scholarly journals Population Pharmacokinetic (PK)/Pharmacodynamic (PD) Modeling of Myelosuppression in Patients with Hematologic Malignancies for CPX-351 and Standard-of-Care 7+3 Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4037-4037
Author(s):  
Qi Wang ◽  
Sarah F. Cook ◽  
Scott A. Van Wart ◽  
Donald E. Mager ◽  
Stefan Faderl
Keyword(s):  
Platelet Count ◽  
Median Time ◽  
Median Duration ◽  
Model Development ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Compartment Models ◽  
Platelet Counts ◽  
Population Pk ◽  
Equity Ownership

Abstract CPX-351 (Vyxeos®), a liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, has demonstrated a significant survival benefit vs standard 7+3 in patients (pts) with high-risk/secondary AML. A population PK/PD analysis assessed the correlation between cytarabine and daunorubicin plasma concentrations and myelosuppressive effects (neutropenia, thrombocytopenia) of CPX-351 and 7+3. The PK/PD population for model development included pts with advanced hematologic malignancies from 3 clinical studies. For CPX-351 and 7+3, respectively, 129 and 79 pts were included in the final neutropenia PK/PD analysis and 137 and 86 pts were included in the final thrombocytopenia PK/PD analysis. For the neutropenia model, median age and body weight were 67 y (range: 23-81) and 78.7 kg (39.5-156.5) for CPX-351 and 68 y (60-75) and 83.0 kg (53.9-136.0) for 7+3. PK/PD analyses were conducted using nonlinear mixed-effects modeling in NONMEM. Pt-specific PK profiles were simulated using previously developed population PK models for CPX-351 and 7+3. Blood cell dynamics were described by transit-compartment models with proliferating, maturating, and circulating neutrophils or platelets. The effects of CPX-351 or 7+3 were applied to the proliferation phases of the compartment models by a molar composite PK driver (plasma cytarabine + daunorubicin). Inhibition of proliferation of blood cells by CPX-351 and 7+3 is assumed to be similar, via a sigmoidal Imax function. Co-medication of granulocyte colony stimulating factor (GCSF) or platelet infusion was accounted for during model development. Covariates (eg, demographics, clinical laboratory measures, disease status) were evaluated. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and graphical representations of goodness-of-fit. In the final neutrophil PK/PD models, baseline circulating neutrophil counts were similar for CPX-351 (3.55 × 109/L) and 7+3 (3.76 × 109/L). Mean transit times (MTT) between maturation compartments were estimated at values of 113 h for CPX-351 and 88 h for 7+3. Effects of GCSF on neutrophil production were assumed to be similar for CPX-351 and 7+3. Both treatments had similar maximum inhibition on neutrophil proliferation, with Imax values around 1. However, estimated IC50 values were very different: 24.9 µM for CPX-351 and 0.0286 µM for 7+3. In the final platelet PK/PD models, baseline circulating platelet counts were the same (98.1 × 109/L) for both CPX-351 and 7+3. The MTTs between each compartment of the maturation processes were 91.2 h for CPX-351 and 120 h for 7+3. Drug-specific parameters for CPX-351 and 7+3, respectively, were as follows: Imax, 0.316 and 1; IC50, 0.324 and 0.0982 µM. To better understand the behavior of the models and parameter estimates, simulations were conducted to evaluate the temporal events of myelosuppression. Model simulations were conducted for 200 pts with characteristics similar to the PK/PD model population. During simulations, no platelet transfusion or GCSF was administered. Pts received CPX-351 100 units/m2 (cytarabine 100 mg/m2 + daunorubicin 44 mg/m2) as a 90-min IV infusion on Days 1, 3 and 5 or 7+3 (cytarabine 100 mg/m2/day IV for 7 days continuously + daunorubicin 60 mg/m2 IV on Days 1-3). Median time to initially observe a blood neutrophil count <0.5 × 109/L was longer following CPX-351 (8.3 d) vs 7+3 (7.4 d) treatment. The median duration with neutrophil counts <0.5 × 109/L was longer with CPX-351 (23 d) vs 7+3 (14 d). The median lowest neutrophil counts were well below 0.2 × 109/L for both CPX-351 (0.007 × 109/L) and 7+3 (0.026 × 109/L). Median time to initially observe a platelet count <50 × 109/L was 6.4 d after CPX-351 and 5.8 d after 7+3, while the median time to an observed platelet count <20 × 109/L was 10.8 d and 8.9 d, respectively. The median duration with platelet counts <20 × 109/L was longer with CPX-351 (18 d) vs 7+3 (8 d), and the median duration of platelet counts <50 × 109/L was 22 d and 15 d, respectively. The median lowest platelet counts were 11.3 × 109/L with CPX-351 and 4.7 × 109/L with 7+3. In summary, the median duration of myelosuppressive effects was longer with CPX-351 than 7+3, and the median time for initial detection of myelosuppression with CPX-351 was 1 to 2 days later than with 7+3, which might affect the clinical monitoring scheme. Disclosures Wang: Jazz Pharmaceuticals: Employment, Equity Ownership. Cook:Jazz Pharmaceuticals: Consultancy. Van Wart:Jazz Pharmaceuticals: Consultancy. Mager:Jazz Pharmaceuticals: Consultancy. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership.

