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INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent. ispartof: Journal of Thoracic Oncology vol:15 issue:3 pages:392-403 ispartof: location:United States status: published

Purpose Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug–drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively. Methods This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily. Results Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC. Conclusion Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

Introduction Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure. Methods ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients. Results As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities. Conclusion Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC.

Background: Therapy options for pts with HR-MDS or AML who are not candidates for intensive chemotherapy (IC) or hematopoietic stem cell transplantation (HSCT) are limited, and clinical outcomes are poor. Novel, effective and tolerable therapies are urgently needed. TIM-3 is an inhibitory receptor that regulates both adaptive and innate immune responses. It is expressed on immune cells and on leukemic stem cells (LSCs) and blasts, but not on normal hematopoietic stem cells, making it a promising target in MDS and AML. Sabatolimab is a high-affinity, humanized, anti-TIM-3 IgG4 (S228P) antibody that simultaneously targets TIM-3 on immune and myeloid cells; this may restore immune function while also directly targeting LSCs and blasts. In preclinical studies, sabatolimab enhanced immune cell-mediated killing of AML cells in vitro. In early results from a ph 1b study (NCT03066648), sabatolimab + hypomethylating agents (HMAs; decitabine [Dec] or azacitidine [Aza]) demonstrated encouraging overall response rates in pts with high-/very high-risk MDS (+ Dec, 61%; + Aza, 57%) and newly diagnosed AML (+ Dec, 47%; + Aza, 29%), and a favorable safety profile. Study Design and Methods: The STIMULUS clinical trial program currently includes 3 trials evaluating the efficacy and safety of sabatolimab combination therapy in pts with HR-MDS or AML who are ineligible for IC or HSCT: STIMULUS-MDS1 (NCT03946670; ph 2) in pts with HR-MDS, STIMULUS-MDS2 (NCT04266301; ph 3) in pts with HR-MDS or chronic myelomonocytic leukemia-2 (CMML-2), and STIMULUS-AML1 (NCT04150029; ph 2) in pts with AML. STIMULUS-MDS1 is a randomized, double-blind, placebo-controlled ph 2 study evaluating the addition of sabatolimab to HMA in pts with HR-MDS. The 2 primary endpoints are complete remission (CR) rate and/or progression-free survival. Secondary endpoints include overall survival (OS), event-free survival (EFS), leukemia-free survival, duration of CR, transfusion independence, safety, pharmacokinetics (PK), and immunogenicity. Approximately 120 pts will be randomized 1:1 to receive sabatolimab 400 mg or placebo IV Q2W (D8 and D22 of each 28-d cycle), + Dec 20 mg/m2 IV on D1-D5 or Aza 75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9, of each 28-d cycle. STIMULUS-MDS2 is a randomized, double-blind, placebo-controlled ph 3 study of sabatolimab in combination with Aza in pts with HR-MDS or CMML-2; the primary endpoint is OS. Secondary endpoints include measures related to pt quality of life, such as time to definitive deterioration of fatigue, improvement of fatigue, transfusion-free intervals, and physical/emotional functioning, as well as additional efficacy and safety parameters. Approximately 500 pts will be randomized 1:1 to sabatolimab 800 mg or placebo IV Q4W at D8 of each 28-d cycle + Aza using the same Aza dosing schedule as in STIMULUS-MDS1. Eligible pts for STIMULUS-MDS1 or -MDS2 are treatment-naïve adults with HR-MDS (Revised International Prognostic Scoring System [IPSS-R] intermediate-/high-/very high-risk MDS). Pts with intermediate-risk MDS enrolling in STIMULUS-MDS1 are also required to have ≥5% bone marrow blasts at baseline. Pts with CMML-2 are eligible for STIMULUS-MDS2 only. STIMULUS-AML1 is a single-arm ph 2 study evaluating the safety and efficacy of sabatolimab in combination with Aza and venetoclax in pts with AML who are not candidates for IC or HSCT. Primary endpoints are incidence of dose-limiting toxicities (safety run-in) and CR rate. Secondary endpoints include safety and tolerability, CR/CRi rate, measurable residual disease-negative rate, durability of CR, relapse-free survival, EFS, OS, PK, transfusion independence, and immunogenicity. Eligible pts for STIMULUS-AML1 are adults with newly diagnosed AML who are not candidates for IC or HSCT, based on comorbidities (including renal and hepatic impairments, cardiac and pulmonary comorbidities), age (≥75 years old), or Eastern Cooperative Oncology Group performance status of 2 or 3. STIMULUS-AML1 will enroll approximately 86 pts. Part 1 consists of a safety run-in (≈18 pts) across 2 escalating sabatolimab dose levels (400/800 mg IV Q4W on D8 of each 28-d cycle) in combination with Aza (75 mg/m2 IV/SC on D1-D7, or D1-D5 + D8 and D9) and venetoclax 400 mg PO QD. If this triple combination is assessed to be safe, part 2 (expansion) will open and enroll approximately 68 additional pts who will receive sabatolimab 800 mg Q4W in combination with Aza and venetoclax. Disclosures Zeidan: Incyte: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Celgene / BMS: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CCITLA: Other; Taiho: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Leukemia and Lymphoma Society: Other; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; BeyondSpring: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; ADC Therapeutics: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kim:SL VaxiGen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AML Global Portal: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Yuhan: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; BL&H: Research Funding; Sanofi Genzyme: Honoraria; Abbvie: Honoraria. Miyazaki:Novartis Pharma KK: Honoraria; NIPPON SHINYAKU CO.,LTD.: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria. Platzbecker:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Malek:Novartis: Current Employment. Scott:Novartis: Current Employment. Niolat:Novartis: Current Employment. Peyrard:Novartis: Current Employment. Ma:Novartis: Current Employment. Kiertsman:Novartis: Current Employment. Stegert:Novartis AG: Current Employment, Current equity holder in publicly-traded company. Hertle:Novartis Pharma AG: Current Employment, Current equity holder in publicly-traded company. Fenaux:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Santini:Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Novartis: Consultancy, Honoraria; Acceleron: Consultancy; Takeda: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria.

Ceritinib is a potent inhibitor of anaplastic lymphoma kinase (ALK), which has shown acceptable safety and substantial antitumor activity in ALK-positive non-small cell lung cancer (NSCLC) patients. Two food-effect studies were conducted in healthy adults to investigate the influence of food on the oral bioavailability of ceritinib: a study with low- or high-fat meals at 500 mg and a study with a light snack at 750 mg. Compared with the fasted state, AUC0-∞ (90%CI) of ceritinib was increased by 58% (34%, 86%) after the intake of a low-fat meal, by 73% (46%, 105%) after the intake of a high-fat meal, and by 54% (19%, 99%) after the intake of a light snack. Safety assessments also suggested that food may improve gastrointestinal (GI) tolerability after a single ceritinib dose. Based on the pharmacokinetic results, it is essential to avoid any type of meal during dosing of ceritinib because the intake of food may increase the occurrence of exposure-dependent, non-GI toxicities at the labeled dose of 750 mg daily during fasting. A randomized trial is ongoing to determine an alternative way to give ceritinib (450 mg or 600 mg with food) that may enhance GI tolerability in ALK-positive NSCLC patients.

