Efficacy Of Dasatinib In Patients Research Articles

XS004 Dasatinib (XS004) Improves Variability and Bioavailability in Humans Using Amorphous Solid Dispersion Formulation of Dasatinib with Potential Implications for Its Clinical Use

Tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of patients with chronic myeloid leukemia (CML). Dasatinib, one of the most utilized TKIs, is formulated as a crystalline dasatinib monohydrate. This results in a low and pH-dependent solubility with highly variable intestinal absorption and plasma pharmacokinetics (PK). Poor dissolution of an anti-cancer drug is generally expected to result in low and highly variable bioavailability and plasma exposure, consequently jeopardizing an optimal and anticipated therapeutic response. Applying bioavailability enhancement techniques, such as amorphous solid dispersion (ASD) formulations, will reduce variability in plasma PK as solubility and intestinal absorption improves, and most importantly increase patient compliance, safety, and efficacy. XS004 dasatinib (XS004) (Xspray Pharma, Solna, Sweden) is a novel immediate release and ASD formulation of dasatinib produced with the HyNap™ technique. XS004 is designed to provide an increased solubility of dasatinib in acidic to neutral pH conditions, mitigating gastric pH dependency and leading to reduced variability and increased absorption and bioavailability of dasatinib. Here we report the results of a clinical study comparing the PK of XS004 and the original dasatinib product (reference) (Sprycel®, Bristol-Myers Squibb Company, NJ, USA), and results of a comparative in vitro solubility study. Plasma PK parameters were compared following single doses of XS004 (100 mg dasatinib ASD) and the reference product (140 mg dasatinib non-ASD) in 107 healthy volunteers at fasting conditions in a randomized, single dose, laboratory-blinded, 2 treatments, 4 period, 2 sequence, full replicate crossover, bioavailability study. In the in vitro study, dasatinib ASD and dasatinib monohydrate solubility was determined in the gastrointestinal (GI) relevance pH-interval of 1.2 to 8.0 at 37°C. The plasma exposure of XS004 (100 mg dasatinib ASD) was equivalent for all PK parameters with the reference product (140 mg dasatinib non-ASD) with least square geometric mean Cmax, AUC0-24h and AUC0-inf ratios of 100.8 (CI 90%, 90.8-112.0%), 94.2 (CI 90%, 87.5-101.4) and 92.2 (CI 90%, 86.2-98.6), respectively (Table 1). The intra-subject variability (coefficient of variation (CV%)) for AUC0-24 and AUC0-inf for the reference was approximately 3-fold and 2.5-fold higher than for XS004 (Table 2). For Cmax, the intra-subject variability was approximately 2-fold greater with the reference compared to XS004 (Table 2). The inter-individual variability was generally higher in all plasma PK parameters for the reference formulation (range: 38-128%) when compared to XS004 (range: 20-48%). There was considerably greater inter-subject variability (CV%) in Cmax, AUC0-24 and AUC0-inf after single dose administration of the reference product, when compared with XS004 (Table 2). The inter-individual variability was 4.5-fold, 4.3-fold and 4.8-fold greater for the reference product when compared to the test formulation for the three PK parameters. The in vitro solubility study provided higher apparent solubility of dasatinib ASD compared to the original crystalline dasatinib, explaining the improved in vivo GI absorption for the new preparation. Dasatinib ASD was unaffected and kept in solution over at least 2 hours in the pH range 1.2 to 5.0 and the solubility was at least 10-fold higher for dasatinib ASD compared to the dasatinib monohydrate at pH-values in the range 5.0 to 8.0. In conclusion, XS004 displayed a more robust and consistent GI-absorption and bioavailability, with significantly reduced intra- and inter-individual variability in plasma dasatinib concentrations, compared to the original non-ASD formulated dasatinib. The in vitro data showed that the solubility of dasatinib ASD was substantially less pH-dependent at GI-relevant pH values of 2.0 to 5.0. The results suggest that XS004, an ASD formulation of dasatinib, with improved biopharmaceutical features, reduces the risk of both low exposure and high exposure outliers, with lower risk of exposure outside the therapeutic window. This would likely diminish the risk of adverse events and optimize the therapeutic efficacy of dasatinib in patients with CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and efficacy of dasatinib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib: A single arm, multicenters, phase 2 trial.