Durable Responses with the JAK1/ JAK2 Inhibitor, INCB018424, In Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 313-313 ◽  
Author(s):  
Srdan Verstovsek ◽  
Francesco Passamonti ◽  
Alessandro Rambaldi ◽  
Giovanni Barosi ◽  
Peter J. Rosen ◽  
...  
Keyword(s):  
Median Duration ◽  
The United States ◽  
Study Medication ◽  
Employment Equity ◽  
Allele Burden ◽  
Platelet Counts ◽  
Upper Limit ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 313 Background: While advanced PV and ET patients at high thrombotic risk are managed primarily with HU, patients who are intolerant or refractory to HU have limited therapeutic options. Identification of a dominant gain-of-function mutation in the JAK2 kinase, V617F, in myeloproliferative neoplasms (MPNs), including PV and ET, provided a key rationale for the development of a molecularly targeted therapy for these diseases. Long term follow-up data from an ongoing trial of INCB018424, a selective JAK 1/ JAK 2 inhibitor, in PV and ET patients refractory or intolerant to HU are presented. Methods: Study 18424-256 is an uncontrolled open-label Phase 2 study being conducted at 6 sites in the United States and Italy. An initial 8-week run-in evaluation established 10-mg and 25-mg twice daily as starting doses for expansion cohorts in PV and ET, respectively; dose adjustments for safety and efficacy are allowed so that each subject is titrated to their most appropriate dose. For PV, response is defined based on Hct control in the absence of phlebotomy, improvement or elimination of palpable splenomegaly when present, and normalization of leukocytosis and thrombocytosis. For ET, response is defined based on improvement or normalization of WBC and platelet counts and, when present, elimination of palpable splenomegaly. PV results (n=34; median 108 months from diagnosis): After a median follow-up of 15 months (range 8–21), 97% of enrolled subjects achieved Hct control to <45% in the absence of phlebotomy, and all continued to maintain phlebotomy-independence at the time of last follow-up visit. Splenomegaly was present in 74% of subjects at entry: 59% of those achieved ≥ 50% reduction in palpable spleen length, or the spleen became non-palpable with all maintaining spleen response at the time of the last follow-up visit. Leukocytosis > 15×109/L was present in 47% of subjects and improved (≤ 15×109/L) or normalized (≤ upper limit of normal) in 88% and 63%, respectively. Thrombocytosis > 600×109/L was present in 38% of subjects and improved (≤ 600×109/L) or normalized (≤ upper limit of normal) in 92% and 69%, respectively. 59% of subjects achieved phlebotomy independence, resolution of splenomegaly and normalization of leukocytosis and thrombocytosis. 6 patients discontinued therapy (3 due to AEs, 2 withdrew consent, 1 for no response). Grade 3 AEs potentially related to study medication included thrombocytopenia (2 patients), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No Grade 4 drug-related AEs have occurred. ET results (n=39; median 84 months from diagnosis): After a median follow-up of 15 months (range 4–21), 49% of enrolled subjects normalized platelet counts to ≤ upper limit of normal after a median of 0.5 months and for a median duration of 3.5 months. 82% maintained platelet counts < 600×109/L, for a median duration of 9.8 months. Of 14 patients with baseline platelet counts > 1000×109/L, 13 have experienced > 50% reduction. 88% maintained normal WBC (median duration 14.5 months). Palpable spleens resolved in 3 of 4 subjects; 1 reduced >50% from baseline. 49% of subjects achieved normalization of WBC and platelet counts in the presence of non-palpable splenomegaly. 9 patients discontinued therapy (4 due to AEs, 2 withdrew consent, 3 for no response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No Grade 4 drug-related AEs have occurred. Both patient groups demonstrated reductions in patient-reported symptom scores for pruritus, night sweats, and bone pain. Of 26 PV patients reporting pruritus at baseline (median score of 6 on a 10-point scale), 24 reported scores of 0 after a median duration of 1 month and for a median duration of 7 months. 42% of PV and 56% of ET patients had at least a 20% decrease in JAK2V617F allele burden; 6% of PV and 12% of ET had >50% decrease. Clinical responses were unrelated to the presence/absence of JAK2V617F mutation at entry or to the allele burden changes following treatment. Conclusions: Rapid and durable clinical benefits (normalization of hematological parameters, resolution of splenomegaly and alleviation of symptoms) have been demonstrated in advanced PV and ET patients with >1 year of follow-up. In this study, INCB018424 continues to be a well tolerated, effective therapy in patients with PV and ET refractory or intolerant to hydroxyurea. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Levy:Incyte Corporation: Employment, Equity Ownership. Bradley:Incyte Corporation: Employment. Garrett:Incyte Corporation: Employment. Vaddi:Incyte corporation: Employment. Huber:Incyte Corporation: Employment, Equity Ownership. Schacter:Pfizer Corporation: Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.