Objectives Approximately 15% of patients with multiple myeloma (MM) exhibit a t(4;14) translocation, which often results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). This study evaluated the efficacy and safety of dovitinib, an RTK inhibitor with in vitro inhibitory activity against FGFR, in patients with relapsed or refractory MM with or without t(4;14) translocation. Methods Adult patients with relapsed or refractory MM who had received ≥2 prior regimens were enrolled in this multicenter, 2-stage, phase 2 trial. Patients were grouped based on their t(4;14) status. Dovitinib (500 mg/day orally) was administered on a 5-days-on/2-days-off schedule. The primary endpoint was overall response rate by local investigator review (per International Myeloma Working Group criteria). In non-responding patients, treatment could continue with the addition of low-dose dexamethasone. Results In total, 43 patients (median age, 63 years) were enrolled (13 t(4;14) positive, 26 t(4;14) negative, and 4 t(4;14) status non-interpretable). Patients had received a median of 5 prior regimens. Median duration of treatment was 8.7 weeks in the t(4;14)-positive group and 3.7 weeks in the t(4;14)-negative group. None of the patients on dovitinib had objective responses. The stable disease rate was 61.5% in the t(4;14)-positive group and 34.6% in the t(4;14)-negative group. Overall, 39 patients (90.7%) had adverse events suspected to be related to study drug, most commonly diarrhea (60.5%), nausea (58.1%), vomiting (46.5%), and fatigue (32.6%). Conclusion Dovitinib showed no single-agent activity in relapsed or refractory MM but may stabilize disease in some t(4;14)-positive patients.

The impact of proton pump inhibitors (PPIs) on the pharmacokinetics (PK) and efficacy of ceritinib was evaluated. A healthy subject drug–drug interaction (DDI) study was conducted to assess the effect of esomeprazole on the PK of a single 750 mg dose of ceritinib. To further investigate the impact of PPIs on the PK and efficacy of ceritinib in ALK-positive cancer patients, two subgroup analyses were performed. Analysis 1 evaluated ceritinib steady-state trough concentration (Ctrough,ss) and overall response rate (ORR) by concomitant use of PPIs in patients from the ASCEND-1, -2, and -3 studies; analysis 2 evaluated ceritinib single-dose and steady-state AUC0–24h and C max by concomitant PPI use in patients from ASCEND-1 using a definition of PPI usage similar to that used in the healthy subject study. In the healthy subject study, co-administration of a single 750 mg dose of ceritinib with esomeprazole 40 mg for 6 days decreased ceritinib AUC0–∞ by 76% and C max by 79%. However, based on subgroup analysis 1, patients had similar C trough,ss and ORR regardless of concomitant PPI usage. Based on analysis 2, co-administration of a single 750 mg ceritinib dose with PPIs for 6 days in patients suggested less effect on ceritinib exposure than that observed in healthy subjects as AUC0–24h decreased by 30% and C max decreased by 25%. No clinically meaningful effect on steady-state exposure was observed after daily dosing. Long-term administration of ceritinib with PPIs does not adversely affect the PK and efficacy of ceritinib in ALK-positive cancer patients.

This 2-arm, phase 1, crossover study compared the relative bioavailability of two dovitinib (TKI258) capsule formulations [anhydrate clinical service form (CSF) and monohydrate final market image (FMI); Arm 1] and determined the effect of food on dovitinib exposure (Arm 2). Patients with advanced solid tumors were enrolled in one of the 2 arms. Arm 1 randomized patients to a single 500-mg dose of either CSF or FMI followed by 7 days of rest and 500 mg of the other formulation. Arm 2 patients received 300 mg of FMI once daily and were randomized to follow one of six meal sequences, each with three prandial conditions: low fat (LF), high fat (HF), or no meal (NM). Twenty-three and 37 patients were enrolled and 19 and 21 were evaluable in Arms 1 and 2, respectively. In Arm 1, the adjusted geometric means for FMI had small reductions relative to CSF [area under the plasma concentration–time curve (AUClast) decreased by 12 %, maximum concentration (C max) decreased by 3 %]. In Arm 2, the HF meal versus NM showed a 2 % increase in the adjusted geometric mean for AUClast and a 5 % decrease for C max. The LF meal versus NM comparison showed 9 and 6 % increases for AUClast and C max, respectively. Overall, common adverse events included nausea, vomiting, diarrhea, and fatigue. Systemic exposure to dovitinib was similar for the FMI and CSF capsule formulations. Additionally, since prandial conditions did not affect the systemic exposure, dovitinib can be taken with or without food.

A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer. In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase. A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUClast, 0.95 (90 % CI 0.88–1.01); C max, 0.98 (90 % CI 0.91–1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients. Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.

AML progenitor cells (AML-PC) undergo significant apoptosis in response to the deacetylase inhibitor (DACi) LAQ824 and lose the replating capacity which was not observed with the DACi valproic acid. Treatment of normal hematopoietic progenitor cells (HPC) with LAQ824 resulted in (i) inhibition of differentiation, (ii) an G2/M cell cycle arrest exclusively in multipotent CD34 + HPC and (iii) induction of apoptosis predominantly in committed CD34 − HPC. Gene expression analysis showed induction of coactivator and target genes of the notch pathway as well as cell cycle arrest-inducing genes in the most primitive CD34 + CD38 − HPC population which may in part be responsible for the considerable, but reversible haematotoxicity of this drug.

Summary There are few treatment options for patients with Hodgkin Lymphoma (HL) who relapse after conventional therapies. Panobinostat is an orally available pan deacetylase inhibitor with evidence of activity in myeloid malignancies and cutaneous T cell lymphoma. Thirteen HL patients were treated with escalating doses of this novel agent in a phase IA/II multicentre study. A computed tomography partial response was achieved in 5/13(38%), and a metabolic response by 18 F-fluoro-2-deoxy-d- glucose positron emission tomography scanning in 7/12 (58%) evaluable patients. This report describes the preliminary evidence of anti-tumour activity seen in the early phase of this study, which recently closed to accrual.

