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Yanfeng Wang - One of the best experts on this subject based on the ideXlab platform.
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comparison of two endogenous biomarkers of cyp3a4 activity in a drug drug interaction study between Midostaurin and rifampicin
European Journal of Clinical Pharmacology, 2014Co-Authors: Catherine Dutreix, Sebastien Lorenzo, Yanfeng WangAbstract:Purpose Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This Midostaurin drug–drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.
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investigation into cyp3a4 mediated drug drug interactions on Midostaurin in healthy volunteers
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Catherine Dutreix, Johannes Roesel, Florence Munarini, Sebastien Lorenzo, Yanfeng WangAbstract:Purpose Midostaurin (PKC412), a multitargeted tyrosine kinase inhibitor that targets FMS-related tyrosine kinase 3 and KIT, is in clinical trials for the treatment for acute myeloid leukemia and advanced systemic mastocytosis. In vitro studies showed that Midostaurin is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) and that Midostaurin inhibits and/or induces the same enzyme. Here, we address the clinical relevance of CYP3A4-related drug–drug interactions with Midostaurin as either a “victim” or “perpetrator.”
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Investigation into CYP3A4-mediated drug–drug interactions on Midostaurin in healthy volunteers
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Catherine Dutreix, Johannes Roesel, Florence Munarini, Sebastien Lorenzo, Yanfeng WangAbstract:Purpose Midostaurin (PKC412), a multitargeted tyrosine kinase inhibitor that targets FMS-related tyrosine kinase 3 and KIT, is in clinical trials for the treatment for acute myeloid leukemia and advanced systemic mastocytosis. In vitro studies showed that Midostaurin is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) and that Midostaurin inhibits and/or induces the same enzyme. Here, we address the clinical relevance of CYP3A4-related drug–drug interactions with Midostaurin as either a “victim” or “perpetrator.”
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Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers.
Cancer Chemotherapy and Pharmacology, 2012Co-Authors: Adam Del Corral, Catherine Dutreix, Sebastien Lorenzo, Joel Morganroth, Robert Harrell, Alice Huntsman-labed, Yanfeng WangAbstract:Purpose Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with Midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated Midostaurin’s effect on cardiac repolarization.
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A Phase I Study of Midostaurin (PKC412) Investigating Cardiac Interval Effects In Healthy Subjects
Blood, 2010Co-Authors: Adam Del Corral, Catherine Dutreix, Alice Huntsman Labed, Kai Grosch, Joel Morganroth, Robert Harrell, Yanfeng WangAbstract:Abstract 4362 Midostaurin (PKC412) is a multi-targeted tyrosine kinase inhibitor (TKI) of several receptors, including wild-type and mutant variants of KIT and the FMS-like tyrosine kinase 3 (FLT3) receptor, and has known roles in hematopoiesis and leukemia. Midostaurin has demonstrated activity in acute myeloid leukemia (AML) and myelodysplastic syndrome in phase 1 and 2 trials, and is currently under investigation in a randomized phase 3 AML study at 50mg twice daily (bid) in combination with chemotherapy and a phase 2 monotherapy study of aggressive systemic mastocytosis (ASM) at 100mg bid. Despite the absence of specific Midostaurin-related cardiac toxicity issues, we conducted a dedicated phase 1 study to directly investigate the effect of Midostaurin on QTc interval. Healthy subjects were randomized to 3 treatment arms: placebo; Midostaurin administered orally at 75mg bid on days 1 and 2 and once daily (od) on day 3; or an active control arm of moxifloxacin administered orally at 400mg od on day 3. The primary variable was QTcF interval on day 3 corrected for baseline and placebo in the Midostaurin and moxifloxacin treatment arms. Drug exposure levels at each time point were confirmed for moxifloxacin, Midostaurin, and its two metabolites – CGP62221 and CGP52421. Of 192 subjects enrolled, 166 completed the study. 