Carfilzomib

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Carfilzomib
	File:Carfilzomib.svg
Names
	IUPAC name (S)-4-Methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)pentanamide
	Other names PX-171-007
Identifiers
CAS Number	868540-17-4;
3D model (JSmol)	Interactive image;
ChEBI	CHEBI:65347 ;
ChEMBL	ChEMBL451887 ;
ChemSpider	9731489;
ECHA InfoCard	Lua error in Module:Wikidata at line 879: attempt to index field 'wikibase' (a nil value). Lua error in Module:Wikidata at line 879: attempt to index field 'wikibase' (a nil value).
KEGG	D08880 ;
PubChem CID	11556711;
	InChI InChI=1S/C40H57N5O7/c1-27(2)22-32(36(47)40(5)26-52-40)42-39(50)34(24-30-14-10-7-11-15-30)44-38(49)33(23-28(3)4)43-37(48)31(17-16-29-12-8-6-9-13-29)41-35(46)25-45-18-20-51-21-19-45/h6-15,27-28,31-34H,16-26H2,1-5H3,(H,41,46)(H,42,50)(H,43,48)(H,44,49)/t31-,32-,33-,34-,40+/m0/s1 Key: BLMPQMFVWMYDKT-NZTKNTHTSA-N; InChI=1/C40H57N5O7/c1-27(2)22-32(36(47)40(5)26-52-40)42-39(50)34(24-30-14-10-7-11-15-30)44-38(49)33(23-28(3)4)43-37(48)31(17-16-29-12-8-6-9-13-29)41-35(46)25-45-18-20-51-21-19-45/h6-15,27-28,31-34H,16-26H2,1-5H3,(H,41,46)(H,42,50)(H,43,48)(H,44,49)/t31-,32-,33-,34-,40+/m0/s1 Key: BLMPQMFVWMYDKT-NZTKNTHTBE;
	SMILES O=C(N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)[C@@]1(OC1)C)CC(C)C)Cc2ccccc2)CC(C)C)CCc3ccccc3)CN4CCOCC4;
Properties
Chemical formula	C40H57N5O7
Molar mass	719.92 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
	verify (what is ?)
	Infobox references

Template:Chembox E number

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Carfilzomib (CFZ) is a tetrapeptide epoxyketone and a selective proteasome inhibitor. It is an analog of epoxomicin.^[1]

Discovery, early development and regulatory approval

Carfilzomib is derived from epoxomicin, a natural product that was shown by the laboratory of Craig Crews at Yale University to inhibit the proteasome.^[2] The Crews laboratory subsequently invented a more specific derivative of epoxomicin named YU101,^[3] which was licensed to Proteolix, Inc.. Scientists at Proteolix modified YU101 to create carfilzomib, which they advanced to multiple Phase 1 and 2 clinical trials, including a pivotal Phase 2 clinical trial designed to seek accelerated approval. Clinical trials for carfilzomib continue under Onyx Pharmaceuticals, which acquired Proteolix in 2009. In January 2011, the U.S. FDA granted carfilzomib fast-track status, allowing Onyx to initiate a rolling submission of its new drug application for carfilzomib.^[4] In December 2011, the FDA granted Onyx standard review designation, ^[5]^[6] for its new drug application submission based on the 003-A1 study, an open-label, single-arm Phase 2b trial. The trial evaluated 266 heavily-pretreated patients with relapsed and refractory multiple myeloma who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide.^[7] Carfilzomib was approved by the FDA for use in patients with relapsed and refractory multiple myeloma on 20 July 2012.^[8] Onyx expects to launch the drug in the U.S. on 1 August 2012. When it launches, it will cost $10,000 per 28-day cycle, making it the most expensive FDA-approved drug for multiple myeloma.^[9]

Mechanism

Carfilzomib irreversibly binds to and inhibits the chymotrypsin-like activity of the 20S proteasome, an enzyme that degrades unwanted cellular proteins. Inhibition of proteasome-mediated proteolysis results in a build-up of polyubiquinated proteins, which may cause cell cycle arrest, apoptosis, and inhibition of tumor growth.^[1]

Clinical trials

A phase 2 trial for multiple myeloma showed promising results.^[10]^[11]

A single-arm, phase 2 trial of carfilzomib in patients with relapsed and refractory multiple myeloma showed that single-agent carfilzomib had durable responses in 36 percent of the 257 patients evaluated.^[12]^[13]

In another phase 2 trial of patients with relapsed and/or refractory multiple myeloma, carfilzomib in combination with lenalidomide and dexamethasone demonstrated an overall response rate of 78 percent. Researchers found carfilzomib could be administered over a period of 14–23 months with no new or overlapping toxicities.^[13]^[14]

In a phase 2 trial, carfilzomib had a 53 percent overall response rate among patients with relapsed and/or refractory multiple myeloma who had not previously received bortezomib. This study also found prolonged carfilzomib treatment is well-tolerated with approximately 22 percent of patients continuing treatment beyond one year.^[15]

In phase 2 trials of carfilzomib, the most common grade 3 or higher treatment-emergent adverse events were thrombocytopenia, anemia, lymphoenia, neutropenia, pneumonia, fatigue and hyponatremia.^[16]

A phase 3 trial comparing carfilzomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone in patients with relapsed multiple myeloma is ongoing.^[17]

In a frontline phase 1/2 study, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone was highly active and well tolerated, permitting the use of full doses for an extended time in newly-diagnosed multiple myeloma patients, with limited need for dose modification. Responses were rapid and improved over time, reaching 100% very good partial response.^[18]

