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25 november 2011: Bron: Celgene

Een fase III studie met revlimid - lenalidomide voor hormoonresistente prostaatkanker  onder de naam - Actimid - is stopgezet door de producent omdat er bij tussentijdse evaluaties van de studie geen positief effect is geconstateerd op de overlevingstijd. Hier het persbericht waarin Celgene deze stop aankondigt. Voor myelodysplastic syndromes (MDS), chronische lymfatische leukemia (CLL), en non-Hodgkin lymfoom (NHL) gaan de studies wel door. Bovenaan dit artikel het recente persbericht. Daaronder meer informatie over revlimid - lenalidomide bij andere vormen van kanker met wel positieve resultaten, dus wellicht de moeite waard het hele artikel te lezen c.q. uit te printen.

Celgene is stopping its Phase III trial of lenalidomide in patients with castrate-resistant prostate cancer (CRPC). The decision was based on the recommendation from the Data Monitoring Committee (DMC) that the study, called Mainsail, would not demonstrate a statistically significant effect against the primary endpoint of overall survival.

The compound is the active ingredient in the marketed drug Revlimid. Halting the CRPC trial means that the firm’s nearest hope for expanding its label now falls on studies in myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphoma (NHL).

“We have accepted this recommendation of the DMC and following formal notification and review of the analysis, physicians and patients, internationally, will be officially advised of this action,” Celgene says. The double-blinded Mainsail trial was set up to evaluate the efficacy and safety of docetaxel and prednisone with or without lenalidomide.

The compound, branded as Revlimid, is indicated in nearly 70 countries in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy. In Australia and New Zealand it is also sanctioned in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy.

In the U.S., Canada, several Latin American countries, Malaysia, and Israel, Revlimid is marketed for transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. Marketing applications are reportedly being evaluated in a number of other countries.

The molecule is currently under Phase III investigation as a treatment for other types of MDS, CLL, and NHL. Celgene also has a Phase II solid tumor trial that includes lenalidomide. It is reportedly in over 300 clinical trials around the globe.

Revlimid makes ups a significant portion of Celgene’s sales. In the third quarter, the drug brought in $820 million, over 67% of total sales for that quarter, which reached almost $1.22 billion. During all of 2010, Revlimid sales increased approximately 44% to approximately $2.47 billion.

For Q3 2011, Revlimid sales grew 28% from Q2 2011. This was reportedly driven by continued market share gains, increased treatment duration, and geographic expansion. U.S. sales of $467 million and international sales of $353 million increased 25% and 32%, respectively, during Q3

20 mei 2005:"Bron: Anticancer Drugs. 2003 Jun;14(5):331-5. In onderstaande fase I/II studie uit 2003 wordt Thalidomide al aangeprezen als een effectief medicijn tegen Kahler - Multiple Myeloma en gemestateerde Melanoom. Op ASCO 2005 zijn recentere studies gepresenteerd met aangepaste vormen van Thalidomide medicijnen onder de naam REVLIMID bij MSD = Myelodyplastisch Syndroom, voorloper vaak van kankersoorten in beenmerg of bloed als ziekte van Waldenström en Kahler en vormen van leukemie. Er loopt inmiddels een fase III trial bij Kahler - Multiple Myeloma en gemestasteerde melanoom onder de naam Thalidomide - REVLIMID en fase I/II trials onder de naam ACTIMID bij prostaatkanker en borstkanker.

