ALBERT

Description: Background: Crenolanib is a type I oral FLT3 TKI, which inhibits both FLT3-ITD and FLT3-TKD mutations (D835, N841, etc). Crenolanib has a half-life of 6-8 hours and does not accumulate with repeated dosing. Crenolanib does not inhibit c-kit at clinically achievable concentrations, potentially allowing for full count recovery even when combined with myelosuppressive chemotherapy. We report here the first analysis of a phase II trial evaluating the tolerability and efficacy of crenolanib combined with standard induction chemotherapy in patients (pts) with newly diagnosed FLT3 mutant AML. Methods: Pts (≥ 18yrs) (no upper age limit) with newly diagnosed AML characterized by FLT3 (ITD and/or TKD) mutations were enrolled. Pts received standard 7+3 induction with cytarabine 100 mg/m2/d for 7 days and either daunorubicin (200,000). Three pts had AML following antecedent MDS or MPN. Mutational Analysis: Twenty-two pts had either FLT3-ITD (n=19) or FLT3-D835 (n=3) mutations. Genomic sequencing revealed multiple concurrent FLT3 activating mutations in four pts. One pt had a dual-activating kinase domain mutation in trans (D835Y+N841T). Three other pts had FLT3-ITD together with N841 (n=2), I836del (n=2), and V592/593 (n=2). Fifteen (60%) pts had FLT3 and NPM1 mutations, and 11 (52%) had FLT3 and DNMT3A mutations. Five pts (24%) had AML with three mutations (FLT3 + NPM1+ DNMT3A). WIT (WT1, IDH1/2, TET2) mutations were present in 11 (52%) pts. Three pts had trisomy 8; one pt each having monosomy 7, trisomy 4, and t(3;18)del(6q)der(3). Treatment Outcome: Eighteen (69%) pts received induction with cytarabine+daunorubicin (10 pts at 90 mg/m2, 8 pts at 60 mg/m2) and eight pts (31%) received cytarabine+idarubicin. To date, crenolanib has been well-tolerated in combination with chemotherapy. Six pts required crenolanib dose reductions for periorbital edema (n=2), delayed count recovery (n=1), LFT elevation (n=1), nausea (n=1) and rash (n=1). Out of the twenty-five pts evaluable for response, twenty-two (88%) achieved complete remission (CR) with full count recovery after one cycle of induction. Overall CR/CRi rate was 96% (Table 1). Sixteen pts (10 pts〈 60yrs; 6 pts≥ 60yrs) have received a total of 26 cycles of consolidation with HiDAC and crenolanib. Twelve pts (46%) have been bridged to allogeneic SCT. With a median follow up of 6 months, only three pts (all 〉 60yrs) have relapsed. Overall survival is shown in Figure 1. Conclusion: Crenolanib, a type I pan-FLT3 TKI, can be safely combined at full doses with cytarabine/daunorubicin or cytarabine/idarubicin induction and HiDAC consolidation chemotherapy for upfront AML therapy. A high CR rate of 88% with full count recovery was observed after one cycle of induction with an overall CR/CRi rate of 96%. HiDAC consolidation and allo SCT could be administered on schedule. Encouraging anti-leukemic activity has been observed with no relapses in FLT3 mutant AML pts

Description: Background: High-dose cytarabine and mitoxantrone (HAM) have been used as salvage chemotherapy in patients (pts) with relapsed/refractory AML. Mitoxantrone is less cardiotoxic than other anthracyclines and can be tolerated in older pts. Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with promising single-agent activity in multiply relapsed/refractory FLT3+ve AML. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. We here report data from the first 8 pts with primary relapsed or refractory AML treated with HAM followed by crenolanib. Design: Pts with AML and/or prior MDS regardless of FLT3 status (wild-type or mutant) were enrolled in this study. Eligible pts must have progressed on or be refractory to their first line AML therapy. Pts were treated with HAM (cytarabine 1.0 g/m2/d for d1-6 and mitoxantrone 10 mg/m2 for d1-3) followed by crenolanib 100 mg TID, starting from d8 continuously for a maximum of 49d per cycle (2 cycles of treatment were allowed). Older pts (≥60 yr) or pts who had prior SCT or who required a second induction cycle received lower dose of HAM (cytarabine 0.5 g/m2/d for d1-6 and mitoxantrone 8 mg/m2 for d1-3). Pts in remission following salvage induction were eligible to proceed to allo SCT. Results: 8 pts (4 males, 4 females) with first relapsed or primary refractory AML have been enrolled and received HAM followed by crenolanib. The median age on study was 64 (range 36-78) with 6/8 pts ≥ 60yr and 3 pts older than 70yr. 3/8 pts came on study with FLT3 activating mutations, including ITD (2 pts) and D835 (1 pt). 7/8 pts had de novo AML, and 1 had prior-MDS after receiving prior chemotherapy for ovarian cancer. 