138 Background: Regorafenib is recommended to treat advanced gastrointestinal stromal tumor (GIST) refractory to imatinib and sunitinib. However, the efficacy is not satisfied, other active agents need to be explored to advanced patients. Methods: In this single arm, multi-center, phase 2 trial, we enrolled patients aged 18 years and older with advanced GIST who had received previous imatinib and sunitinib treatment. Participants were treated with oral dasatinib 50mg twice a day for 2 weeks. If patients were tolerable, then they received dasatinib 70mg twice a day treatment, to tumor progression or intolerable toxicities. The primary endpoint was RECIST-based progression-free survival (PFS) in the intention-to-treat population. The secondary endpoints included response rate, overall survival (OS) and advent events. ctDNA will be analysis in some patients to explore the sensitive biomarker to dasatinib. Results: From May 2016 to June 2018, 58 patients from nine medical centers were enrolled in this study. Two patients had partial response and disease control rate was 62.0%. The median PFS was 3.0 months (95% CI, 2.6-3.4 months). There was no statistic difference of PFS in both subgroup with different primary mutations and in subgroup with different secondary mutations. The patients with wild type GIST had a trend of longer PFS of 5.5 months. In 4 patients with PDGFRA D842V mutation, two patients had stable disease. The median OS was 14.0 months (95% CI, 10.8-17.2 months). The most frequently observed grade 3 adverse events included anemia (10.3%), diarrhea (1.7%). The analysis of ct DNA is ongoing. Conclusions: Dasatinib is an active treatment for patients with GIST who are refractory to imatinib and sunitnib. This study is registered with ClinicalTrials.gov, NCT02776878 . Clinical trial information: NCT02776878.

Abstract IA11: The role of bone microenvironment in the lethal progression of prostate cancer

Abstract Lethal prostate cancer (PCa) is clinically characterized by bone-homing and bone- forming metastases, and bone is frequently the initial organ involved in castrate-resistant progression. These clinical observations led investigators to develop bone-tropic radiopharmaceuticals to treat men with advanced PCa. The ability of the bone-homing alpha emitter (RAD-223) to prolong progression free and overall survival establishes the therapeutic relevance of targeting bone 1. The long accepted paradigm of PCa progression has been dominated by the model of evolution from androgen dependence to androgen independence under the selective pressure of castration. Thus, Src family kinases (SFKs) were investigated experimentally and clinically for the treatment of putative “androgen independent” PCa, as SFKs play a role in both tumor growth and bone turnover. The roles of SFKs in migration, invasion, survival of tumor cells, and osteoclast and osteoblast function in tumor microenvironment were supported by numerous clinical and laboratory observations 2, 3. Despite promising phase I /II reports of dasatinib, a multikinase and potent SFK inhibitor, in men with advanced PCa 4, 5, a phase III trial failed to yield the expected survival advantage 6. The result of this trial highlights the difficulties in translating data from cell line models to biologically heterogeneous clinical PCa and in transitioning from phase I/II to phase III clinical trials. The efficacy of dasatinib was not observed likely due to persistent AR signaling, which remains the primary driver of progression in bone by the transition from paracrine to intracrine androgen signaling 7. Based on these considerations, we are testing the efficacy of an androgen biosynthesis inhibitor in combination with dasatinib to better understand the relevance of mechanism(s). A co–clinical investigational strategy is being applied to better define biomarkers to predict clinical efficacy. These studies also highlight the importance of preclinical work that utilizes models that better reflect the heterogeneity of PCa. This problem is partly overcome by patient- derived xenografts (PDX) 8, 9 10. These models reflect many aspects of PCa in bone and can be used to identify therapy targets and better identify both mechanisms of drug efficacy and development of resistance. Studies in PDX have led to identification of FGF signaling as a therapy target 11. Additional studies in PDX implicated the tumor microenvironment in the striking bone responses observed with cabozantinib 13. These observations led us to propose a model of prostate cancer progression founded on the hypothesis that cancer progresses from being an endocrine-driven cancer (Dihydrotestosterone-dependent) to paracrine/intracrine driven (microenvironment-dependent), and then finally to a cell autochthonous phase 12. Continued studies should lead to decisions on therapy treatment that are based on an understanding of markers that predict disease progression. This new paradigm will also result in more effective therapy combinations.