De werking van Thalidomide schijnt zo te zijn dat het de T cellen = afweercellen (immuunsysteem) mede stimuleert en anti-angiogenetische (remt vorming van nieuwe bloedvaten) en/of anti-ontstekings effecten heeft of bewerkstelligt. En vooral mensen met ontbrekend 5q31 chromosoom lijken baat te hebben met dit medicijn. Echter het oorspronkelijke Thalidomide gaf nogal wat bijwerkingen te zien en nieuwe vormen van Thalidomide zoals REVLIMID en ACTIMID vertonen minder ernstige bijwerkingen. De bijwerkingen schijnen overigens ook opgevangen te kunnen worden met extra goede voeding en extra bepaalde voedingsuppletie. Lees daarvoor als bewijs het verhaal van meneer HA die met de combinatie Thalidomide en vegetarische voeding met wel vette vis plus extra bepaalde voedingsuppletie zijn Kahler - Multiple Myeloma onder controle houdt en zelfs zijn lichamelijke gezondheid zeer sterk verbeterde de laatste anderhalf jaar na de start met Thalidomide. Een prachtig ervaringsverhaal van iemand die samen met vrouw en kinderen met een complementaire aanpak kanker overleeft met uitstekende kwalitiet van leven.

Achtereenvolgens het abstract van enkele studies met Thalidomide, waaronder naast de studie met MSD een kleinschalige en beperkte maar wel dubbelblinde gerandomiseerde studie van Thalidomide bij lepra patiënten met opvallend goede resultaten en een studie al uit 1986 waarin Thalidomide significant positief effect heeft bij orale en geniatele aften en wonden bekend onder het syndroom van Behcet, waarbij opvalt dat zodra de toediening van Thalidomide stopt de aandoening weer terugkomt, wat ook gebeurde in de lepra studie.

Curr Hematol Rep. 2005 May;4(3):182-5.

Lenalidomide (Revlimid, CC-5013) in myelodysplastic syndromes: is it any good?

Sekeres MA, List A.
H Lee Moffitt Cancer Center & Research Institute, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612-9497, USA.

The myelodysplastic syndromes (MDS) can be divided into "early" and "advanced" disease by evaluation of prognostic variables such as the number of cytopenias, karyotype, and percentage of myeloblasts. Patients with an isolated interstitial deletion of chromosome 5q31 represent a distinct subset who may derive particular benefit from immunomodulatory drugs. Goals of therapy for early MDS focus on hematologic improvement and maximizing quality of life. Thalidomide, the prototype of the immunomodulatory drugs, yields major erythroid responses in some patients with early MDS, but dose-limiting neurologic toxicities limit its potential clinical benefit. Lenalidomide, a more potent and non-neurotoxic derivative, has shown promising results in early MDS, yielding hematologic improvement in almost half of patients, and transfusion independence with cytogenetic remissions in approximately two thirds of patients harboring the chromosome 5q31 deletion.

PMID: 15865869 [PubMed - in process]

Thalidomide analogs as emerging anti-cancer drugs.

Dredge K, Dalgleish AG, Marriott JB.

Division of Oncology, St George's Hospital Medical School, London, UK. kdredge@sghms.ac.uk

Recently, it has been demonstrated that a number of novel thalidomide analogs possess anti-cancer properties due to their T cell co-stimulatory, anti-angiogenic and/or anti-inflammatory effects. Based on such effects, a class of thalidomide analogs known as Immunomodulatory Drugs (IMiDs) have recently entered into phase I clinical trials for the treatment of a number of cancers. The lead IMiD CC-5013 (referred to clinically as REVIMID) is now entering phase III clinical trials for multiple myeloma and metastatic melanoma, while CC-4047 (ACTIMID) is currently under investigation in phase I/II and II trials for multiple myeloma and prostate cancer, respectively. The other group of compounds, classified as Selective Cytokine Inhibitory Drugs (SelCIDs), do not co-stimulate T cells, but have anti-inflammatory and anti-angiogenic properties. Moreover, a subset of SelCIDs has been found to possess direct anti-tumor activity both in vitro and in vivo. This minireview highlights the various mechanisms of action associated with these compounds and their subsequent clinical development. The enhanced efficacy and lower side-effect profiles of the analogs in comparison to thalidomide make the use of these agents very attractive as novel anti-cancer agents.