This 2-arm crossover study compared the relative bioavailability of two dovitinib (TKI258) formulations [anhydrate clinical service form (CSF) capsule and monohydrate final market image (FMI) tablet; Arm 1] and determined the effect of food on dovitinib exposure (Arm 2).Patients with advanced solid tumors, excluding breast cancer, were enrolled in 1 of the 2 arms of the study. Patients in Arm 1 were randomized to a single 500-mg dose of CSF capsule or FMI tablet followed by 7 days of rest and 500 mg of the other formulation. Patients in Arm 2 received 300 mg of FMI tablet daily and were randomized to follow 1 of 6 meal sequences, each with 3 prandial conditions: low fat (LF), high fat (HF), or no meal (NM).In Arm 1 (n = 21), 17 patients were evaluable. FMI tablet compared with CSF capsule showed only slight reductions in the adjusted geometric means for area under the plasma concentration-time curve (AUClast; 3%) and maximum plasma concentration (C max; 1%). In Arm 2 (n = 42), 19 patients were evaluable. HF meal versus NM showed a 9% decrease in the adjusted geometric mean for AUClast and an 18% decrease for C max. Comparison of LF meal versus NM showed a 1% decrease for AUClast and a 10% decrease for C max. Common adverse events suspected to be study drug related included vomiting, diarrhea, nausea, and fatigue.Dovitinib FMI tablet had similar systemic exposure to the CSF capsule and was not affected by food.

Purpose We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 +/- capecitabine. Experimental design Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors. Results In Arm1 (n = 40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 +/- capecitabine at saturation of clearance (a parts per thousand yen10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses. Conclusions LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 +/- capecitabine was defined. Clearance was saturated at doses a parts per thousand yen10 mg/kg.

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.

To the Editor: We read with interest Dawn Holcombe's recent article in Journal of Oncology Practice/The American Journal of Managed Care joint issue, entitled “Oncology Managed Programs for Payers and Physicians: Evaluating Current Models and Diagnosing Successful Strategies for Payers and Physicians.”1 As oncologists and others in the industry increasingly turn to Journal of Oncology Practice as a source for impartial and accurate information about new approaches to cancer care, we wanted to take the opportunity to offer additional perspective on what we see as some factual inaccuracies in that article. First, the article identifies nine models for oncology management and generally paints a picture of these nine models as being separate and distinct. From our viewpoint, cancer care pathway concepts are evolving very quickly, and few of the cancer care pathways programs that are currently in operation fall neatly into any one of the nine models outlined in the article. Most of the pathways programs that we lead, for example, are a hybrid of many of the different models identified in the article. Second, as the article reviewed the approaches of various clinical pathways models, it made a number of incorrect assertions. For example, the article incorrectly stated that the pathways model used by P4 Healthcare (Dublin, OH; acquired by Cardinal Health in June 2010) “does not address any aspect of oncology care other than drugs,” “[focuses] solely on the price of drugs,” and operates “without direct medical insight into the individual patient's medical situation and disease.”1(pe46s) The article also incorrectly stated that the P4 pathways model is creating “potential for adverse/unintended consequences that affect patient care or efficacy of the drug combinations” and that “physicians are not involved in this model.”1(pe46s) Because we have both personally helped develop P4's approach to pathways development, we can confirm that each of these assertions is untrue. The P4 pathways model is, by definition, highly collaborative and intimately involves physicians. Steering committees composed of physicians within each payer network actually lead the development of the pathways they'll be expected to follow. Every one of our pathways programs also begins with a clear mandate that physicians have ultimate control of treatment decisions at the point of care. To further ensure physician control, neither P4 pathways medical directors nor payer representatives are permitted voting rights when determining pathways. Only steering committee physicians are extended that right. We believe it's impossible for 100% of patients to be cared for using a limited set of treatment protocols. That's why the P4 pathways model expressly provides room for individualized medicine and physician discretion. We set compliance goals, but in all cases, the physician has ultimate control of treatment decisions at the point of care. For example, we generally expect physicians to be pathways compliant at least 70 percent of the time in year 1 and at least 80 percent in year 2, recognizing that doctors have the direct medical insight into each patient's medical situation and need flexibility to alter treatment regimens to suit unique patient needs. To date, physician compliance in each of our pathways programs has exceeded these goals, which we view as further evidence that this approach is working for physicians and patients alike. The article also referenced a relationship between P4 pathways and one of our payer customers as an example of a payer drug cost reduction program that has shown “cracks and problems.”1(pe46s) On the contrary, the cancer care pathways program to which Ms Holcombe alluded is not only our most mature pathways program, it is also a very successful program. We presented a poster at the 2010 ASCO annual meeting2 regarding the program's success in improving both patient outcomes and reducing cancer costs, not only through reductions in drug costs, but also through patient quality improvements, such as reduced visits to the emergency room. Finally, although this article primarily characterized the P4 pathways model as a drug management model, we believe that points made earlier in this letter illustrate that our model is most closely aligned to fit within the disease management model outlined by the author. In summary, we agree that since P4 Healthcare launched the nation's first cancer care pathways program in 2008, the market has seen a number of new entrants, and new models for leveraging clinical guidelines to improve the quality and costs of cancer care are constantly evolving. As journalists, analysts, and consultants attempt to help practicing oncologists better understand cancer care pathways and the impact these programs can have on patient care, we believe it's important to conduct primary research, directly with the companies that are leading innovations in this field, to ensure that the information shared with clinical audiences is accurate and complete.

Purpose: To determine the safety, maximum tolerated dose, and pharmacokinetic-pharmacodynamic profile of a histone deacetylase inhibitor, LAQ824, in patients with advanced malignancy. Patients and Methods: LAQ824 was administered i.v. as a 3-h infusion on days 1, 2, and 3 every 21 days. Western blot assays of peripheral blood mononuclear cell lysates and tumor biopsies pretherapy and posttherapy evaluated target inhibition and effects on heat shock protein-90 (HSP90) client proteins and HSP72. Results: Thirty-nine patients (22 male; median age, 53 years; median Eastern Cooperative Oncology Group performance status 1) were treated at seven dose levels (mg/m2): 6 (3 patients), 12 (4 patients), 24 (4 patients), 36 (4 patients), 48 (4 patients), 72 (19 patients), and 100 (1 patient). Dose-escalation used a modified continual reassessment method. Dose-limiting toxicities were transaminitis, fatigue, atrial fibrillation, raised serum creatinine, and hyperbilirubinemia. A patient with pancreatic cancer treated at 100 mg/m2 died on course one at day 18 with grade 3 hyperbilirubinemia and neutropenia, fever, and acute renal failure. The area under the plasma concentration curve increased proportionally with increasing dose; median terminal half-life ranged from 8 to 14 hours. Peripheral blood mononuclear cell lysates showed consistent accumulation of acetylated histones posttherapy from 24 mg/m2; higher doses resulted in increased and longer duration of pharmacodynamic effect. Changes in HSP90 client protein and HSP72 levels consistent with HSP90 inhibition were observed at higher doses. No objective response was documented; 3 patients had stable disease lasting up to 14 months. Based on these data, future efficacy trials should evaluate doses ranging from 24 to 72 mg/m2. Conclusions: LAQ824 was well tolerated at doses that induced accumulation of histone acetylation, with higher doses inducing changes consistent with HSP90 inhibition.