3/8 pts were primary refractory to first line therapy with the remaining 5 pts having relapsed following response to first line therapy. Pt demographics are summarized in Table 1. 8 pts received 1 cycle of salvage treatment with HAM followed by continuous daily crenolanib (100 mg TID). 6 pts were evaluable for responses with a complete remission rate of 67% (2 CR, 2 CRi), including 2 pts who were refractory to front line chemotherapy. 2 of 3 pts with FLT3 activating mutations (1 with ITD and 1 with D835) achieved complete remission with complete count recovery; the third pt (FLT3-ITD) had 10% residual blasts after 1 cycle of induction, and is currently planned for transplant. Crenolanib with salvage chemotherapy was well-tolerated in all 8 pts administered full dose crenolanib (100 mg TID) following HAM. No crenolanib dose reductions were required in any of the 8 pts during induction; however crenolanib was held for intercurrent illnesses, such as C. difficile diarrhea. 2 events of grade 1 ALT/AST elevation were noted during salvage treatment with HAM, but did not cause delays in the initiation of crenolanib. Moreover, the addition of crenolanib did not cause any further elevation of ALT/AST in these 2 pts and no dose reductions or holds were required. Only 1/8 pts showed an elevation in total bilirubin, this event was a transient grade 2 elevation attributed to concomitant medication for fever and returned to normal within 3-5d with no intervention required. Conclusions: Full-dose crenolanib was well-tolerated when given sequentially with HAM in an older pt population (median 64 yrs) with primary relapsed/refractory AML. Four pts achieved CR/CRi following 1 cycle of HAM/crenolanib, including 2 pts with WT FLT3 and 2 pts with FLT3 activating mutations (1 ITD, 1 D835). This trial has been expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF). A phase III is initiated combining crenolanib and salvage chemotherapies in first relapse or primary refractory AML pts with FLT3+ve activating mutations. Disclosures Iyer: Genentech: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Incyte: Research Funding; Arog: Research Funding; Celgene: Research Funding. Karanes:Arog: Research Funding. Eckardt:Arog: Employment, Equity Ownership.

Description: Background: Crenolanib is a novel type I pan-FLT3 inhibitor, which inhibits both FLT3-ITD, as well as FLT3 tyrosine kinase domain (TKD) activating mutations. Combination of crenolanib (Type I) and sorafenib (Type II) has been shown to have synergistic apoptotic effects in FLT3+ve AML blasts derived from patients (pts) who have relapsed after prior sorafenib treatment. We hypothesized that the combination of crenolanib and sorafenib may provide enhanced FLT3 inhibition by targeting both inactive as well as active FLT3 kinase conformations. We here report the results of a dose finding study of sorafenib given with fixed doses of crenolanib in pediatric pts with FLT3+ve AML. Design: This pilot study was designed to assess the tolerability of escalating doses of sorafenib with full doses of crenolanib (66.7 mg/m2 TID) in pediatric pts with relapsed or refractory FLT3+ve AML. Crenolanib was administered continuously at 66.7 mg/m2 TID starting on d1. Sorafenib was administered continuously starting from d8 at 150 mg/m2/d (dose level 1). The rolling-6 design was used and if no DLTs were seen, sorafenib was escalated to 200 mg/m2/d (dose level 2). Additionally, triple intrathecal therapy with methotrexate, hydrocortisone, and cytarabine was given on d8 and continued weekly in pts with CNS leukemia until CSF was free of blasts. Results: From April 2015 to March 2016, 7 children (median age, 9yrs; range, 5-14yrs) have been enrolled. All pts had progressed after a median of 3 prior AML therapies (range, 1-7). Four pts had progressed after frontline treatment, which included sorafenib maintenance; the other 3 pts had progressed after standard chemotherapy. Two pts had undergone prior allo SCT. Median WBC count prior to therapy was 1.7 x 109/L (range 0.7-7.5 x 109/L) with median blast percentage of 15% (range 0-60%). All 7 pts had a FLT3-ITD (mutant to wild-type FLT3 ratio ranged from 0.048 to 22, with one pt not having any wild type FLT3 allele). At the time of study entry, 2 pts had active CNS leukemia and required additional intrathecal therapy. Crenolanib 66.7 mg/m2 TID was well tolerated with no pt requiring crenolanib dose reduction. Sorafenib was administered to the first 3 pts at 150 mg/m2 QD from d8 onward. As no DLTs were observed at 150 mg/m2 QD dose, sorafenib was dose escalated to 200 mg/m2 QD for the next 4 pts. No DLTs were observed at either of the sorafenib doses. The combination of crenolanib/sorafenib was well tolerated with most AEs being grade 1 and 2 in severity. Rash was