PMID: 12782937 [PubMed - indexed for MEDLINE]

Expert Opin Biol Ther. 2004 Dec;4(12):1963-70.

Thalidomide-derived immunomodulatory drugs as therapeutic agents.

Galustian C, Labarthe MC, Bartlett JB, Dalgleish AG.

St George's Hospital Medical School, Division of Oncology, Department of Cellular & Molecular Medicine, Cranmer Terrace, London, SW17 0RE, UK. cgalusti@sghms.ac.uk

Thalidomide, a drug originally used to treat morning sickness, was removed from the market place in the early 1960s after it was found to cause serious congenital birth defects. However, thalidomide has recently been investigated in a new light following its activity in a number of chronic diseases. Moreover, like thalidomide itself, its second-generation immunomodulatory drug (IMiD) analogues have been shown to act as powerful anticancer agents and are clearly active in the treatment of patients with relapsed multiple myeloma. These new drugs, in particular the second-generation IMiDs, lenalidomide (CC-5013, REVLIMID; Celgene Corp., NJ, USA) and CC-4047 (ACTIMID; Celgene Corp.), offer improvements over thalidomide (a first-generation IMiD) in terms of efficacy and safety in human studies. The key to the therapeutic potential of IMiDs lies in the fact that the drugs have multiple mechanisms of action, which may produce both anti-inflammatory and antitumour effects. These effects are probably contextual, depending both on the cell type and the stimulus involved. Mechanisms associated with IMiD activity include TNF-alpha-inhibitory, T cell costimulatory and antiangiogenic activities. Studies of the mechanisms of action of these drugs are ongoing and will facilitate the continued development of this class of compound in a number of diseases.

PMID: 15571458 [PubMed - in process]

Am J Trop Med Hyg. 2005 May;72(5):518-526. Related Articles, Links A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, CONTROLLED DOSE COMPARISON OF THALIDOMIDE FOR TREATMENT OF ERYTHEMA NODOSUM LEPROSUM. Villahermosa LG, Fajardo TT Jr, Abalos RM, Balagon MV, Tan EV, Cellona RV, Palmer JP, Wittes J, Thomas SD, Kook KA, Walsh GP, Walsh DS. Leonard Wood Memorial Center for Leprosy Research (American Leprosy Foundation) Cebu City, The Philippines; Statistics Collaborative, Inc., Washington, District of Columbia; Celgene Corporation, Warren, New Jersey; Salamandra, Inc., Bethesda, Maryland; Dermatology Service, Eisenhower Army Medical Center, Fort Gordon, Georgia. In a randomized, double-blind, double-dummy controlled study, 22 men with erythema nodosum leprosum (ENL) received six capsules containing either 100 mg (group A, n = 12) or 300 mg (group B, n = 10) of thalidomide daily for one week. A six-week, four capsules per day taper followed, in which group A received 50 mg/day of thalidomide in weeks 2 and 3, then dummy capsules in weeks 4 through 7, while group B had gradual decrements every two weeks. Both regimens caused comparable improvement in 19 patients at day 7 (group A [12 of 12] versus group B [7 of 10]; P = 0.08), but slower tapering in group B showed less re-emergence of ENL through week 7 (P = 0.02, versus group A). Most patients developed new lesions soon after stopping treatment. Slower tapering from a higher initial thalidomide dose may improve clinical ENL responses, but high recurrence rates after discontinuation indicates further assessment is needed to identify better tapering regimens. PMID: 15891124 [PubMed - as supplied by publisher]

Am J Trop Med Hyg. 2005 May;72(5):518-526.

A RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, CONTROLLED DOSE COMPARISON OF THALIDOMIDE FOR TREATMENT OF ERYTHEMA NODOSUM LEPROSUM.

Villahermosa LG, Fajardo TT Jr, Abalos RM, Balagon MV, Tan EV, Cellona RV, Palmer JP, Wittes J, Thomas SD, Kook KA, Walsh GP, Walsh DS.