Background: Dovitinib (TKI258) is a potent oral tyrosine kinase inhibitor of FGFR as well as VEGFR, PDGFR, cKIT, and FLT3. Early clinical trials used an oral solution or a clinical service form (CSF) capsule of a lactate anhydrous formulation, which was challenging to produce on a large scale. Thus, a lactate monohydrate salt was developed as the final market image (FMI) and has been tested in both capsule and tablet form. Methods: The objective was to characterize the relative bioavailability of the CSF capsule, the FMI capsule, and the FMI tablet to the oral solution. Relative bioavailability was quantified via the area under the concentration time curve from time zero until the last time point sampled (AUClast) and by the maximum concentration (Cmax) following a single dose. First, population pharmacokinetic (PK) modeling from 2 phase 1 studies was used to characterize the relative bioavailability of the CSF capsule to the oral solution. Then, results from 2 formal relative bioavailability studies (FMI capsule vs CSF capsule and FMI tablet vs CSF capsule) were used to bridge the FMI formulations to the oral solution. The ratio of an FMI formulation's AUClast or Cmax to that of the oral solution was found as the product of the ratio of the FMI formulation to the CSF capsule times the ratio of the CSF capsule to the oral solution. In the 2 phase 1 studies, the oral solution was used in 9 patients (dose range, 50-600 mg), and the CSF capsule was used in 67 patients (dose range, 200-600 mg). The sample sizes of the 2 relative bioavailability studies for the CSF capsule were 20 and 21 for the FMI capsule and tablet, respectively. Results: The population PK model showed that the ratios of PK parameters (90% CI) comparing the CSF capsule to the oral solution were 0.85 (range, 0.65-1.14) for AUClast and 0.85 (range, 0.64-1.12) for Cmax. Then using the bioavailability ratio of the FMI capsule to the CSF capsule (AUClast, 0.88 [range, 0.82-0.94]; Cmax, 0.97 [range, 0.89-1.06]), bridging found the AUClast ratio of the FMI capsule to the oral solution to be 0.75 (range, 0.56-1.02), and the Cmax ratio was 0.83 (range, 0.61-1.10). Similarly, the bioavailability ratio of the FMI tablet to the CSF capsule (AUClast, 0.97 [range, 0.88-1.07]; Cmax, 0.99 [range, 0.91-1.08]) was used to calculate the ratio of FMI tablet to the oral solution: 0.82 (range, 0.62-1.14) for AUClast and 0.85 (range, 0.62-1.13) for Cmax. Conclusions: The relative bioavailabilities of dovitinib CSF capsules (≈ 0.85), FMI capsules (0.75-0.83) and FMI tablets (0.82-0.85) to oral solution were found to be similar to each other with respect to both AUClast and Cmax. This is consistent with the fact that the FMI capsule and CSF capsule as well as the FMI tablet and CSF capsule were similarly bioavailable. Citation Format: Samira Garonzik, Jerry Nedelman, Jeffrey Scott, Jeffrey Cramer, Eugene Tan. Relative bioavailability of dovitinib (TKI258) formulations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4635. doi:10.1158/1538-7445.AM2014-4635

Background Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. A phase 3 study in renal cell carcinoma used a capsule (cap) formulation of dovitinib. However, the planned commercial formulation is a tablet (tab). Therefore, this study evaluated the bioequivalence of the tab and cap formulations using a crossover design. Methods Patients (pts) ≥ 18 years of age with advanced solid tumors (excluding breast cancer) were randomized to receive caps or tabs (500 mg po once daily, 5 days on/2 days off) for 3 weeks, followed by the same dose and schedule of the other formulation for 1 week. Following the bioequivalence phase, pts could continue to receive dovitinib caps (500 mg once a day, 5 days on/2 days off). Blood samples for dovitinib plasma concentrations were collected before and after the fifth dose in weeks 3 and 4. The pharmacokinetic (PK) analysis set (PAS) comprised pts with ≥ 2 evaluable PK profiles following cap and tab administration, who did not vomit ≤ 4 hours after dosing on blood collection days and received ≥ 7 of the first 10 doses and 4 consecutive days of dosing prior to blood collection. A linear mixed-effects model was fitted to log-transformed parameters (area under the curve [AUClast] and maximal concentration [Cmax]). Results A total of 173 pts were randomized to receive the cap/tab sequence (n = 88) or the tab/cap sequence (n = 85). The median age was 60 years, and the most common primary sites of cancer were colon (n = 48), lung (n = 18), and rectum (n = 14). Sixty-nine pts were in the PAS (32 in the cap/tab sequence and 37 in the tab/cap sequence). The most common reason for PAS exclusion was dose interruption due to disease progression or adverse events (AEs). Geometric means of PK parameters were similar for the tab vs cap formulations: AUClast (5379 vs 5705 h·ng/mL), Cmax (247 vs 252 ng/mL), half-life (14.5 vs 15.3 h), oral clearance (89.5 vs 82.5 L/h), and apparent volume of distribution (1876 vs 1823 L). The geometric mean ratios (90% CI) for AUClast and Cmax comparing tab vs cap were 0.95 (0.88-1.01) and 0.98 (0.91-1.05), respectively. In pts who received at least 1 dose of dovitinib throughout the entire study (including the postbioequivalence phase; n = 168), the most common AEs suspected to be related to study drug (any grade) were diarrhea (58.9%), nausea (50.0%), fatigue (42.3%), vomiting (41.7%), and decreased appetite (20.8%). Grade 3/4 AEs were < 5% except for fatigue (11.9%), diarrhea (5.4%), and hypertension (5.4%). Conclusions The tab and cap formulations were bioequivalent. The safety profile was similar to that observed in other dovitinib studies in pts with advanced solid tumors. The tab formulation is used in selected current studies and will be used in future clinical dovitinib studies. Citation Format: John Sarantopoulos, Sanjay Goel, Vincent Chung, Pamela Munster, Shubham Pant, Manish Patel, Jeffrey Infante, Hussein Tawbi, Carlos Becerra, Justine Bruce, Fairooz Kabbinavar, Howard Kaufman, A. Craig Lockhart, Eugene Tan, Shu Yang, Mariama Diallo, Jeffrey Scott, Sunil Sharma. Randomized, phase 1 crossover study assessing the bioequivalence of tablet and capsule formulations of dovitinib (TKI258). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4640. doi:10.1158/1538-7445.AM2014-4640

2581 Background: Dovitinib (TKI258) is an oral tyrosine kinase inhibitor targeting kinases involved in tumor cell proliferation and survival, including FGFR, VEGFR, PDGFR, c-KIT, and FLT3. In vitro...