Final Results of Open-Label Treatment with Eltrombopag During ENABLE 1: A Study of Eltrombopag As An Adjunct for Antiviral Treatment of Hepatitis C Virus Associated with Thrombocytopenia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2232-2232 ◽  
Author(s):  
Geoffrey Dusheiko ◽  
Nezam H Afdhal ◽  
Edoardo Giannini ◽  
Pei-Jer Chen ◽  
Kwang-Hyub Han ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hepatitis C ◽  
Research Funding ◽  
Antiviral Treatment ◽  
Treatment Phase ◽  
Open Label ◽  
Employment Equity ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 2232 Introduction: Thrombocytopenia (TCP) is a common complication of cirrhosis in patients with hepatitis C virus (HCV) infections (Louie et al 2011); the presence of TCP impairs the ability to initiate peginterferon alpha (PEG) therapy and necessitates PEG dose reduction or discontinuation, thus reducing the potential for sustained virologic response (SVR). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic immune thrombocytopenia, increases platelet counts in patients with TCP due to HCV-related cirrhosis (McHutchison et al 2007). ENABLE 1 was a phase 3, multicenter, two-part study of eltrombopag for the treatment of HCV-associated TCP. Part 1 involved open-label, pre-antiviral treatment with eltrombopag. Patients achieving platelet counts ≥90,000/μL were randomized in Part 2 to receive eltrombopag or placebo in combination with antiviral therapy (PEG-2a plus ribavirin). Aim: To assess the safety and efficacy of eltrombopag during the open-label, pre-antiviral treatment phase (Part 1) of ENABLE 1 in patients with cirrhosis. Methods: Patients with chronic HCV and a baseline platelet count <75,000/μL were enrolled. In Part 1, all patients received open-label oral eltrombopag (25 mg daily with dose escalations every 2 weeks to a maximum dose of 100 mg) for up to 9 weeks or until platelet counts reached ≥90,000/μL. Patients who failed to achieve platelet counts ≥90,000/μL following 3 weeks of eltrombopag 100 mg daily did not enter Part 2 and attended scheduled follow-up visits. Patients achieving these counts were randomized 2:1 to eltrombopag or placebo (Part 2) at the final dose received in Part 1, in combination with antiviral therapy for up to 48 weeks. Results: A total of 716 patients were enrolled; 1 patient withdrew due to a protocol deviation, and 715 entered the open-label pre-antiviral phase. At study entry, most patients were male (62%) and Caucasian (72%); 17% were of Japanese/East Asian heritage. The median age was 52 years (range, 19–76). 488 patients (68%) had cirrhosis (FibroSURE™ score equivalent to METAVIR F4). The median duration of treatment during Part 1 was 20 days and the median of the mean daily dose was 25 mg (range, 0.8–75 mg). Median baseline platelets were 59,000/μL; these increased to 89,000/μL by week 2 and remained consistently elevated throughout open-label treatment (Figure). Following a median of 2 weeks of treatment (range, 0.1–9.6 weeks), 691 patients (97%) achieved platelet counts ≥90,000/μL. Treatment was discontinued during Part 1 for 33 patients (5%): platelets <90,000/μL (11); adverse events (AEs, 9); investigator discretion (7); patient decision (3); loss of follow-up (2); or a protocol deviation (1). During Part 2, 682 patients (95%) were randomized, 2 patients withdrew consent following randomization, and 680 patients (95%) initiated antiviral treatment. Of the patients who initiated treatment, 451 (66%) did so within 2 weeks and 627 (92%) did so within 4 weeks. The most common AEs observed during the open-label treatment phase were headache (7%), fatigue (4%), nausea (3%), and diarrhea (3%). Ninety-five patients (13%) experienced platelet counts >200,000/μL. No thromboembolic events were observed during open-label treatment. Conclusions: Eltrombopag was generally well-tolerated and resulted in sustained increase in platelet counts during the open-label, pre-antiviral treatment phase. Platelet count increases were seen as early as 2 weeks following initiation of treatment. The vast majority of patients (97%) achieved platelet count increases to ≥90,000/μL, the threshold for initiating PEG-2a plus ribavirin therapy, and most did so within 4 weeks of initiating eltrombopag treatment. Disclosures: Dusheiko: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Off Label Use: Eltrombopag, inteferon and Ribavirin; eltrombopag is a thrombopoetin receptor agonist. Its efficacy and safety in raising platelet counts in hepatitis C positive patients (most with cirrhosis) and thrombocyotopaenia was studied in this protocol. Afdhal:Merck: Consultancy, Honoraria, Research Funding; Vertex: Consultancy, Honoraria, Research Funding; Idenix: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Springbank: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmasett: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding. Giannini:GlaxoSmithKline: Consultancy, Speakers Bureau; Hoffman-LaRoche: Consultancy, Speakers Bureau. Chen:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Geib:GlaxoSmithKline: Employment. Vasey:GlaxoSmithKline: Employment. Patwardhan:GlaxoSmithKline: Employment, company shares. Campbell:GlaxoSmithKline: Employment, Equity Ownership. Theodore:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 602-602 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil Shah ◽  
Dale Bixby ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutation Status ◽  
Equity Ownership