Leonard Wood Memorial Center for Leprosy Research (American Leprosy Foundation) Cebu City, The Philippines; Statistics Collaborative, Inc., Washington, District of Columbia; Celgene Corporation, Warren, New Jersey; Salamandra, Inc., Bethesda, Maryland; Dermatology Service, Eisenhower Army Medical Center, Fort Gordon, Georgia.

In a randomized, double-blind, double-dummy controlled study, 22 men with erythema nodosum leprosum (ENL) received six capsules containing either 100 mg (group A, n = 12) or 300 mg (group B, n = 10) of thalidomide daily for one week. A six-week, four capsules per day taper followed, in which group A received 50 mg/day of thalidomide in weeks 2 and 3, then dummy capsules in weeks 4 through 7, while group B had gradual decrements every two weeks. Both regimens caused comparable improvement in 19 patients at day 7 (group A [12 of 12] versus group B [7 of 10]; P = 0.08), but slower tapering in group B showed less re-emergence of ENL through week 7 (P = 0.02, versus group A). Most patients developed new lesions soon after stopping treatment. Slower tapering from a higher initial thalidomide dose may improve clinical ENL responses, but high recurrence rates after discontinuation indicates further assessment is needed to identify better tapering regimens.

PMID: 15891124 [PubMed - as supplied by publisher]

Ann Intern Med. 1998 Mar 15;128(6):443-50.

Comment in:
Ann Intern Med. 1998 Mar 15;128(6):494-5.
Ann Intern Med. 1998 Nov 15;129(10):836.

Thalidomide in the treatment of the mucocutaneous lesions of the Behcet syndrome. A randomized, double-blind, placebo-controlled trial.

Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H.
Behcet's Syndrome Research Center, Cerrahpasa Medical Faculty, University of Istanbul, Turkey.

BACKGROUND: Recurrent oral and genital ulcers are the most frequent problem in the management of the Behcet syndrome. Uncontrolled experience suggests that thalidomide may help prevent recurrences of these ulcers.

OBJECTIVE: To determine the efficacy of two thalidomide dosages in the treatment of mucocutaneous lesions of the Behcet syndrome. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Specialist outpatient clinic for the Behcet syndrome in Turkey.

PATIENTS: 96 male patients with the Behcet syndrome who primarily had mucocutaneous lesions without major organ involvement.
INTERVENTION: Thalidomide, 100 mg/d or 300 mg/d, or placebo for 24 weeks.
MEASUREMENTS: Sustained absence of any oral and genital ulceration during treatment (complete response) and changes in the number of mucocutaneous lesions. An additional evaluation was done 4 weeks after treatment ended.

RESULTS: A complete response occurred in 2 of the 32 patients (6% [95% CI, 0.8% to 20.8%]) receiving thalidomide, 100 mg/d; in 5 of the 31 patients (16% [CI, 5.5% to 33.7%]) receiving thalidomide, 300 mg/d; and in none of the 32 patients (0% [CI, 0% to 10.9%]) receiving placebo (P = 0.031). The suppressive effect of thalidomide with either dosage was evident at 4 weeks for oral ulcers (P < 0.001) and at 8 weeks for genital ulcers (P < 0.001) and follicular lesions (P = 0.008). This effect persisted during treatment but diminished rapidly after treatment was discontinued. Both thalidomide dosages led to significant increases in the number of erythema nodosum lesions during the first 8 weeks of treatment (P = 0.03). Polyneuropathy developed in 4 patients (1 in the 100-mg/d group and 3 in the 300-mg/d group); in 3 of these patients, the condition was diagnosed after the trial had ended.

CONCLUSIONS: Thalidomide is effective for treating the oral and genital ulcers and follicular lesions of the Behcet syndrome. A dosage of 100 mg/d is as effective as a dosage of 300 mg/day.

Randomized Controlled Trial
PMID: 9499327 [PubMed - indexed for MEDLINE]


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