2593 Background: Dovitinib (TKI258), an oral multitargeted receptor tyrosine kinase inhibitor, is being studied in a phase 3 trial for renal cell carcinoma. A previous study compared the bioavailability of 2 capsule formulations of dovitinib. Arm 1 of the current study compared relative bioavailability of the final market image (FMI) form (monohydrate tablets) with the clinical service form (CSF; anhydrate capsules) of dovitinib. Arm 2 assessed the effect of food on bioavailability of the FMI tablet in adult patients (pts) with advanced solid tumors. Both arms employed crossover designs. Methods: In arm 1, pts were randomized to receive a single 500-mg dose of dovitinib either as a CSF capsule or FMI tablet, followed by a single 500-mg dose of the other formulation after 7 days of rest. Plasma pharmacokinetic (PK) profiles were determined from blood samples. A linear mixed-effects model fitted to log-transformed PK parameters maximal concentration (Cmax) and area under the curve (AUC0-tlast) was used to determine the relative bioavailability of FMI vs CSF. In Arm 2, pts received 300 mg of the FMI formulation once daily for 22 days after being randomized to 1 of 6 meal sequences with 3 fed or nonfed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) on days 8, 15, and 22. The relative bioavailability of dovitinib under LF and HF vs NM state was determined using the same model as arm 1 for the PK parameters Cmax and AUC0-tlast. Results: The study accrued 21 pts to arm 1 and 42 pts to arm 2. Based on the interim analysis, PK was assessed in 17 evaluable pts in arm 1. The geometric mean ratios (GMRs; 90% CI) for Cmax and AUC0-tlast comparing FMI vs CSF were 0.99 (0.91-1.08) and 0.96 (0.89-1.04), respectively. The FMI formulation was used in arm 2; PK was assessed in 19 pts. Cmax GMR (90% CI) was 0.82 (0.71-0.94) and 0.90 (0.78-1.03) for HF/NM and LF/NM, respectively. AUC0-tlastGMR (90% CI) was 0.91 (0.81-1.02) and 0.99 (0.88-1.10) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI tablet and CSF capsule were comparable, and there was no clinically relevant effect of food (HF or LF meals) on the bioavailability of the FMI tablet form of dovitinib. Clinical trial information: NCT01155713.

Background: Dovitinib (TKI258) is an oral receptor tyrosine kinase inhibitor with demonstrated antitumor activity in patients with advanced cancer including metastatic renal cell carcinoma (mRCC). This phase 1 study was designed to determine the relative bioavailability of 2 capsule formulations of dovitinib (Arm 1), the anhydrate clinical service form (CSF) and the monohydrate final market image (FMI), and to assess the effect of food on dovitinib exposure in the preferred formulation (Arm 2) in patients with advanced solid tumors. Both arms employed crossover designs. Materials and methods: In Arm 1, patients received a single 500-mg dose of either the CSF or FMI formulation, followed by 7 days of rest and then a single 500-mg dose of the other formulation. Blood samples were collected to determine plasma pharmacokinetic (PK) profiles. The relative bioavailability of FMI vs CSF was determined using a linear mixed effects model fitted to log-transformed PK parameters Cmax and AUC0-tlast. In Arm 2, patients received 300 mg of the FMI capsule once daily for 22 days and were randomized to 1 of 6 sequences each with crossover between 3 fed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) during 3 periods (days 1-8, days 9-14, and days 16-22). The relative bioavailability of dovitinib under LF and HF vs the NM state was determined using the same model as described in Arm 1 for the PK parameters Cmax and AUC0-tlast. Results: Based on the interim analysis, PK was assessed in 16 evaluable patients in Arm 1. The geometric mean ratios (GMR; 90% CI) for Cmax and AUC0-tlast comparing FMI vs CSF were 0.94 (0.85-1.04) and 0.88 (0.80-0.95), respectively. Based on comparable bioavailability, Arm 2 employed the FMI formulation. PK was assessed in 19 patients. Cmax GMR (90% CI) was 0.94 (0.83-1.06) and 1.07 (0.94-1.21) for HF/NM and LF/NM, respectively. AUC0-tlast GMR (90% CI) was 1.00 (0.91-1.11) and 1.09 (0.99-1.20) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI and CSF formulations were comparable, and there was no clinically relevant effect of HF or LF food on the bioavailability of dovitinib. Based on these results, dovitinib can be taken with or without food, and the FMI capsule formulation was selected for the ongoing pivotal phase 3 study of dovitinib compared with sorafenib in patients with mRCC. Citation Format: Sunil Sharma, Carolyn D. Britten, Joanne Mortimer, Swarupa Kulkarni, Michelle Quinlan, Alaeddin Homsi, Eugene Tan, Suraj Anand, Angela Liu, Jeffrey Scott, Daniel George. The effect of formulation and food consumption on the bioavailability of dovitinib (TKI258) in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 30. doi:10.1158/1538-7445.AM2013-30