Abstract Abstract 602 Background: Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

scholarly journals Population Pharmacokinetics of Ivosidenib (AG-120) in Patients with IDH1-Mutant Advanced Hematologic Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1394-1394 ◽  
Author(s):  
Kha Le ◽  
Russ Wada ◽  
David Dai ◽  
Bin Fan ◽  
Guowen Liu ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Eastern Cooperative Oncology Group ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Disease Characteristics ◽  
Population Pk ◽  
Cyp3a4 Inhibitors ◽  
Equity Ownership ◽  
The Impact

Abstract BACKGROUND: Ivosidenib, a potent mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is being assessed in a phase 1 study of mIDH1 advanced hematologic malignancies (NCT02074839). We characterized the pharmacokinetics (PK) of ivosidenib in this population, and the effects of patient/disease characteristics and concomitant medications. METHODS: Ivosidenib was given in continuous 28-day cycles at 100 mg twice daily and 300 mg, 500 mg, 800 mg, and 1200 mg once daily (QD). Enrollment is complete; 258 patients received ≥1 ivosidenib dose (78 in escalation, 180 in expansion); samples were available from 253 patients (223 received ivosidenib 500 mg QD). Ivosidenib concentrations were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based methods. Population PK modeling was conducted using NONMEM software. The impact of demographics, renal and hepatic function, disease type, Eastern Cooperative Oncology Group (ECOG) performance status, and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and gastric acid reducers on ivosidenib PK was explored. RESULTS: Ivosidenib PK were best described using a 2-compartment model with first-order absorption, dose-dependent bioavailability, and a time-dependent change in relative bioavailability and clearance between Day 1 and steady state. Mean steady-state apparent clearance (CL/F) was 5.39 L/h (between-patient variability ~35%) and mean central volume of distribution (Vc/F) was 234 L (~47%). Less than dose-proportional bioavailability was observed, with a dose doubling translating to a ~40% increase in exposure. The moderate/strong CYP3A4 inhibitors voriconazole, fluconazole, and posaconazole were associated with 36%, 41%, and 35% reductions in CL/F, and hence 57%, 69%, and 53% increases in area under the plasma ivosidenib concentration-time curve (AUC), respectively (Figure 1). Baseline body weight had a significant impact on Vc/F. Low albumin at baseline and during treatment correlated with decreased CL/F and Vc/F. However, the effects of body weight and albumin did not appear to be clinically relevant. No effects of creatinine clearance or measures of liver function (alanine aminotransferase, aspartate aminotransferase, bilirubin, within the range studied) on ivosidenib CL/F were detected. Concomitant use of pantoprazole or famotidine did not affect ivosidenib CL/F. CONCLUSION: This population PK model of ivosidenib suggests that no dose adjustments are needed based on the range of patient and disease characteristics analyzed. Disclosures Le: Millennium: Patents & Royalties; Agios: Employment, Equity Ownership. Wada:Certara: Employment; Agios: Consultancy. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Attar:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Yang:Agios: Employment, Equity Ownership.