24 of 80 subjects discontinued in the Midostaurin arm: 19 (23%) due to adverse events (AEs), 17 of which encompassed expected gastrointestinal events. No patients were discontinued for AEs in the other 2 treatment groups. Discontinued patients were not included in the ECG analysis. In time-matched analysis of QTcF interval change, the maximum mean change in the Midostaurin arm corrected for baseline and placebo was 0.72ms with a 90% confidence interval (CI) upper bound of 4.71ms, which excluded 10ms. At each nominal time point, the mean change from baseline placebo-corrected for Midostaurin was 30ms or >480ms change from baseline for QTcF or QTcI. For QTcB the only occurrences of change were in the 30–60ms category: 1 (1.3%) of the subjects on Midostaurin met this non-specific outlier criterion; 7 (15.9%) on moxifloxacin; and 1 (1.5%) on placebo. 1 new U-wave abnormality was noted in the moxifloxacin group. The peak plasma concentration of Midostaurin achieved in the present study (mean 2273ng/mL) covered the peak and trough plasma exposure observed at 50mg bid (2220ng/mL and 1005ng/mL, respectively) in AML patients. The peak level achieved for Midostaurin was also above the steady-state trough level of 1060ng/mL, but below the peak concentration of 3500ng/mL, for the 100mg bid dose. Midostaurin was safe and generally well tolerated: 97% of the AEs noted in subjects while on study drug (n=61; 40%) were reported as grade 1. No grade 3/4 AEs were reported. While some TKIs exert pharmacologic effects on QTc interval, this carefully conducted trial demonstrates that Midostaurin at 75mg bid has no effect on heart rate, AV conduction, or cardiac depolarization. The Midostaurin exposure achieved in this study exceeds the peak and trough levels for the 50mg bid dose regimen under investigation in the AML phase 3 trial. The Midostaurin exposure achieved also exceeds the steady state trough level, but not the peak level, of the 100mg bid dose regimen under investigation in the phase 2 ASM trial. Further, the effects of the long-acting metabolite CGP52421 cannot be fully addressed by this short study. Due to the lack of QT prolongation observed in this trial, we recommend reduced but continued ECG monitoring and omission of QT-related exclusion criteria in future Midostaurin clinical trials. Disclosures: del Corral:Novartis Pharmaceuticals Corporation: Employment. Dutreix:Novartis Pharmaceuticals Corporation: Employment. Huntsman Labed:Novartis Pharmaceuticals Corporation: Employment. Rai:Novartis Pharmaceuticals Corporation: Employment. Grosch:Novartis Pharmaceuticals Corporation: Employment. Morganroth:eResearchTechnology Inc: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding. Wang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.
Camille N Abboud - One of the best experts on this subject based on the ideXlab platform.
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phase i study of cladribine cytarabine granulocyte colony stimulating factor clag regimen and Midostaurin and all trans retinoic acid in relapsed refractory aml
International Journal of Hematology, 2014Co-Authors: Giridharan Ramsingh, Peter Westervelt, Ali Mcbride, Keith Stockerlgoldstein, Mark A Fiala, Geoffrey L Uy, Amanda F Cashen, John F Dipersio, Camille N AbboudAbstract:We conducted a phase I study using Midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose-limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of Midostaurin achieved therapeutic levels with no significant interaction between Midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and Midostaurin in FLT3-ITD AML, this combination warrants further investigation.