Once-daily Dasatinib: Expansion of Phase II Study Evaluating Safety and Efficacy of Dasatinib in Patients With Metastatic Castration-resistant Prostate Cancer

To determine the activity and tolerability of 100-mg once-daily (QD) dasatinib in patients with metastatic castration-resistance prostate cancer (CRPC). Dasatinib, an oral Src family kinase inhibitor, has demonstrated both preclinical and clinical activity with twice-daily dosing in patients with metastatic CRPC. Chemotherapy-naive men with metastatic CRPC and increasing prostate-specific antigen levels were treated with dasatinib 100 mg QD. The primary measurement was a composite lack of disease progression, according to the Prostate Cancer Working Group 2 criteria, determined every 12 weeks during the study. The other analyses included changes in the prostate-specific antigen level, bone lesions, soft tissue disease, and bone turnover markers (urine N-telopeptide and bone alkaline phosphatase). The present trial was designed before the publication of the recent Prostate Cancer Working Group 2 criteria; however, the analyses are presented to conform to the updated guidelines. A total of 48 patients received dasatinib. A lack of disease progression was observed in 21 patients (44%) at week 12 and in 8 (17%) at week 24. Urine N-telopeptide was reduced by ≥40% from baseline in 22 (51%) of 43 patients, and bone alkaline phosphatase was decreased in 26 (59%) of 44 patients. Dasatinib was well-tolerated, with only 6 patients (13%) with drug-related grade 3-4 adverse events and 3 (6%) with grade 3 adverse events. The most common treatment-related adverse events (≥20%) were fatigue, nausea, diarrhea, headache, and anorexia. Dasatinib 100 mg QD has a favorable safety profile and maintains a similar degree of activity as the previously reported twice-daily dosing schedules. These data support additional study of dasatinib 100 mg QD for metastatic CRPC.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Abstract 338▪▪This icon denotes an abstract that is clinically relevant.Dasatinib, a potent inhibitor of ABL and SRC, is approximately 300 times more potent than imatinib in vitro and has significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims:To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods:The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 months from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results:Sixty-two pts have been enrolled (31 on the QD schedule, 31 BID). Median age was 47 years (yrs) (range 18–76 yrs). Median follow-up is 24 months (mo) (range, 1 to 39 mo). All 45 pts who were not in CHR at the start of therapy achieved CHR. Among 50 pts followed for at least 3 months, 49 (98%) achieved complete cytogenetic response (CCyR). Major molecular response has been achieved in 35 (70%), including 5 (10%) with complete molecular response. The CCyR rate at different timepoints (intention-to-treat) compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily:Mo on therapyPercent with CCyRDasatinibImatinibImainibDasatinibImatinib 400mgImatinib 800mg3823763694548512986589188967892484678830836789Major molecular response was achieved by 45% by 12 mo and 71% by 24 mo (corresponding rates with imatinib 400mg 34% and 55%, and with imatinib 800mg 58% and 66%, respectively). There was a trend for higher MMR rate with the QD schedule: overall 75% vs 65% (p=0.54), and by 12 months 52% and 38% (p=0.54). Grade 3-4 non-hematologic toxicity (regardless of causality) included fatigue (6%), pain (muscle or joint) (6%), dyspnea, neuropathy and memory impairment (5% each). Pleural effusion occurred in 13% evaluable pts (grade 3-4 in 2%). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 10%, neutropenia 21%, and anemia 6%. Thirty (48%) of 62 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (3%) vs BID (10%; p=0.26). Three pts lost CCyR: 2 because of non-compliance, 1 due to treatment interruption because of pleural effusion. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 88%. All patients are alive. Conclusion:Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 18 months was 71%, with a favorable toxicity profile. Because of favorable trends in response and toxicity, only QD arm will continue accrual. Disclosures:Cortes:BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of dasatinib as initial therapy for CML, and indication for which dasatinib is not approved.. Borthakur:BMS: Speakers Bureau. O'Brien:BMS: Research Funding. Jabbour:BMS: Speakers Bureau; Novartis: Speakers Bureau. Ravandi:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Genzyme: Research Funding; BMS: Research Funding; MGI Pharma (Eisai): Research Funding; Novartis: Research Funding.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP.Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP.Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD).Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily:Percent with CCyR (No. evaluable)Mo on therapyDasatinibImatinib 400mgImatinib 800mgP value378 (45)37 (49)62 (202)0.0003693 (41)54 (48)82 (199)<0.00011297 (35)65 (48)86 (197)0.00011888 (33)68 (38)89 (179)0.0042480 (25)70 (40)88 (173)0.006MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%.Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 >3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 >200 nM; n=21) achieved a response. Among 70 patients with >1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 >3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 >3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 >3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes.TableAnalysis by dasatinib IC50No BCR-ABL mutationBCR-ABL mutationBCR-ABL mutation treated with 100 mg QD>3 nM (excl. T315I)3 nM*Unknown IC50**Patients, n641402494425483Response rates (≥24 mos of follow-up), %CHR939090829496MCyR655655345873CCyR564441254754MMR453336183443Median time to MCyR, mos2.82.92.85.72.92.8Median time to CcyR, mos3.05.33.05.75.43.424-mo PFS (95% CI), %83 (79.8–86.5)70 (65.3–75.2)73 (60.1–86.3)48 (31.2–64.7)73 (66.6–78.9)89 (82.3–96.3)24-mo OS (95% CI), %94 (91.4– 95.7)89 (85.1– 92.1)90 (81.2– 98.3)81 (68.8– 93.8)90 (85.8– 94.2)96 (91.2–100)Some patients had >1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 >3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50.

Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP)

7013 Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC with significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Forty pts have been enrolled (21 on the QD schedule, 19 BID). Median age was 41 years (yrs) (range 18–76 yrs). The rate of complete cytogenetic response [CCyR] at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily (Table 1). At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. There was a trend for improved molecular response with the QD schedule. Grade 3–4 non-hematologic toxicity (regardless of causality) included fatigue (5%), headache (3%), and rash (3%). Pleural effusion occurred in 5 (13%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) were thrombocytopenia 10%, neutropenia 5%, and anemia 3%. With median follow-up of 18 mo, 18 (46%) pts required transient treatment interruption and dose reduction. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Conclusions: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues. Months on therapy Percent with CCyR (No. evaluable) P value Dasatinib Imatinib 400 mg Imatinib 800 mg 3 mo 72 (36) 37 (49) 62 (202) 0.0003 6 mo 94 (34) 54 (48) 82 (199) <0.0001 12 mo 100 (26) 65 (48) 86 (197) 0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP.Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤ 0.05% in our lab) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD) schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed.Results: Thirty-seven pts have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41 years (yrs) (range 18–76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median baseline WBC count was 29.1 x 109/L (range 3.4–300.0). Three pts had clonal evolution at start of therapy. At 3 mo, complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg) and high-dose (800 mg) at our institution:At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain (n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1–2). Grade 3–4 non-hematologic toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural effusion occurred in 5 (14%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) included neutropenia in 4 (11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%) pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant difference in grade 3–4 toxicity by treatment schedule.Conclusion: Rapid, complete cytogenetic responses to dasatinib 100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be associated with less toxicity. Accrual to this trial continues.Percent with CCyR (No. evaluable)Months on TherapyDasatinibImatinib 400 mgImatinib 800 mgP value3mo79 (33)37 (49)62 (202)0.00036mo94 (32)54 (48)82 (199)<0.000112mo100 (24)65 (48)86 (197)0.0001

Efficacy of Dasatinib in Patients with Accelerated-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-A (CA180-005).

Dasatinib (SPRYCEL®), a potent inhibitor of BCR-ABL and SRC-family kinases, has been shown to be effective and safe for patients with accelerated-phase chronic myelogenous leukemia (AP-CML) who are resistant or intolerant to imatinib. START-A is a 39-center, international study to which patients with AP-CML who failed prior imatinib therapy were enrolled between December 2004 and July 2005. Here we report an update of the efficacy and safety of dasatinib (70 mg BID) from this open-label study of 174 patients with imatinib-resistant (n=161) or -intolerant (n=13) AP-CML after a median follow-up of 14.1 mo (range 0.1–21.7). Dose escalation (100 mg BID) or reduction (50 or 40 mg BID) were allowed for a lack of response or toxicity, respectively. Median time from original diagnosis of CML was 82 mo (range 4–359). Prior therapy included interferon-α in 72% of patients and stem-cell transplantation (SCT) in 13%; 52% had received prior imatinib doses >600 mg/d and 59% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 79% of patients, major cytogenetic response (MCyR) in 33%, and complete cytogenetic response (CCyR) in 21%. CHRs were attained by 45% of patients, while MCyRs and CCyRs were seen in 39% and 32%, respectively. Responses were achieved irrespective of imatinib status (with MCyR of 39% for both imatinib-resistant and -intolerant subgroups), prior stem-cell transplantation (26% MCyR), or the presence of prior BCR-ABL mutations (with the exception of T315I) (40% MCyR for both the mutation-positive and -negative subgroups). Twelve-month progression-free survival and overall survival were 66% and 82%, respectively. Dose interruptions were required for 85% of patients and dose reduction for 65%; the average daily dose administered was 126 mg (range 32–196). Grade 3–4 neutropenia and thrombocytopenia were reported in 76% and 82% of patients. Non-hematologic toxicity was generally mild to moderate and consisted primarily of diarrhea (52% all grades, 8% grade 3–4), headache (29%, <1%), nausea (28%, <1%), pleural effusion (27%, 5%), fatigue (26%, 4%), and superficial edema (22%, 1%). Dasatinib is effective in patients with AP-CML following imatinib treatment failure and the overall benefit-risk evaluation is favorable in this poor prognosis population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Response to Dasatinib after Imatinib Failure According to Type of Preexisting BCR-ABL Mutations.

Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with preclinical activity against 20/21 imatinib resistant BCR-ABL mutations and clinical phase I/II efficacy in patients with chronic myelogenous leukemia (CML) and BCR-ABL positive acute lymphoblastic leukemia (ALL). We sought to establish a relationship between type of preexisting BCR-ABL mutations associated with imatinib resistance and efficacy of dasatinib in patients (pts) with CML and ALL. We have investigated 872 peripheral blood samples from 394 pts (53% male, median age 60 yrs, range 17–85) who had been enrolled in international phase II studies investigating the activity of 70mg dasatinib BID after imatinib failure (chronic phase, CP, n=198; accelerated phase, AP, n=78; myeloid blast crisis, MyBC, n=53; lymphoid blast crisis, LyBC, or ALL, n=65).Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. During follow up, pts were monitored in 3-monthly intervals by RQ-PCR for BCR-ABL mRNA transcripts and by mutation analysis to determine the quantitative course of the preexisting mutation or the emergence of new mutations. Hematologic and cytogenetic response data have been collected sequentially for a median of 8 months (range, 2–11) after start of therapy. Prior to dasatinib, 46 different BCR-ABL mutations involving 36 amino acids were detected in 202/394 pts (51%). 162 pts showed one, 33 pts two, 6 pts three, and 1 pt four mutations. Mutations were observed in 84 pts in CP (42%), 47 pts in AP (60%), 23 pts in MyBC (43%), and 48 pts in LyBC and ALL (74%). In patients with mutations, hematologic response was 91% in CP, 62% in AP, 41% in MyBC, and 34% in LyBC/ALL (p<0.01), major and complete cytogenetic response did not differ significantly (47% and 34% in CP, 35% and 27% in AP, 33% and 28% in MyBC, 53% and 51% in LyBC/ALL). Major cytogenetic response rates were comparable in pts bearing no mutations (44%), mutations within the P-Loop (43%), SH2 domain (47%), activation loop (56%), or other sites (49%), but not for T315I (0%, p<0.001). Sorting individual pts by the underlying mutation and cellular IC50 values of dasatinib revealed clearly higher hematologic and cytogenetic response rates in those with lower IC50 values. In line with the virtual insensitivity to dasatinib in vitro, none of the 17 pts carrying a T315I mutation showed any hematologic response. Two distinct patterns of response were observed:a parallel decrease of the BCR-ABL load and the mutated clone ora decrease of the BCR-ABL load followed by a decrease of the mutated clone after a delay of up to 4–6 months.Up until now 5 pts developed new mutations associated with dasatinib resistance (T315I, n=2, AP and MyBC pts; F317L+F486S, n=2, LyBC and MyBC pts; E507G, n=1, CP pt). We conclude that dasatinib is capable of inducing hematologic and cytogenetic remissions in a significant proportion of imatinib resistant pts harboring BCR-ABL mutations, except T315I. Response dynamics depend on the individual type of mutation which may be a basis for individual dose adaptation according to the mutation pattern.