Associations Between Platelet Count and Survival and Disease Progression In Thrombocytopenic Patients with Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2905-2905
Author(s):  
Mellissa Yong ◽  
Carrie Kuehn ◽  
Michael Kelsh ◽  
Meghan Wagner ◽  
Allen Yang ◽  
...  
Keyword(s):  
Platelet Count ◽  
Survival Time ◽  
Disease Progression ◽  
Median Survival ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Employment Equity ◽  
Classification Schemes ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 2905 Introduction: Myelodysplastic syndromes (MDS) are a group of malignant bone marrow stem cell disorders characterized by a predisposition for transformation to acute myelogeneous leukemia (AML). MDS disorders are heterogeneous in their morphology, cytogenetics, survival time, and ability to transform to AML. Although numerous classification schemes have been developed to provide a reproducible method for estimating patient survival and risk of leukemic evolution, research continues to identify factors that affect prognosis and survival time (e.g., treatment type, WHO FAB subgroups, karyotype, and transfusion status) and refine existing classification schemes. The goal of this analysis was to evaluate the effect of platelet counts on survival and disease progression to AML among thrombocytopenic (platelet count <100 × 109/L) MDS patients (n = 303) using the International MDS Risk Analysis Workshop (IMRAW) database. Methods: The IMRAW dataset includes demographic, clinical and prognostic information for patients treated in the United States, Europe, and Japan who were diagnosed with MDS between 1972 and 1994. Platelet count (× 109/L) was categorized as follows: 0 to <20, 20 to <30, 30 to <50, 50 to <70, 70 to <80, 80 to <90, 90 to <100, and ≥100. Survival was modeled using the Kaplan-Meier (K-M) estimator. One-, two-, and three-year survival rates and median, quartile, and restricted mean survival time were estimated using K-M methods. Time to evolution to AML was modeled using the Nelson-Aalen (N-A) cumulative hazard estimator with death prior to onset of AML as a competing risk event. One-, two-, and three-year cumulative rates of AML evolution were generated using N-A methods. Mean, median, and quartile values for time to AML evolution were also summarized. Cox proportional hazards modeling was used to estimate the hazard ratio (HR) for survival and evolution of MDS to AML. Results: Among thrombocytopenic MDS patients (n = 303), one-, two- and three-year survival were 58%, 44%, and 33%, respectively. Median survival was 19.6 months, with the lowest among those with a platelet count 0 to <20 × 109/L (10.9 months) and the highest among those with a platelet count 90 to <100 × 109/L (33.2 months). Patients with platelet counts (x 109/L) <70, 70 to <90, and ≥90 formed three distinct survival groups for approximately three years after MDS diagnosis (Figure 1). Across platelet categories, one-, two- and three-year survival ranged from 48.2% to 83.4%, 37.3% to 68.0%, and 30.5% to 39.9%, respectively (Table 1). Among non-thrombocytopenic MDS patients (platelet count ≥100 × 109/L), the one-, two- and three-year survival were 83.1%, 68.6%, and 59.1%, respectively, and the median survival was 47.3 months. Results of Cox models for thrombocytopenic MDS patients suggested an increased risk of death with platelet counts <90 × 109/L compared to platelet counts 90 to <100 × 109/L and no relationship was shown between strength of the HR and decreasing platelet count when adjusted for gender, age, year of diagnosis and institution (Table 1). Among thrombocytopenic MDS patients who developed AML (n = 73), median time to AML diagnosis from MDS diagnosis was 9.2 months. One-, two- and three-year evolution to AML rates were 21%, 30%, and 38%, respectively. Conclusions: Platelet count in thrombocytopenic MDS patients may be clinically relevant to survival and should be evaluated further. Platelet count does not appear to be associated with risk of evolution to AML. Evaluation of these relationships in a larger sample is warranted. Disclosures: Yong: Amgen Inc: Employment, Equity Ownership. Kuehn:Amgen Inc: Research Funding. Kelsh:Amgen Inc: Research Funding. Wagner:Amgen Inc: Research Funding. Yang:Amgen Inc: Employment, Equity Ownership. Franklin:Amgen Inc: Employment, Equity Ownership.

Novel Population Pharmacokinetic Modeling of Arabinosyl Cytosine Triphosphate: Insights On Potential Preferential Formation of Ara-CTP Directly From Elacytarabine As Well As From Ara-C

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3547-3547
Author(s):  
Corinne Seng Yue ◽  
Varsha V. Gandhi ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Tove Flem Jacobsen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Research Funding ◽  
Hematologic Malignancies ◽  
Employment Equity ◽  
Cholesterol Levels ◽  
Population Pk ◽  
Equity Ownership ◽  
Quality Of Fit ◽  
Arabinosyl Cytosine