frequently seen in pts following the addition of sorafenib and one pt developed grade 2 hand-foot syndrome which resolved within 5d on the same dosing regimen. No grade 4 LFT elevations were seen in any pt. During cycle 1 of therapy, crenolanib/sorafenib combination resulted in clearance of peripheral blood blasts in 5/6 pts and 1 pt without blasts at baseline had resolution of extramedullary neck mass. Reduction of bone marrow blasts was seen in 4/7 pts. By Cheson criteria, one patient achieved a CR (with FLT3 negativity), two had a PR, and one had a marrow response of CRi but with persistent CNS disease. Three pts had NR although 2 had transient benefit from crenolanib on day 8 as determined by BM blast percentage. Peripheral blood and bone marrow blast percentages are summarized in Figure 1 and Table 1, respectively. Median overall survival was 221d (Figure 2) with 2 pts currently still alive. Conclusions: Crenolanib 66.7 mg/m2 TID can be safely combined with sorafenib at 200 mg/m2 QD. Even in pts with prior exposure to sorafenib, this combination showed clinical benefits, represented by rapid reduction of bone marrow or peripheral blasts, and was able to have improved quality of life. Although dual TKI combinations targeting the same receptor have not been tried in AML, such strategies have been shown to have efficacy in other diseases like HER2+ve breast cancer. Pharmacokinetics of crenolanib and sorafenib and FLT3-TKD mutation analysis will be presented. Accrual to this trial continues. Disclosures Inaba: Arog: Research Funding. Eckardt:Arog: Employment, Equity Ownership.

Description: Background: Crenolanib is a novel, type I, oral pan-FLT3 inhibitor with in vitro activity against FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutations. Crenolanib has a half-life of 6-8 hrs and does not accumulate after chronic dosing. As a single agent, an overall response rate (ORR) of 30% (CR/CRi 19%, PR 12%) has been reported among patients (pts) with multiply relapsed/refractory (R/R) AML pts with FLT3 mutations despite sixty-five percent of the patients having prior exposure to FLT3 inhibitors. We report data from the first 13 pts with R/R FLT3+ AML treated with salvage idarubicin (Ida) and high-dose ara-C (HiDAC) followed by crenolanib. Design: Pts received Ida (12 mg/m2 for 3d) with HiDAC (1.5 g/m2/d over 3 hrs for 4d or for 3d if 〉60y), followed by crenolanib starting on d5 and continued until 72 hrs. prior to next chemotherapy regimen. Standard rolling-6 design was implemented with dose escalation of crenolanib as follows: 60 mg TID (dose level 1), 80 mg TID (dose level 2), and 100 mg TID (dose level 3). Responding pts were eligible to proceed to allogeneic stem cell transplant (allo-SCT) or receive consolidation with ara-C (750 mg/m2 for 3d) and Ida (8 mg/m2 for 2d) followed by crenolanib at the same dose received during induction. Patients could then continue on maintenance with crenolanib. Post-SCT crenolanib maintenance therapy was not allowed. Results: To date, all 3 dose escalation cohorts have been completed, which included 13 pts (11 males, 2 female) with a median age of 51 yrs (range 19-73). All pts had R/R FLT3+ AML. 6/13 pts had relapsed after 1 or 2 prior AML therapies, with the remaining 7 pts having 3-8 prior AML therapies (allo-SCT in 3). Nine pts had received prior FLT3 inhibitors including sorafenib (n=7), quizartinib (n=2), and E6201 (n=2). Nine pts had a FLT3-D835 kinase domain mutation, of which 4 pts also had FLT3-ITD; the remaining 4 pts had FLT3-ITD alone. Conventional cytogenetic testing included: normal karyotype (n=4; 31%), miscellaneous (n=5; 36%), and complex (n=4; 31%). Besides FLT3, multiple other leukemia-associated mutations were present at baseline: NPM1 (36%), DNMT3A (36%), NRAS/KRAS (27%), WT1 (18%), TET2 (18%), RUNX1 (18%), IDH1 (9%), IDH2 (9%), and ASXL1 (9%). No dose-limiting toxicities were observed at any of the dose levels explored and there were no dose reductions required. Non-hematologic adverse events assessed as possibly or probably related to crenolanib were all grade 1 in severity, including: nausea (n=2), vomiting (n=2), diarrhea (n=1), and abdominal pain (n=1). No deaths were attributed to crenolanib. The ORR in 11 pts evaluable for response was 36% (1 CR, 3 CRi; 2 not evaluable because of early discontinuation of therapy). Among 6 pts who received ≤2 prior AML therapies, 4 pts (67%) achieved a CR/CRi (including 2 pts with prior exposure to FLT3 inhibitors). These remissions occurred in pts with FLT3-ITD (n=2), FLT3-D835 (n=1) and FLT3-ITD+FLT3-D835 (n=1) (Table 1). No CRs were seen in the 5 pts who had 3 or more prior therapies (including 3/5 who had received prior FLT3 inhibitors) before