2016
A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma
Holkova B, Zingone A, Kmieciak M, Bose P, Badros AZ, Voorhees PM, Baz R, Korde N, Lin HY, Chen JQ, Herrmann M, Xi L, Raffeld M, Zhao X, Wan W, Tombes MB, Shrader E, Weir-Wiggins C, Sankala H, Hogan KT, Doyle A, Annunziata CM, Wellons M, Roberts JD, Sullivan D, Landgren O, Grant S. A Phase II Trial of AZD6244 (Selumetinib, ARRY-142886), an Oral MEK1/2 Inhibitor, in Relapsed/Refractory Multiple Myeloma. Clinical Cancer Research 2016, 22: 1067-1075. PMID: 26446942, PMCID: PMC4775365, DOI: 10.1158/1078-0432.ccr-15-1076.Peer-Reviewed Original ResearchConceptsRefractory multiple myelomaPartial responseMultiple myelomaRelapsed/Refractory Multiple MyelomaMedian progression-free survival timeResponse rateProgression-free survival timeTwo-stage Simon designCommon grade 3Good partial responsePhase II studyPhase II trialMEK1/2 inhibitorSignificant preclinical activityMultiple myeloma cellsPrior therapyStable diseaseII trialClinical responseII studyProgressive diseaseMedian ageMean durationPreclinical activityDisease progression
2014
Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms
Holkova B, Kmieciak M, Perkins EB, Bose P, Baz RC, Roodman GD, Stuart RK, Ramakrishnan V, Wan W, Peer CJ, Dawson J, Kang L, Honeycutt C, Tombes MB, Shrader E, Weir-Wiggins C, Wellons M, Sankala H, Hogan KT, Colevas AD, Doyle LA, Figg WD, Coppola D, Roberts JD, Sullivan D, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and “Nonhybrid” (Bolus) Infusion Schedule of Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-cell Neoplasms. Clinical Cancer Research 2014, 20: 5652-5662. PMID: 25248382, PMCID: PMC4233160, DOI: 10.1158/1078-0432.ccr-14-0805.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityCombination of bortezomibCommon hematologic toxicityCommon nonhematologic toxicitiesIndolent B-cell neoplasmsRefractory multiple myelomaDose-escalation designNon-Hodgkin lymphomaTotal response rateB-cell malignanciesB-cell neoplasmsPharmacodynamic study resultsNonhematologic toxicitySchedule regimenStable diseaseComplete remissionHematologic toxicityPartial remissionClinical responseInvestigator's discretionDosing regimenI trialPharmacokinetic findingsSensory neuropathyInfusion schedule
2012
Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib.
Holkova B, Perkins E, Bose P, Sullivan D, Baz R, Tombes M, Shrader E, Ramakrishnan V, Wan W, Sankala H, Kmieciak M, Roberts J, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib. Blood 2012, 120: 2959. DOI: 10.1182/blood.v120.21.2959.2959.Peer-Reviewed Original ResearchAdverse eventsInfusion scheduleMultiple myelomaI trialDose levelsAbsolute neutrophil count decreaseGrade 2 adverse eventsCTCAE version 4Grade 5 eventsIndolent B-cell neoplasmsNeutrophil count decreasePrior systemic therapyPhase II studyECOG performance scoreRefractory multiple myelomaTreatment of recurrentTumor lysis syndromePhase I trialSchedule of administrationCombination of bortezomibIndolent B-cellExpression of pJNKB-cell neoplasmsNF-κB DNA bindingMcl-1
2011
A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma
Holkova B, Badros A, Geller R, Voorhees P, Zingone A, Korde N, Lin H, Tombes M, Shrader E, Sankala H, Kmieciak M, Roberts J, Sullivan D, Landgren O, Grant S. A Phase II Study of the MEK 1/2 Inhibitor AZD6244 (Selumetinib, ARRY-142866) in Relapsed or Refractory Multiple Myeloma. Blood 2011, 118: 2931. DOI: 10.1182/blood.v118.21.2931.2931.Peer-Reviewed Original ResearchPhase II studyAspartate aminotransferaseRefractory MMII studyCommon treatment-related adverse eventsPresent phase II studyTreatment-related adverse eventsTwo-stage Simon designAcute kidney injuryCommon grade 3Objective partial responsePeripheral sensory neuropathyECOG performance scoreRefractory multiple myelomaFavorable clinical profilePre-clinical activityResponse/resistanceEffects of AZD6244Multiple myeloma cellsCompetitive small molecule inhibitorBone marrow microenvironmentPost-treatment expressionOrtho BiotechPrior regimensStable diseasePhase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms
Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D, Kang L, Dawson J, Stuart RK, Peer C, Figg WD, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S. Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory B-Cell Neoplasms. Clinical Cancer Research 2011, 17: 3388-3397. PMID: 21447728, PMCID: PMC3096752, DOI: 10.1158/1078-0432.ccr-10-2876.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityCombination of bortezomibFebrile neutropeniaPharmacodynamic studiesDay 1Refractory B-cell neoplasmsElevated aspartate aminotransferase levelsCommon hematologic toxicityCommon nonhematologic toxicitiesPhase II studyRefractory multiple myelomaPhase I studiesAspartate aminotransferase levelsB-cell malignanciesB-cell neoplasmsHematologic toxicityIntravenous pushNonhematologic toxicityStable diseaseAminotransferase levelsI trialII studyPartial responseComplete responseDose escalation