Abstract Abstract 3547 Objectives: Elacytarabine (CP-4055) is an elaidic acid ester of arabinosyl cytosine (Ara-C), administered as a liposomal formulation, that is being developed to treat hematologic malignancies. CP-4055 is metabolized to Ara-C, which is transformed intracellularly to active arabinosyl cytosine triphosphate (Ara-CTP) and inactive deaminated metabolite arabinosyl uracil (Ara-U). The present analysis aimed to elucidate the pharmacokinetics (PK) of Ara-CTP and identify its relationship with CP-4055, Ara-C, Ara-U and various blood parameters measured in the target patient population. Methods: Patients suffering from hematologic malignancies, including refractory/relapsing acute myeloid leukemia (AML), who participated in Phase I or II CP-4055 trials, were included in this analysis. CP-4055 monotherapy was given as an intravenous infusion over 2 h/day for 5 days, 4 h/day for 5 days or continuously over 120 hours at doses ranging from 200 to 2500 mg/m2/day. Blood samples were collected at various time-points (until 168 hours post-dose) and plasma was assayed for CP-4055, Ara-C, and Ara-U using a validated LC-MS/MS method. Ara-CTP was measured by HPLC in isolated leukemic blast cells from AML patients. Cholesterol levels were also measured. Population PK analyses were conducted using the iterative two-stage method in ADAPT 5®. First, a model was determined for cholesterol, which was incorporated into a PK model for CP-4055, Ara-C and Ara-U. Individual PK parameters from this model were fixed and then used for the analysis of Ara-CTP. For Ara-CTP modeling, 1-compartment (cpt) models were tested with various routes of formation. For all models, model discrimination was performed using standard criteria (residual variability, quality of fit graphs, Akaike information criterion test). Results: In the cholesterol analysis, 13 patients (57 concentrations) were included while 43 patients (around 27 concentrations per patient) were included in the modeling of CP-4055, Ara-C and Ara-U. A subset of 17 patients (46 concentrations) was part of the Ara-CTP analysis. Cholesterol was described by an indirect model with a rate of elimination and a rate of formation that was increased by phospholipids infused along with CP-4055. CP-4055 PK was best described by a 2-cpt model, where the central cpt was partitioned into 2 sub-cpts. The first sub-cpt represented a lipid depot cpt where liposomal-bound CP-4055 was infused, and which transferred CP-4055 into the other sub-cpt, which represented CP-4055 released from liposomes. The transfer of CP-4055 from the liposomes was unidirectional and saturable, and cholesterol level influenced the size of the second sub-cpt. Ara-CTP appeared to be formed from unbound CP-4055, presumably within cancer cells, and was also formed as expected from Ara-C which was best described by a 2-cpt model, while Ara-U followed a 1-cpt model with an elimination that was dependent upon creatinine clearance. The proposed model is depicted below. Based on the model, terminal elimination half-life values for CP-4055, Ara-C, Ara-U and Ara-CTP were around 9, 68, 5 and 3 hours, respectively, and were independent of dose and infusion time. Residual variabilities for cholesterol, CP-4055, Ara-C, Ara-U and Ara-CTP were 21.0%, 34.0%, 39.4%, 12.5% and 29.2%, respectively. Conclusions: For the first time, a population PK approach was used to describe the PK of a triphosphate metabolite in relation to a parent drug as well as other metabolites. Indeed, the novel multi-cpt model developed herein simultaneously described and explained the PK of cholesterol, elacytarabine, Ara-C, Ara-U and Ara-CTP. The inclusion of cholesterol levels in the model improved the overall quality of fit, especially for administered liposomal-elacytarabine. The proposed PK model describing Ara-CTP disposition suggests that Ara-CTP is formed not only from Ara-C but also from elacytarabine, presumably within cancer cells, although the exact mechanism is unknown. Disclosures: Seng Yue: Learn and Confirm: Employment; Clavis Pharma: Consultancy. Gandhi:Clavis Pharma: Research Funding. O'Brien:Clavis Pharma: Research Funding. Ravandi:Clavis Pharma: Research Funding. Jacobsen:Clavis Pharma: Employment, Equity Ownership. Dirven:Clavis Pharma: Employment. Hagen:Clavis Pharma: Employment, Equity Ownership. Hals:Clavis Pharma: Employment. Ducharme:Learn and Confirm: Employment, Equity Ownership; Clavis Pharma: Consultancy.

scholarly journals PETIT and PETIT 2: Treatment with Eltrombopag in 171 Children with Chronic Immune Thrombocytopenia (ITP)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1450-1450 ◽  
Author(s):  
James B. Bussel ◽  
John D. Grainger ◽  
Purificacion Garcia de Miguel ◽  
Jenny M. Despotovic ◽  
Franco Locatelli ◽  
...  
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Thrombopoietin Receptor ◽  
Count Response ◽  
Equity Ownership