Abstract 4055 Introduction: Approximately 15% of patients (pts) with multiple myeloma (MM) exhibit a t(4;14) translocation that results in constitutive activation of the receptor tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3) in the absence of ligand. This translocation has been strongly linked with a poor prognosis and short survival compared with pts without this translocation. Dovitinib (TKI258) is an RTK inhibitor that has demonstrated in vitro inhibitory activity against FGFR (including FGFR3), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR), with IC50values of approximately 10 nM. Tumor growth inhibition was observed in xenograft tumor models of MM treated with dovitinib. This study was designed to evaluate the efficacy and safety of dovitinib in pts with relapsed or refractory MM that is either t(4;14) positive or negative. Patients and Methods: Adult pts who had received at least 2 prior antimyeloma regimens and who had relapsed or were refractory to their last treatment regimen were enrolled in this multicenter, open-label, 2-stage, phase 2 trial. Pts were evaluated for t(4;14) status at the baseline visit and classified according to the result into either a t(4;14)-positive or a t(4;14)-negative group. Dovitinib was administered at a dose of 500 mg/day on a 5-days-on/2-days-off schedule. Response was characterized as per the International Myeloma Working Group (IMWG) criteria. The primary endpoint was extended overall response rate as defined by the rate of pts with best overall response of complete response, very good partial response, partial response, or minor response. Secondary endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. After disease progression, pts had the option to continue treatment with the addition of low-dose dexamethasone (40 mg every 7 days) with M-protein levels at the time of progression considered as the new baseline. Results: A total of 43 pts were enrolled in this study; 26 pts were t(4;14) negative, 13 were t(4;14) positive, and 4 pts had unknown/indeterminate t(4;14) status. Median age was 63 years. Most pts (86%; n = 37) had received ≥ 3 prior lines of therapy. No objective responses were observed in either group of pts. Due to the apparent lack of efficacy, the study did not proceed to stage 2. The following observations are based on the preliminary data. In the t(4;14)-negative group, median duration of exposure to the study drug was 4.0 weeks, and 9 of the 26 pts (35%) had stable disease, 13 (50.0%) had progressive disease, and 4 (15%) were not evaluable. Due to slow enrollment and lack of efficacy among the earlier enrolled t(4;14)-positive pts, enrollment for the t(4;14)-positive group was closed prematurely. Among the 13 enrolled t(4;14)-positive pts, median duration of exposure to the study drug was 8.7 weeks. Best responses were stable disease for 8 pts (62%), disease progression for 3 pts (23%), and unknown for 2 pts (15%). Among both groups, the most common adverse events of any grade, regardless of study drug, were nausea (67%), diarrhea (58%), vomiting (51%), fatigue (47%), thrombocytopenia (33%), and anemia (28%). Most of the nonhematologic events were mild. The most common grade 3/4 adverse events were thrombocytopenia (26%) and anemia (23%). The principal reasons for discontinuation of dovitinib monotherapy were disease progression (72%) and adverse events (19%). Six pts continued on the dovitinib plus dexamethasone regimen; 1 pt is ongoing, and 5 pts discontinued due to disease progression (n = 4) and adverse events (n = 1). Conclusion: Dovitinib was found to have no or minimal single-agent activity in relapsed/refractory myeloma irrespective of t(4;14) status. Although the patient numbers are small, the rate of patients with stable disease during study treatment who may have had a clinical benefit was higher in the t(4;14)-positive group, suggesting that this subgroup may be a candidate to explore combination treatment of dovitinib with other agents, such as proteasome inhibitors. Gastrointestinal toxicity, while mostly mild, remains a challenge, and timely monitoring and supportive care during dovitinib treatment may alleviate these symptoms. Dovitinib may be a promising agent for combination therapies to improve prognosis of patients with t(4;14)-positive MM. Disclosures: Scheid: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Reece:Millennium Pharmaceuticals: Research Funding; Otsuka: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Spencer:Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria. Callander:Millennium Pharmaceuticals: Research Funding. Sonneveld:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding. Kalimi:Novartis Pharmaceuticals: Employment. Cai:Novartis: Employment. Shi:Novartis: Employment, Equity Ownership. Scott:Novartis: Employment. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Abstract 2898 Poster Board II-874 Introduction: Panobinostat (LBH589) is a potent pan-deacetylase inhibitor (DACi) targeting epigenetic and non-epigenetic oncogenic pathways. Panobinostat is currently under clinical investigation in a variety of solid tumors and hematologic malignancies. A Phase IA/II trial evaluating oral panobinostat in patients (pts) with advanced hematologic malignancies is currently ongoing, and encouraging clinical activity has been reported previously in pts with lymphoma, myeloma, or leukemia. Here, preliminary activity of oral panobinostat in pts with myelofibrosis (MF) is described. Patients and methods: Pts with advanced hematologic malignancies were treated in cycles of 28 days with two schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in two pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): Group X includes pts with MF, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL); and Group Y includes pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM). For MF patients, response was assessed according to the 2006 International Working Group (IWG) consensus response categories. Presence of an activating mutation (JAK2V617F) of the Janus kinase 2 (JAK2) tyrosine kinase was assessed. Results: To date, a total of 176 pts have been treated at 20–80 mg/dose MWF every week, or 30–80 mg/dose MWF every other week. The adverse event (AE) profile has been similar between the two schedules. In Group X (n=119), the most common drug-related Grade 3/4 AEs (≥10%) have been thrombocytopenia (28%), fatigue (22%), neutropenia (18%), and anemia (10%). The maximum tolerated dose (MTD) for Group X, in which cytopenia(s) in the presence of persistent disease is not considered dose limiting, was 60 mg/dose MWF every week, and the principal DLT was fatigue. MTD was not determined for the every other week schedule. In Group Y (n=57), the most common drug-related Grade 3/4 AEs (≥10%) have been thrombocytopenia (72%), neutropenia (26%), and fatigue (16%). The MTDs for Group Y, in which cytopenias are considered dose limiting, were 40 mg/dose MWF every week or 60 mg/dose MWF every other week, and the principal DLT was thrombocytopenia. Thirteen patients (10 male) with MF have been treated, including 10 pts with idiopathic MF and 3 pts with post-polycythemic disease. Eight patients were transfusion dependent at study entry and two pts had no prior therapy for MF. Median age is 59 years (range 31–86). Among previously treated pts (11 pts), the median number of prior therapeutic regimens was 3 (range 1–6); prior therapies included chemotherapy, which may have included hydroxyurea (11 pts), radiotherapy (1 pt), splenectomy (1 pt), and stem cell transplantation (2 pts, both with prior chemotherapy). JAK2 status has been identified as wild-type for 1 pt and mutant (JAK2V617F) for 9 pts (unknown for 3 pts). Pts received panobinostat at 30 (n=1) or 60 mg/dose (n=11) MWF every week, or 80 mg/dose (n=1) MWF every other week. A preliminary assessment of efficacy has been performed by the investigators. Among 12 pts evaluable for response, one previously untreated pt (JAK2V617F) has demonstrated a partial response, including an 85% reduction in spleen size; treatment is ongoing in Cycle 9. Three pts demonstrated clinical improvement lasting ≥8 weeks: 1 pt, ongoing in Cycle 39, has demonstrated an 86% reduction in spleen size and transfusion independence for >1 year; another pt, ongoing in Cycle 19, has demonstrated an 83% reduction in spleen size; the third pt demonstrated a 57% reduction in spleen size and improvement in other disease-related symptoms. An additional 4 pts had stable disease, ranging from 4 to 8 cycles, with 1 pt ongoing in Cycle 8. Conclusions: Panobinostat shows promising clinical activity, with disease control for up to 39 cycles, in patients with MF. These encouraging preliminary data support the investigation of panobinostat activity in patients with MF in subsequent studies. Updated safety and efficacy data will be presented. Disclosures: DeAngelo: Bristol-Meyers Squibb: Consultancy, Research Funding; Celgene: Speakers Bureau; Enzon Pharmaceuticals: Speakers Bureau; Novartis: Speakers Bureau. Ottmann:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Prince:Novartis: Consultancy, Honoraria, Research Funding. Giles:Novartis: Research Funding; Merck: Research Funding; BMS: Research Funding; Vion: Research Funding. Cortes:Nerviano: Research Funding. Liu:Novartis: Employment. Parker:Novartis: Employment. Yan:Novartis: Employment. Scott:Novartis: Employment. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria.