Clone wars in CML

In many recent leukemia presentations, the suggestion that leukemia can be turned into a long-term minimum residual disease, consistent with prolonged life, but without offering the prospect of cure, is raised. Obviously, any intervention that prolongs life at a reasonable quality of life is a significant advance. However, there is precious little evidence to support the notion that leukemia can lie dormant for many years without undergoing genetic change. Such changes are usually associated with eventual clinically overt relapse and resistance to subsequent therapy. Imatinib has transformed the survival potential for patients with chronic phase CML, has had a significant impact for those in accelerated phase and had a minimal impact for those patients with blastic phase disease.1 It is clear that most patients in chronic phase who have clinically responded to imatinib and who have achieved complete cytogenetic responses have easily detectable disease at the molecular level. The connection between the amount of 'residual' disease, detectable abl mutations in the leukemic cells and overt evidence of relapse at the molecular, cytogenetic or hematological levels is a major focus of interest at present.2 The qualitative and quantitative relationships between non-mutated and mutant clones are not well understood. The percentage of patients with detectable mutations varies markedly by report and by stage of disease. The mechanism of resistance in approximately half of the patients who have acquired imatinib resistance but no detectable mutation is unclear. A major emerging issue is that of patient compliance and persistence – patients are not good at taking oral medications long-term. Possible mechanisms of true imatinib resistance that do not involve abl mutations include overexpression of Bcr-abl, increased MDR activity, cytogenetic progression or possibly the involvement of other kinases including members of the src family.1 The next generation abl-kinase inhibitors AMN-107 and Dasatinib can both inhibit in vitro all of the common Bcr-abl mutations except T315I.3, 4, 5 In patients, the activity of either drug against most of these mutations, except T315I, has been seen (Giles F et al. A phase I/II study of AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, on a continuous daily dosing schedule in adult patients with imatinib-resistant advanced phase chronic myeloid leukemia or relapsed/refractory Philadelphia chromosome acute lymphocytic leukemia. ASH Annual Meeting Abstracts 2004; 104: 22; Hochhaus A et al. Efficacy of Dasatinib in patients with chronic phase Philadelphia chromosome-positive CML resistant or intoleant to imatinib: first results of the CA180013 'START-C' phase II study. ASH Annual Meeting Abstracts 2005; 106: 41).

Efficacy of Dasatinib in Patients with Chronic Phase Philadelphia Chromosome-Positive CML Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C' Phase II Study.

After 3 years of imatinib (IM) therapy, hematologic relapse occurred in 7% of newly diagnosed chronic myeloid leukemia (CML) pts, and 20% of chronic phase (CP)-CML pts after failure to interferon alpha (IFN), which was mostly associated with BCR-ABL mutations and/or clonal evolution. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Dasatinib has been shown to have 325-fold greater potency compared with imatinib in cells transduced with BCR-ABL and is active against 18/19 BCR-ABL mutants tested that confer imatinib resistance. A Phase I dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients in CP-CML, which was followed by ‘START-C' (CA180013), the first Phase II open-label study in dasatinib in CP IM-R or IM-I CML pts. Between February-May 2005, 186 pts (86 male, median age 60 yrs [range 25–82]) were recruited from 40 institutions. Data from 30 pts accrued prior to March 20, 2005, are available for the initial analysis. The definition of IM-R required a failure of IM doses >600 mg/d or the occurrence of BCR-ABL mutations associated with virtual insensitivity to IM. Dasatinib was administered at 70 mg twice daily (BID), based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in pts lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. In the group of 30 evaluable pts, median age was 59 yrs (range 25–78), 50% were male. Median time from diagnosis of CML was 70.8 months (range 7.9–202.1). Prior therapy included IFN in 77% and stem cell transplantation in 10% of pts. 60% of pts were considered IM-R, with the maximum prior IM dose of >600 mg in 60% of pts. 60% of pts received IM for >3 yrs. Best response to prior IM therapy was a complete hematologic response in 83%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 17% and 13% of pts, respectively. Median (range) baseline hematologic parameters were: white blood cells 16.1/nl (4.3–84.3); platelets 437/nl (173–960). IM-R BCR-ABL mutations were documented in 6/12 pts with currently available data. Within the first 3 months, 2 pts required dose escalations and 6 had a dose reduction, mostly due to thrombocytopenia. Hematologic responses were documented in 21/24 pts with available data. From 16 pts evaluable for 3-month cytogenetic analysis, 7 cytogenetic responses were observed, including CCyR (n=4) and PCyR (n=1). Analysis of molecular response is in progress. Grade 3/4 neutropenia or thrombocytopenia were reported in 6 pts each. Most common non-hematologic toxicities were diarrhea (6 pts, 1 grade 3), rash (5 pts, all grade 1), edema (3 pts, all grade 1) and pleural effusion (1 pt, grade 2). In conclusion, despite the short follow up, major hematologic and cytogenetic responses were seen in a group of pretreated CP-CML pts, which further supports the activity of dasatinib in this disease. An updated analysis based on 186 pts with 6-month follow up will be presented.