References

↑ ^1.0 ^1.1 Carfilzomib, NCI Drug Dictionary
↑ Meng, L (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". Proc Natl Acad Sci USA. 96 (18): 10403–8. PMID 10468620. Unknown parameter |coauthors= ignored (help)
↑ Myung, J (2001). "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors". Mol Cell. 7 (2): 411–20. PMID 11239469. Unknown parameter |coauthors= ignored (help)
↑ "Onyx multiple myeloma drug wins FDA fast-track status". San Francisco Business Times. 2011-01-31. Retrieved 2011-09-01.
↑ "Beacon Breaking News – Carfilzomib to Get Standard, Not Priority, FDA Review". The Myeloma Beacon. Retrieved 2012-02-27.
↑ "Fast Track, Accelerated Approval and Priority Review; Accelerating Availability of New Drugs for Patients with Serious Diseases". FDA. Retrieved 2012-02-27.
↑ "PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis". ASCO 2009. Unknown parameter |http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview= ignored (help); Missing or empty |url= (help); |access-date= requires |url= (help)
↑ "FDA approves Kyprolis for some patients with multiple myeloma". U.S. Food and Drug Administration.
↑ "FDA Approves Kyprolis (Carfilzomib) For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2012-07-20.
↑ Onyx Says Carfilzomib Results Promising, Drug Discovery & Development, July 27, 2010
↑ "Phase II results of Study PX-171-007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors" - ASCO 2009; Abstract 3515.
↑ "ASCO Showcasing Bay Area Cancer Therapies". San Francisco Business Times. 2011-06-02. Retrieved 2011-09-01.
↑ ^13.0 ^13.1 "PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis". ASCO 2011; Abstract 8027. 2011. Retrieved 2011-09-01.
↑ "Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM)". ASCO 2011; Abstract 8025. 2011. Retrieved 2011-09-01.
↑ "The effect of carfilzomib (CFZ) in patients (Pts) with bortezomib (BTZ)-naive relapsed or refractory multiple myeloma (MM): Updated results from the PX-171-004 study". ASCO 2011; Abstract 8026. 2011. Retrieved 2011-09-01.
↑ "Siegel DS, Martin T, Wang, M, et al. Results of PX-171- 003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida". OncLive.com. 2011-03-09. Retrieved 2011-09-01.
↑ "Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Versus Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma". ClinicalTrials.gov. 2011-08-04. Retrieved 2011-09-01.
↑ "Final Results of a Frontline Phase 1/2 Study of Carfilzomib Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)". ASH 20111; Abstract 631. Retrieved 2012-02-27.

[dd-1] 1.0 ^1.1 Carfilzomib, NCI Drug Dictionary

[2] Meng, L (1999). "Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity". Proc Natl Acad Sci USA. 96 (18): 10403–8. PMID 10468620. Unknown parameter |coauthors= ignored (help)

[3] Myung, J (2001). "Lack of proteasome active site allostery as revealed by subunit-specific inhibitors". Mol Cell. 7 (2): 411–20. PMID 11239469. Unknown parameter |coauthors= ignored (help)

[4] "Onyx multiple myeloma drug wins FDA fast-track status". San Francisco Business Times. 2011-01-31. Retrieved 2011-09-01.

[dd1-5] "Beacon Breaking News – Carfilzomib to Get Standard, Not Priority, FDA Review". The Myeloma Beacon. Retrieved 2012-02-27.

[6] "Fast Track, Accelerated Approval and Priority Review; Accelerating Availability of New Drugs for Patients with Serious Diseases". FDA. Retrieved 2012-02-27.

[7] "PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis". ASCO 2009. Unknown parameter |http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview= ignored (help); Missing or empty |url= (help); |access-date= requires |url= (help)

[8] "FDA approves Kyprolis for some patients with multiple myeloma". U.S. Food and Drug Administration.

[9] "FDA Approves Kyprolis (Carfilzomib) For Relapsed And Refractory Multiple Myeloma". The Myeloma Beacon. Retrieved 2012-07-20.

[10] Onyx Says Carfilzomib Results Promising, Drug Discovery & Development, July 27, 2010

[11] "Phase II results of Study PX-171-007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors" - ASCO 2009; Abstract 3515.

[12] "ASCO Showcasing Bay Area Cancer Therapies". San Francisco Business Times. 2011-06-02. Retrieved 2011-09-01.

[ASCO_2011;_Abstract_8027-13] 13.0 ^13.1 "PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis". ASCO 2011; Abstract 8027. 2011. Retrieved 2011-09-01.

[14] "Interim results from PX-171-006, a phase (Ph) II multicenter dose-expansion study of carfilzomib (CFZ), lenalidomide (LEN), and low-dose dexamethasone (loDex) in relapsed and/or refractory multiple myeloma (R/R MM)". ASCO 2011; Abstract 8025. 2011. Retrieved 2011-09-01.

[15] "The effect of carfilzomib (CFZ) in patients (Pts) with bortezomib (BTZ)-naive relapsed or refractory multiple myeloma (MM): Updated results from the PX-171-004 study". ASCO 2011; Abstract 8026. 2011. Retrieved 2011-09-01.

[16] "Siegel DS, Martin T, Wang, M, et al. Results of PX-171- 003-A1, an open-label, single-arm, phase 2 study of carfilzomib in patients with relapsed and refractory multiple myeloma. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida". OncLive.com. 2011-03-09. Retrieved 2011-09-01.

[17] "Phase 3 Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Versus Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma". ClinicalTrials.gov. 2011-08-04. Retrieved 2011-09-01.

[18] "Final Results of a Frontline Phase 1/2 Study of Carfilzomib Lenalidomide, and Low-Dose Dexamethasone (CRd) in Multiple Myeloma (MM)". ASH 20111; Abstract 631. Retrieved 2012-02-27.

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