Introduction: Histone deacetylase inhibitors (DACi) have shown promising antileukemic activity by overcoming the differentiation block and inducing apoptosis in AML blasts. Recent data demonstrating enhanced maintenance and functional capacity of normal, but also leukemic hematopoietic progenitor cells (HPC) by the selective class I DACi valproic acid (VPA) have raised concerns about VPA in AML therapy. As more potent pan-DACi have entered clinical trials, we analysed the impact of the hydroxamic acid LAQ824 on phenotype and function of normal and leukemic CD34+ HPC and studied LAQ824- induced gene expression in the most primitive CD34+CD38- population of normal HPC. Methods: Differentiation and proliferation of CD34+ cells of bone marrow of healthy donors and peripheral blood samples of newly diagnosed AML patients were evaluated after one week of culture in presence of SCF, FLT3 ligand, TPO, IL-3 +/− LAQ824. The effect of LAQ824 on gene expression profiles in normal CD34+CD38− cells was assessed in three independent cell samples following incubation with cytokines +/− LAQ824 for 48 hours using Affymetrix GeneChip Human Genome U133 Plus 2.0 and Gene Spring Software. Serial replating of murine Sca1+Lin- HPC was performed in the presence of SCF, G-CSF, GM-CSF, IL-3, IL-6 +/− LAQ824. Results: Treatment of murine Sca1+Lin- HPC with LAQ824 (10 nM) significantly augmented colony numbers (p

Introduction. Current treatments for MDS include supportive care and the use of newer agents. The costs of supportive care and treatment with hypomethylating agents differ significantly. This study represents a budget impact model comparing the relative costs of supportive care and individual hypomethylating agents in this setting varying the model by average duration of treatment, time to response, and response rate. Method. The P4 Healthcare database of over 1,300,000 lives was accessed for the period of January 1, 2007, to December 31, 2007, and includes key information such as dates of service, ICD-9 codes, procedure codes, costs associated with hospitalizations, and the payment amounts per date(s) of service. The average cost figures for the indicated procedures were determined from a Medicare (MC) and non-Medicare (nMC) payer perspective. Clinical response measures, side effects and other clinical event rates were established from published studies for the respective treatments. A 2-year budget impact model was developed that allows for evaluation of the various phases of treatment, including time to initial response and continued treatment due to ongoing clinical benefit. Each scenario includes estimated costs for drug therapy and administration, supportive care including transfusions, and costs associated with side effects such as febrile neutropenia and infections. Three potential scenarios were evaluated. The first analysis (Time to Response Model) established cost impact associated with initial time to response for the individual agents. This scenario used an initial estimate of time to response of 6 and 9 cycles for DAC and VID, respectively. The next scenario demonstrated the cost impact of ongoing treatment (Ongoing Treatment Model) for three treatment scenarios: Supportive Care (SC) only, Azacitidine (VID) followed by supportive care, Decitibine (DAC) followed by supportive care using the mean duration of response. The third analysis established the complete sequence of treatment (Complete Treatment Model) in which mean time to response, mean response rate and mean duration of response were used to model the overall impact comparing DAC and VID to SC for the entire 2-year period. The assumed overall response (complete response, partial response and hematologic improvement) rates were 73%, 60%, and 5% for DAC, VID, and SC respectively. Sensitivity analyses were conducted to demonstrate the impact based on differences in time to response, duration of response, and response rates. All analyses are reported by the MC and nMC perspectives. Results. 1,929,974 remittance observations on 393,840 patients contributed to the analytic models. The Time to Response Model suggested that Dacogen (Mean MC ≈ $53,277; Mean nMC ≈ $56,464) results in lower cost than Vidaza (Mean MC ≈ $144,726; Mean nMC ≈ $140,322) relative to the time to response. Results of the Ongoing Treatment Model suggested that both treatment with Dacogen (Mean MC ≈ $88,795; Mean nMC ≈ $94,106) and Vidaza (Mean MC ≈ $176,887; Mean nMC ≈ $171,504) result in lower costs than supportive care alone (Mean MC ≈ $167,563; Mean nMC ≈ $174,225). The Complete Treatment Model suggests lower cost for the Dacogen regimen (Mean MC ≈$267,509; Mean nMC ≈ $280,512) over the Vidaza regimen (Mean MC ≈ $368,153; Mean nMC ≈ $365,183) and the Supportive Care regimen (Mean MC≈ $335,127; Mean nMC≈$348,451). Discussion. The cost of SC for MDS is significant and interestingly the cost of hypomethylating agent treatment in this setting is less than SC. The budget impact model suggests there is utility in considering utilization of DAC as first line therapy over VID to minimize cost through the optimal application of the differential response rates and time to response rates.

Panobinostat (LBH589) is a novel and potent pan-deacetylase inhibitor (DACi) with broad preclinical activity in models of hematologic malignancies. This trial is evaluating panobinostat in patients (pts) with advanced hematologic malignancies with 2 schedules of oral administration: Monday/Wednesday/Friday (MWF) every week or MWF every other week. Each schedule is being assessed in 2 pt groups that differ by disease and the definition of hematologic dose-limiting toxicity (DLT): pts with Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), or multiple myeloma (MM); and pts with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic idiopathic myelofibrosis (CIMF), acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), or chronic lymphocytic leukemia (CLL). A 3-parameter Bayesian logistic regression model guides dose escalation, and a minimum of 6 evaluable pts at each dose level is required prior to dose escalation. To date, 128 pts have been enrolled: 79 pts with weekly dosing at 20, 30, 40, 60, and 80 mg/dose; and 49 pts dosed every other week with 30, 45, 60, and 80 mg/dose. The most common diseases have included AML (65 pts), HL (23 pts), and MM (12 pts). Panobinostat has rapid oral absorption (median Tmax 1 h, range 0.5–3 h), AUC and Cmax are dose-related, and mean effective t½ is 16.7 h. The adverse-event (AE) profile has been similar between the 2 schedules; the most common grade 3/4 AEs (≥10%) have been thrombocytopenia (43%), neutropenia (22%), febrile neutropenia (20%), fatigue (20%), and anemia (11%). In pts with lymphoma and myeloma, the principal DLT is thrombocytopenia, whereas in patients with AML, in whom grade 4 thrombocytopenia is not considered dose-limiting, the principal DLT is fatigue. With weekly dosing, the maximum tolerated dose (MTD) is 40 mg/dose in pts with lymphoma and myeloma, whereas the MTD is 60 mg/dose in pts with AML. The MTD has not been established for dosing every other week in either group of pts, but this regimen is not expected to provide greater dose intensity than weekly treatment. Anti-tumor activity has been observed in a group of 13 response-evaluable pts with relapsed/refractory HL, treated at doses ≥30 mg with both schedules: PR by computed tomography (CT), 5/13 pts (38%); metabolic PR by positron emission tomography (PET), 7/12 pts (58%) (PET assessment not performed in 1 pt); symptom improvement in 7 of the 9 pts with disease-related symptoms at baseline (78%); and disease control for up to 16+ cycles. Anti-tumor activity has also been observed in a group of 26 response-evaluable pts with AML, treated at doses ≥40 mg on the weekly schedule: 2 CRs, including 1 pt ongoing >1 yr; 1 pt aleukemic (marrow not assessable due to fibrosis) >10 months; 2 pts ongoing with decreased marrow blasts and disease control for 9 and 12 months. Activity has also been observed with panobinostat doses ≥30 mg in pts with other hematologic malignancies: CIMF (2 pts, both ongoing, 1 pt with decreased splenomegaly and transfusion independence >20 months, 1 pt with decreased splenomegaly >3 months); MDS (1 pt PR); MM (1 pt PR); and CD4+/56+ hematodermic neoplasm (1 pt PR). For future studies of single-agent panobinostat in HL, the recommended regimen is 40 mg p.o. MWF every week. A regimen of 60 mg p.o. MWF every week is recommended for further evaluation of panobinostat’s single-agent activity in AML.