Abstract Background: Eltrombopag (EPAG), an oral thrombopoietin receptor agonist, is approved for treating thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) with insufficient response to prior therapy. Pooled data from 2 similarly designed, randomized, double-blind, placebo (PBO)-controlled studies investigating safety and efficacy of EPAG in pediatric ITP are presented here. Methods: Subjects aged 1 to <18 years with a confirmed diagnosis of persistent or chronic ITP and a platelet count <30 Gi/L at day 1 were randomized 2:1 to EPAG or PBO and stratified by age: 12–17 years (Cohort 1), 6–11 years (Cohort 2), and 1–5 years (Cohort 3). Subjects could continue baseline ITP medications. After the PBO-controlled randomized phase, subjects were permitted to complete 17 or 24 weeks of treatment with open-label (OL) EPAG. Dose was adjusted based on platelet counts to a maximum of 75 mg daily. Results: A total of 174 subjects were enrolled in both studies; 171 received ≥1 dose of EPAG. 159 subjects were randomized (intent-to-treat population), and 157 received ≥1 dose of randomized study treatment (safety population). In the randomized period, 3 EPAG and 1 PBO subject discontinued study treatment, of which 2 EPAG and 1 PBO discontinued due to adverse events (AEs). In the OL-EPAG period, an additional 14 EPAG subjects discontinued study treatment, 6 due to AEs. Males comprised 47% of the EPAG and PBO groups and 20% and 24% were East Asians, respectively. Most subjects (93%) were diagnosed with ITP for ≥12 months, and 13% were receiving ITP medications at baseline. The majority of subjects (81%) received ≥2 prior ITP therapies. Most subjects (59%) had a baseline platelet count <15 Gi/L. All 9 (6%) splenectomized subjects were randomized to the EPAG group. Randomized Period A higher proportion of EPAG versus PBO subjects (62% vs 24%; P < 0.001) achieved a response with platelet counts ≥50 Gi/L at least once between weeks 1–6 (Cohort 1, 64% vs 11%; Cohort 2, 64% vs 27%; Cohort 3, 54% vs 36%, respectively). At each week, a higher proportion of EPAG subjects had a response versus PBO (Fig. 1). A lower proportion of EPAG subjects (13%) received rescue treatment compared with PBO subjects (31%; P = 0.009). The odds of having World Health Organization (WHO) bleeding grades 1–4 (0.19; P = 0.011) and clinically significant (WHO grades 2–4) bleeding (0.29; P = 0.007) were lower for EPAG versus PBO subjects. EPAG-Only Period Sustained reduction or discontinuation of baseline ITP medications, primarily corticosteroids, was achieved by 50% of subjects; 81% of subjects had a platelet count response at least once; 52% (n = 80/154) had a platelet count response for ≥50% of assessments; and 38% (n = 58/154) responded for ≥75% of assessments. For >13 of 24 weeks, 47% of subjects achieved responses (Fig. 2). The median average daily dose for EPAG-exposed patients in Cohorts 1, 2, and 3 were 64.0 mg (0.93 mg/kg), 57.6 mg (1.50 mg/kg), and 37.0 mg (2.02 mg/kg), respectively. AEs Similar proportions of subjects in the EPAG and PBO groups reported an AE during the randomization period. The most common AEs (≥10% of subjects) were headache, upper respiratory tract infection, and nasopharyngitis in the EPAG group, and headache, epistaxis, and vomiting in the PBO group. Serious AEs (SAEs) were reported in 8% of EPAG subjects versus 12% of PBO subjects. No SAEs were reported by >1 subject in either treatment group except epistaxis, which was reported by 2 subjects in the PBO group. No SAEs were common to both treatment groups. In the randomized period, an ALT elevation of ³3 x ULN occurred in 5 (4.7%) subjects in the EPAG group and no subjects in the PBO group. In the OL period, there were an additional 7 subjects with ALT ³3 x ULN. All elevations resolved either while still on treatment or after discontinuation of study treatment. Overall, the hepatobiliary laboratory findings were mostly mild, reversible, and not accompanied by impaired liver function. Fewer EPAG than PBO subjects reported bleeding AEs (17% vs 36%, respectively). No thromboembolic events were reported. Cataract events were experienced by 2 subjects who received EPAG; both had used corticosteroids and 1 had pre-existing cataracts. Conclusions: EPAG was safe and raised platelet counts in 62% of pediatric patients with persistent and chronic ITP during the randomized phase. Treatment with EPAG was well tolerated in both studies as evidenced by the low incidence of treatment discontinuations due to AEs. Disclosures Bussel: Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Honoraria; Novartis: Honoraria; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Equity Ownership, Honoraria, Research Funding; Genzyme: Research Funding; Eisai, Inc.: Research Funding; Cangene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding. Off Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Grainger:GlaxoSmithKline: Honoraria; Baxter: Honoraria, Research Funding; Amgen: Honoraria. Pongtanakul:GlaxoSmithKline: Research Funding. Komvilaisak:GlaxoSmithKline: I am an investigator on this study. Other. Sosothikul:CSL Behring: Research Funding; GlaxoSmithKline: Research Funding. Drelichman:GlaxoSmithKline: I am investigator on this study. Other. David:GlaxoSmithKline: Research Funding. Marcello:GlaxoSmithKline: Employment. Iyengar:GlaxoSmithKline: Employment. Chan:GlaxoSmithKline: Employment. Chagin:GlaxoSmithKline: Employment. Theodore:GlaxoSmithKline: Employment, Equity Ownership. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership.

scholarly journals Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3178-3178
Author(s):  
Robert J. Laliberte ◽  
Paul F. Glidden ◽  
Brian L. Hamilton
Keyword(s):  
Platelet Count ◽  
Controlled Release ◽  
Multiple Dose ◽  
Phase 1 ◽  
Controlled Study ◽  
Plasma Exposure ◽  
Employment Equity ◽  
Platelet Counts ◽  
Dose Ranging ◽  
Equity Ownership