coming on study. Three CRi pts have undergone allo-SCT: 1 pt (43/F) achieved CRi (with persistent FLT3-ITD) after 1 cycle and maintained remission with FLT3-ITD negativity for 6 months post allo-SCT, 1 pt (67/M) achieved CRi with FLT3-D835 negativity after 2 cycles and maintained remission for 3 months post allo-SCT, and 1 pt (58/M) achieved CRi after 1 cycle and relapsed 1.5 months post allo-SCT. One pt (73/M) achieved a full CR with FLT3 negativity and count recovery and is currently receiving crenolanib maintenance. The median OS for all patients was 259d; median OS by prior therapies was 259d for pts with ≤ 2 prior therapies, and 53d for pts with ≥ 3 prior therapies (Figure 1). Conclusions: Full doses of crenolanib (100 mg TID) can be safely combined with idarubicin and HiDAC in multiply relapsed/refractory FLT3+ AML. There is suggestion of clinical efficacy particularly among pts with only 1-2 prior therapies. This trial is being expanded to allow combination of full dose crenolanib with other standard salvage chemotherapies, including MEC (mitoxantrone, etoposide, cytarabine) and FLA(G)-IDA (fludarabine, cytarabine, idarubicin w/ or w/o G-CSF). Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Burger:Pharmacyclics: Research Funding. Eckardt:Arog: Employment, Equity Ownership. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Description: Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2,000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19.5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration—36.84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.

Description: Despite the widespread usage of hydroxyurea in the treatment of both malignant and nonmalignant diseases and a recent expansion in the recognition of its potential therapeutic applications, there have been few detailed studies of hydroxyurea's pharmacokinetic (PK) behavior and oral bioavailability. Parenteral administration schedules have been evaluated because of concerns about the possibility for significant interindividual variability in the PK behavior and bioavailability of hydroxyurea after oral administration. In this PK and bioavailability study, 29 patients with advanced solid malignancies were randomized to treatment with 2,000 mg hydroxyurea administered either orally or as a 30-minute intravenous (IV) infusion accompanied by extensive plasma and urine sampling for PK studies. After 3 weeks of treatment with hydroxyurea (80 mg/kg orally every 3 days followed by a 1-week washout period), patients were crossed over to the alternate route of administration, at which time extensive PK studies were repeated. Three days later, patients continued treatment with 80 mg/kg hydroxyurea orally every 3 days for 3 weeks, followed by a 1-week rest period. Thereafter, 80 mg/kg hydroxyurea was administered orally every 3 days. Twenty-two of 29 patients had extensive plasma and urine sampling performed after treatment with both oral and IV hydroxyurea. Oral bioavailability (F) averaged 108%. Moreover, interindividual variability in F was low, as indicated by 19 of 22 individual F values within a narrow range of 85% to 127% and a modest coefficient of variation of 17%. The time in which maximum plasma concentrations (Cmax) were achieved averaged 1.22 hours with an average lag time of 0.22 hours after oral administration. Except for Cmax, which was 19.5% higher after IV drug administration, the PK profiles of oral and IV hydroxyurea were very similar. The plasma disposition of hydroxyurea was well described by a linear two-compartment model. The initial harmonic mean half-lives for oral and IV hydroxyurea were 1.78 and 0.63 hours, respectively, and the harmonic mean terminal half-lives were 3.32 and 3.39 hours, respectively. For IV hydroxyurea, systemic clearance averaged 76.16 mL/min/m2 and the mean volume of distribution at steady-state was 19.71 L/m2, whereas Cloral/F and Voral/F averaged 73.16 mL/min/m2 and 19.65 L/m2, respectively, after oral administration. The percentage of the administered dose of hydroxyurea that was excreted unchanged into the urine was nearly identical after oral and IV administration—36.84% and 35.82%, respectively. Additionally, the acute toxic effects of hydroxyurea after treatment on both routes were similar. Relationships between pertinent PK parameters and the principal toxicity, neutropenia, were sought, but no pharmacodynamic relationships were evident. From PK, bioavailability, and toxicologic standpoints, these results indicate that there are no clear advantages for administering hydroxyurea by the IV route except in situations when oral administration is not possible and/or in the case of severe gastrointestinal impairment.