3538 Background: LBY135 is a chimeric (mouse/human) IgG1 monoclonal antibody agonist that binds with high specificity to the DR5 receptor and mimics the action of TRAIL. LBY135 has shown activity i...

14587 Background: LBY135 is a chimeric (mouse/human) IgG1 monoclonal antibody agonist that binds with high specificity to the DR5 receptor and mimics the action of TRAIL. In a phase I trial, LBY135...

LBH589 (Novartis) is a potent histone deacetylase inhibitor (HDACi) currently in early phase clinical development. Preliminary data suggests biological activity in a range of malignant hematological disorders including acute myeloid leukemia (AML). To-date, laboratory tumor lysis syndrome (LTLS) has not been described as a complication of LBH589 therapy. We report a case of a 60 year-old man who developed LTLS following treatment for AML with oral LBH589. The patient was diagnosed with refractory anemia with excess blasts (RAEB) in July 2005. Cytogenetic analysis demonstrated trisomy 8 and del(20q). He was initially treated with standard dose cytarabine and idarubicin (7 + 3). Post-induction bone marrow examination revealed ongoing dysplasia but no excess of myeloblasts. He subsequently received further cytarabine and idarubicin as consolidation. This was complicated by prolonged pancytopenia and subsequently by rapid progression to overt AML. Salvage therapy with fludarabine/cytarabine/G-CSF (FLAG) failed and he was referred to our institution for investigational therapy with LBH589. The patient was enrolled in a Phase IA/II trial of oral LBH589 for patients with advanced hematological malignancies and commenced intermittent oral LBH589 (30mg orally Monday, Wednesday and Friday on alternate weeks). He re-presented on day 14 with deteriorating renal function - creatinine 0.28mM/L (baseline 0.12mmol/L) and hyperleukocytosis (WBC 68 × 109/L). He recommenced LBH589 and was also commenced on hydroxyurea 1g bd, allopurinol and hydration. Within 24 hours, associated with a fall in his WBC to 9 × 109/L, he developed LTLS - corrected calcium 1.91mM/L (2.23 – 2.50), phosphate 2.99mM/L (0.70 – 1.30) and uric acid 0.8mM/L (0.15 – 0.50). He recovered uneventfully with the administration of rasburicase, intravenous fluid and electrolytes. Hydroxyurea was ceased and he continued LBH589 as per schedule. On day 28 with a WBC of 60 × 109/L and with prophylactic rasburicase and hyper-hydration, LTLS again recurred within 24 hours of LBH589 administration - WBC fell to 6 × 109/L accompanied by corrected calcium of 2.1 mM/L and serum phosphate of 1.91 mM/L. The patient again recovered uneventfully. This first reported case of LTLS with LBH589 therapy clearly demonstrates the potent anti-leukemic potential of LBH589 and mandates that caution be taken with LBH589 treatment of AML patients exhibiting highly proliferative and/or a high tumor burden disease.

3131 Introduction: LAQ824, a novel cinnamic acid hydroxamate, inhibits HDAC activity (IC50, 0.03 μM) and the hERG channel(IC50, 10 μM). Methods: In 3 phase I studies, LAQ824 was administered as a 3-hr intravenous infusion on several dosing schedules, principally days 1–3 of a 21-day cycle, to adult pts with advanced solid (studies 2102 and 2107) or hematologic (study 2101) malignancies. Pts with impaired cardiac function were excluded; drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (4 ECGs), on days of dosing and post-dose each cycle. ECG data were processed in a core lab by manual analysis. Cardiac enzymes were assessed on days of dosing. LVEF was assessed by MUGA scan or echocardiogram each cycle. Results: 77 pts (median age: 60 yrs; 48 males, 29 females) were treated at 11 dose levels, range 6 - 200 mg/m2/day. PK analysis showed dose proportionality, T1/2of 6 - 26 hrs, and 1.5 fold accumulation at steady state. There was considerable inter-patient var...

3106 Introduction: LBH589 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and inhibits hERG channel with an IC50 of 3.9 μM. Methods: In 2 phase I studies, LBH589 was administered as a 30 minute intravenous infusion on 2 schedules, days 1–3 and 8–10 of a 21 day cycle or days 1–3 and 15–17 of a 28 day cycle to adult pts with advanced solid malignancies (study 2101) or on a schedule of days 1–7 of a 21 day cycle to adult pts with hematologic malignancies (study 2102). Patients with impaired heart function were excluded, and drugs known to prolong QT interval were prohibited. Serial digital ECGs were performed at baseline (6 ECGs), and on days of dosing. ECG data were processed in a core lab by manual analysis. Results: 45 pts (median age: 60 yrs; 23 males, 22 females) were treated at 10 dose levels, range 1.2 - 20.0 mg/m2/day. PK analysis showed dose proportionality, T1/2 of 6 - 26 hr, and approximately 1.5 fold accumulation at steady state (day 3). PD analysis of PBL showe...

3023 Background: Several HDACIs, including LAQ824, are now undergoing clinical evaluation. Preclinical data indicate that as well as promoting histone acetylation, these agents can also affect the ...

3024 Background: LAQ824 is a novel cinnamic acid hydroxamate that inhibits HDAC activity, IC50 of 0.03 μM, and acetylates hsp90 thereby inducing proteosomal degradation of Bcr-Abl and her-2. Method...