FEATURES
Continued from page 9
Then , in February 2016 , the FDA pulled the investigational new drug application for pacritinib , halting the ongoing PER- SIST trials . In their decision letter , the agency noted that the interim OS results generated from the unblinded PERSIST-2 data suggested a detrimental effect on survival for patients treated with pacritinib , consistent with the results of PERSIST-1 . There also was excess mortality among patients who crossed over to the pacritinib arm . The deaths in PERSIST-2 in pacritinibtreated patients were due to intracranial hemorrhage , cardiac failure , and cardiac arrest . 15
The FDA hold was subsequently lifted in January 2017 , after the drug ’ s manufacturer , CTI BioPharma , conducted additional dose-exploration studies and failed to find a significant increase in risk of these complications among pacritinib-exposed patients . In May 2017 , the company initiated the PAC203 trial , a dose-finding study looking for the optimal dose to balance pacritinib ’ s safety and efficacy among patients with primary MF whose disease has failed to respond to ruxolitinib .
Momelotinib Momelotinib , another JAK1 / 2 inhibitor , has been studied as an alternative to ruxolitinib in the SIMPLIFY clinical trials , but these studies have also produced complicated results .
In the phase III SIMPLIFY-1 trial , momelotinib was noninferior to ruxolitinib in splenic volume reduction and superior in reducing rates of transfusion-dependency for MF-associated anemia . However , it failed to improve disease-associated symptoms , compared with ruxolitinib . 16
In the phase III SIMPLIFY-2 trial , momelotinib again failed to improve rates of splenic response , this time compared with best available therapy in patients previously treated with ruxolitinib . 17 But , Dr . Gerds noted , patients did show an improvement in both spleen volume and symptoms , even if the results were not statistically significant . Additionally , some patients who were dependent on blood transfusions no longer required them , which is an important improvement for quality of life , but was not one of the trial ’ s endpoints .
For Dr . Harrison , results from the momelotinib trials underscore how difficult it is to improve on the ruxolitinib-induced symptom response in patients with MPNs . The approval of ruxolitinib , she said , “ has drastically changed the management of these disorders .”
Moving Beyond Symptom Improvement ? Given the recent equivocal trial results with the newer JAK inhibitors , many clinicians treating MPNs agree that clinical trials should incorporate additional trial endpoints beyond symptom improvement .
For example , the pivotal ruxolitinib trials set a primary endpoint precedent of at least a 50 percent improvement in symptom burden and at least a 35 percent reduction in splenic volume . “ These are arbitrary endpoints ,” Dr . Gerds argued . “ Symptom reduction is on a continuum . A patient who experiences a 49 percent reduction in his or her symptoms is clearly benefiting from treatment with a study drug , but not based on the bar set by the ruxolitinib clinical trials .”
According to Dr . Gerds , the MPN clinical community has to come together to help define endpoints that are meaningful to their patients and take the biology of MPN into account . “ Alleviating symptom burden is not always the same as improving quality of life ,” he added .
Getting to this point will require a better understanding of the pathophysiology underlying MPN . While other agents are also in development for MPN , “ we are always looking for better ways to treat our patients , and JAK inhibitors remain a touchstone of care ,” he added . — By Anna Azvolinsky ●
REFERENCES
1 . Vainchenker W , Delhommeau F , Constantinescu SN , et al . New mutations and pathogenesis of myeloproliferative neoplasms . Blood . 2011 ; 118:1723-35 .
2 . James C , Ugo V , Le Couedic JP , et al . A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera . Nature . 2005 ; 434:1144-8 .
3 . Baxter EJ , Scott LM , Campbell PJ , et al . Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders . Lancet . 2005 ; 365:1054-61 .
4 . Kralovics R , Passamonti F , Buser AS , et al . A gain-of-function mutation of JAK2 in myeloproliferative disorders . N Engl J Med . 2005 ; 352:1779-90 .
5 . Levine RL , Wadleigh M , Cools J , et al . Activating mutation in the tyrosine kinase JAK2 in polycythemia vera , essential thrombocythemia , and myeloid metaplasia with myelofibrosis . Cancer Cell . 2005 ; 7:387-97 .
6 . Verstovsek S , Mesa RA , Gotlib J , et al . A double-blind , placebo-controlled trial of ruxolitinib for myelofibrosis . N Engl J Med . 2012 ; 366:799-807 .
7 . Harrison CN , Kiladjian J , Al-Ali HK , et al . JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis . N Engl J Med . 2012 ; 366:787-98 .
8 . Verstovsek S , Mesa RA , Gotlib J , et al . Long-term treatment with ruxolitinib for patients with myelofibrosis : 5-year update from the randomized , double-blind , placebo-controlled , phase 3 COMFORT-I trial . J Hematol Oncol . 2017 ; 10:55 .
9 . Pardanani A , Harrison CN , Cortes JE , et al . Results of a randomized , double-blind , placebo-controlled phase III study ( JAKARTA ) of the JAK2-selective inhibitor fedratinib ( SAR302503 ) in patients with myelofibrosis ( MF ). Blood . 2013 ; 122:393 .
10 . Harrison CN , Schaap N , Vannucchi AM , et al . Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib ( JAKARTA-2 ): a single-arm , open-label , non-randomised , phase 2 , multicentre study . Lancet Haematol . 2017 ; 4 : e317-24 .
11 . Harrison CN , Mesa RA , Jamieson C , et al . Case series of potential Wernicke ’ s encephalopathy in patients treated with fedratinib . Abstract # 4197 . Presented at the 2017 ASH Annual Meeting , December 11 , 2017 ; Atlanta .
12 . Celgene . “ Celgene to acquire Impact Biomedicines , adding fedratinib to its pipeline of novel therapies for hematologic malignancies .” Accessed April 5 , 2018 , from http :// ir . celgene . com / releasedetail . cfm ? releaseid = 1053509 .
13 . Mesa RA , Vannucchi AM , Mead A , et al . Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias ( PERSIST-1 ): an international , randomised , phase 3 trial . Lancet Haematol . 2017 ; 4 : e225-36 .
14 . Mascarenhas J , Hoffman R , Talpaz M , et al . Results of the Persist – 2 phase 3 study of pacritinib ( PAC ) versus best available therapy ( BAT ), including ruxolitinib ( RUX ), in patients ( pts ) with myelofibrosis ( MF ) and platelet counts < 100,000 /µ l . Abstract LBA-5 . Presented at the 2016 ASH Annual Meeting , December 6 , 2016 ; San Diego .
15 . CTI BioPharma . “ CTI BioPharma provides update on clinical hold of investigational agent pacritinib and new drug application in U . S .” Accessed April 5 , 2018 , from https :// www . prnewswire . com / news-releases / cti-biopharma-provides-updateon-clinical-hold-of-investigational-agent-pacritinib-and-new-drug-applicationin-us-300217839 . html .
16 . Mesa RA , Kiladjian J , Catalano JV , et al . SIMPLIFY-1 : a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitor – naïve patients with myelofibrosis . J Clin Oncol . 2017 ; 35:3844-50 .
17 . Harrison CN , Vannucchi AM , Platzbecker U , et al . Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib ( SIMPLIFY 2 ): a randomised , open-label , phase 3 trial . Lancet Haematol . 2018 ; 5 : e73-81 .
14 Focus on Myeloid Malignancies