer, Raylo Chemicals, is also producing quantities of efaproxiral. In December 2003, Allos entered into a long-term development and supply agreement with Baxter Healthcare who will formulate the efaproxiral into an injection. Allos is also seeking to establish an alternate supplier of efaproxiral injection. Allos submitted a rolling NDA to the US FDA consisting of three data components. Submission began in the third quarter of 2003 and was completed by the fourth quarter of 2003. The first part of the application containing non-clinical information was submitted on 5 August 2003.

The second part of the NDA containing information about efaproxiral's chemistry, manufacture and controls (CMC) was submitted in October 2003. Allos submitted its final component of the rolling NDA in December 2003. In February 2004, Allos announced that the FDA had accepted the company's NDA under priority review status. The FDA granted efaproxiral orphan drug status in August 2004 as an adjunct to WBRT for the treatment of brain metastases among breast cancer patients.

Efaproxiral also received fast-track status in November 2000 for the same indication in the US.In February 2004, Allos initiated a phase III trial, called ENRICH (Enhancing Whole Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases) to investigate efaproxiral as an adjunct to WBRT for the treatment of brain metastases. Median survival time is the primary endpoint of the study. The National Breast Cancer Coalition (NBCC) is collaborating with the company to support trial enrolment and to gain additional insight about ways to improve radiation treatment in this patient population. The ENRICH trial protocol was approved by the FDA under a Special Protocol Assessment process; as part of the protocol, two interim analyses for safety and efficacy will be performed.This multicentre, randomised, open-label study has a target enrolment of approximately 360 patients at >100 medical centres across the US, Canada, Europe and South America. Allos announced in September 2004 that recruitment of clinical sites for the trial is ongoing across the US and Canada. Completion of trial enrolment in North America is anticipated in December 2005. Subsequently, Allos announced in January 2005 that recruitment into the ENRICH trial has commenced and is ongoing in Europe; enrolment at European sites is expected to conclude by the third quarter of 2006.

Allos Therapeutics announced in June 2004 that it had filed an MAA with the EMEA for marketing of exaproxiral as an adjunct to WBRT for treatment of patients with brain metastases originating from breast cancer. The application is based on positive data from a pivotal phase III (REACH, RT-009) trial in this indication. The completed REACH trial investigated efaproxiral among patients with brain metastases undergoing WBRT. The trial was conducted at multiple sites in 11 countries, including the US, Canada, Europe and Australia. In August 2002 Allos completed the enrolment of 538 patients in the study. Initially only 408 patients were to be enrolled, but the company increased the size of the trial to conduct an appropriately powered subgroup analysis in patients with brain metastases from breast and NSCLC. The study was designed to demonstrate a 35% increase in median survival in the subgroup of patients compared with standard WBRT alone. The primary endpoint was survival.Allos began screening US patients for a phase III trial in NSCLC in early 2003. However, in May 2003, the company announced that as part of its revised operating plan it had suspended the screening of patients for this trial.

The trial, which was known as ELITE (Enhanced Lung cancer treatment with Induction chemotherapy and Thoracic radiation and Efaproxiral), was comparing induction chemotherapy followed by thoracic radiation therapy with supplemental oxygen, with or without efaproxiral. The trial was enrolling patients with locally advanced, unresectable NSCLC. ELITE was planned to enrol up to 600 patients across North America and Western and Eastern Europe.

Phase II trials in patients with inoperable NSCLC have been conducted in the US and Canada. Patient enrolment in one of these studies was completed in August 2000, with a total of 52 patients enrolled. This was an open-label, multicentre study of induction therapy with paclitaxel plus carboplatin followed by chest irradiation and efaproxiral in patients with locally advanced NSCLC. Positive results from this study were reported at the annual meeting of the European Society for Therapeutics Radiology and Oncology in September 2002. Efaproxiral has completed phase I trials as a treatment of surgical hypoxia in elective surgery patients receiving general anaesthesia. However, no recent development has been reported for these indications.In 1994, Allos signed an agreement with CIT for the exclusive worldwide rights to 17 US patents, a European patent covering the UK, France, Italy and Germany plus two pending patents in these territories, two issued patents in Japan, and a pending patent in Canada. These patents cover methods of allosterically modifying haemoglobin with efaproxiral and other compounds, the binding site of efaproxiral and therapy in certain indications including cancer, ischaemia and hypoxia. In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications. These patents are pending in the US, Canada and Europe, and include an international patent application.

In a May 2002 interview with the Wall Street Transcript, the CEO of Allos estimated the overall market for radiation therapy to be approximately 750 000 patients/year. Of this, brain metastases, NSCLC and glioblastoma therapy accounts for about 170 000, 140 000 and 6000 patients, respectively. Allos intend to use a speciality sales force to market efaproxiral directly to radiation therapists in North America. To penetrate the non-oncology market in the US, the company will seek partnership with one or more pharmaceutical companies with direct sales forces and with established distribution systems. Allos is also hoping to secure an oncology marketing partner for non-North American territories. At the time, the company had been issued 21 patents in the US, Canada, Europe and Japan.

Publication Types:
Review

The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics

The role of emerging and investigational therapies for metastatic brain tumors: a systematic review and evidence-based clinical practice guideline of selected topics

longkanker, efaproxil, RSR 13

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