Abstract Introduction: Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (Cmax) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401). Methods: 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. The trials included an open-label, single dose developmental study; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. Safety parameters included routine laboratory, ECG, and clinical evaluations. PK was assessed by measurements of plasma anagrelide and its active metabolite using a validated HPLC-MS/MS method. Pharmacodynamic activity was assessed by daily platelet count determinations in the multiple dosing studies. Results: Single doses of anagrelide CR were well tolerated, and the only drug-related AE reported in 2 or more subjects was headache. In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported. Anagrelide CR demonstrated dose proportional PK characteristics. Following a single 0.5 mg dose in the fasted state, the mean time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively; in contrast, Tmax and t1/2 following IR was 1.0±0.9 hrs and 1.4±0.2 hrs, respectively. Cmax and total plasma exposure (AUC0-inf) with anagrelide CR were reduced to 26% and 59% of IR, respectively. However, steady-state PK following 6 daily 0.5 mg b.i.d. doses of anagrelide CR or IR showed similar AUC0-inf values, while Cmax with anagrelide CR remained nearly unchanged (29%). Plasma exposure was higher when anagrelide CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for Cmax and AUC0-t, which were increased by 100% and 60%, respectively. The platelet lowering effect of anagrelide CR was evident in the 2 multiple dose ranging studies. In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days, a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time. Figure 1 Figure 1. Conclusion: Anagrelide CR is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced Cmax, while maintaining plasma exposure to induce platelet count reductions. The product was well tolerated with an AE profile that was not distinguishable from placebo. These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET. Disclosures Laliberte: Galena Biopharma, Inc.: Employment, Equity Ownership. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties. Hamilton:Galena Biopharma, Inc.: Employment, Equity Ownership.

Evaluation of Bleeding-Related Episodes in Patients with Chronic Immune Thrombocytopenic Purpura (ITP) Receiving Romiplostim or Medical Standard of Care.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1311-1311 ◽  
Author(s):  
Roberto Stasi ◽  
Magaral Murali ◽  
Marc Michel ◽  
Jean-Francois Viallard ◽  
Aristoteles Giagounidis ◽  
...  
Keyword(s):  
Platelet Count ◽  
Treatment Period ◽  
Rescue Medication ◽  
Standard Of Care ◽  
Employment Equity ◽  
Platelet Counts ◽  
Chronic Itp ◽  
Increased Risk ◽  
Medical Standard ◽  
Equity Ownership

Abstract Abstract 1311 Poster Board I-334 Background Chronic ITP is an autoimmune disease characterized by low platelet counts and increased risk of bleeding that may be severe or even fatal. Rescue medications, most commonly intravenous immunoglobulins, are used to treat or prevent bleeding but produce only transient increases in platelet counts in most cases and may have issues with toxicity. Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor, and is approved for the treatment of adult chronic ITP. Objective To determine the effects of romiplostim treatment on bleeding outcomes during a phase 3b, randomized, open-label study, in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). We have developed a clinically-relevant composite endpoint, termed bleeding-related episode (BRE). A BRE was considered to be either an actual bleeding event, and/or the use of rescue medication to treat or prevent bleeding. Methods Patients were randomized (2:1) to romiplostim or SOC. Eligible patients were required to have either a platelet count <50×109/L or have had their platelet count fall to <50×109/L during or after a clinically-indicated taper or discontinuation of current ITP therapy. Once-weekly subcutaneous romiplostim was administered with dose adjustments to target a platelet count between 50 and 200 × 109/L. SOC treatments were prescribed according to standard institutional practices or therapeutic guidelines. Since many types of ITP treatment could be administered in the SOC group, for the purpose of this analysis rescue medication was defined as any use of immunoglobulins (intravenous immunoglobulin or Anti-D), intravenous steroids, or platelet transfusions. In order to collapse related events into episodes, events (bleeding events and/or the use of rescue medication) that occurred concurrently or within 3 days of each other were considered a single clinical episode. Rates of BREs per 100 patient-weeks were calculated from the number of events/episodes divided by the number of patient-weeks on study treatment, multiplied by 100. Results During the 52-week treatment period, the total number of patient-weeks for the romiplostim group (N=154) was 7087, and for the SOC group (N=70) was 2571. During the treatment period, the rate of BREs was lower in the romiplostim group than the SOC group (see Table), with a 67% reduction in the rate of BREs in patients receiving romiplostim compared to SOC (95% CI, 60% to 73%). The rate of BREs involving the use of immunoglobulins was also lower in the romiplostim group, with a 95% reduction in the rate of BREs in patients receiving romiplostim compared to those receiving SOC (95% CI, 92% to 97%). Conclusions Compared to SOC, romiplostim was associated with a reduction in all BREs as well as BREs involving immunoglobulin use. Disclosures Stasi: Amgen Inc.: Honoraria, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau. Giagounidis:Amgen Inc.: Consultancy, Speakers Bureau. Janssens:Roche: Honoraria. Legg:Amgen Inc.: Employment, Equity Ownership. Danese:Amgen Inc.: Consultancy, Research Funding. Deuson:Amgen Inc.: Employment, Equity Ownership.

Sign in / Sign up

Export Citation Format

Share Document