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phase i study of cladribine 2 chlorodeoxyadenosie cytarabine and g csf based induction therapy clag with atra all trans retinoic acid and Midostaurin for relapsed refractory aml
Blood, 2011Co-Authors: Giridharan Ramsingh, Peter Westervelt, Ali Mcbride, Keith Stockerlgoldstein, Geoffrey L Uy, Amanda F Cashen, John F Dipersio, Andrew Sprau, Camille N AbboudAbstract:Abstract 3609 Patients with relapsed or refractory AML have poor outcomes after conventional salvage chemotherapy with long-term remissions likely only with allogeneic stem cell transplantation. Hence, there is a need for better treatment options for these patients. Since it is known that multiple pathways are dysregulated in AML, combination therapy that targets multiple pathways may improve remission rates. The combination of salvage chemotherapy (CLAG), a multi-targeted tyrosine kinase inhibitor (Midostaurin) and a differentiation inducing agent (ATRA) was investigated in patients with relapsed refractory AML in this study, to assess its tolerability and to identify the maximum tolerated dose (MTD) of Midostaurin in the combination. Midostaurin is a multi-targeted kinase inhibitor that has been shown to inhibit FLT-3 (FMS like tyrosine kinase 3) mutations and wild type and other molecular targets thought to be important for the pathogenesis of AML including VEGFR-1, PDGFR, c-kit, H-ras, K-ras and MDR. FLT-3 mutations are seen in about 25–30% of patients with AML and is associated with poor long term survival. FLT-3 is highly expressed even in patients without FLT-3 mutations making FLT-3 a promising target in AML. In vitro studies have suggested that ATRA induces differentiation not only in AML-M3 but also in AML other than AML-M3. In AML cell lines ATRA has been shown to increase sensitivity to cytarabine. Addition of ATRA to induction therapy has shown to produce superior results in AML patients over 60 years of age. Here we conducted this single institutional phase I trial with the combination of Midostaurin, ATRA and CLAG in patients with relapsed refractory AML. Patients ≥ 18 years of age with relapsed/refractory AML were included in the study. The treatment regimen consisted of CLAG (cladribine 5 mg/m 2 IV days 2–6, cytarabine 2 g/m 2 IV days 2–6, GCSF 300 mcg SC days 1–6), ATRA 15 mg/m 2 PO days 7–20, Midostaurin 25 mg (cohort 1) or 50 mg (cohort 2) PO BID days 7–20. Response was assessed by a bone marrow examination done at day 28–45. A total of 11 patients were enrolled in the study (4 in cohort 1 and 7 in cohort 2) of which 9 (3 in cohort 1 and 6 in cohort 2) were evaluable for the planned end points. The median age was 52 years (range 32–71) and male: female ratio was 45:55. FLT-3 mutation was positive in 6 patients, negative in 1 and unknown in the rest. 4 patients had complex karyotype cytogenetics. 7 patients were in enrolled at first relapse, 2 at second relapse and 2 after refractory disease following the first induction therapy. The ECOG performance score was 0 for all enrolled patients. No dose limiting toxicities was observed in either cohort. Grade 3/4 hematological toxicity was seen in 100% of patients as expected. Grade 3/4 non-hematological toxicity was seen in 2 patients: 1 patient died of pulmonary hemorrhage which was attributed to severe thrombocytopenia and another patient developed grade 4 hyperglycemia. No significant hepatotoxicity occurred in our two dosing cohorts with Midostaurin and ATRA likely as echinocandins were used instead of azoles for antifungal therapy. Overall 3/9 (33.3%) evaluable patients achieved complete remission/ complete remission with incomplete count recovery. Five patients died, 4 of progressive disease and one from pulmonary hemorrhage. The levels of Midostaurin and ATRA were measured at pretreatment, 1 hour, 4 hours, 8 hours, 12 hours, 7 days, 14 days and 20 days on treatment. The median levels of Midostaurin were 2150 ng/ml (range 641–7210) in the 25 mg cohort and 1820 ng/ml (range 850–8930) in the 50 mg cohort. In summary CLAG+ Midostaurin+ATRA regimen has an acceptable toxicity profile for relapsed refractory AML and the MTD of Midostaurin defined in this trial is 50 mg. Additional phase 2 studies to assess the effectiveness of this regimen in relapsed refractory AML are warranted. Disclosures: Off Label Use: The purpose of the study is to investigate the use of Midostaurin and ATRA in relapsed refractory AMl in compbination with chemotehrapy. Westervelt: Novartis: Speakers Bureau. Abboud: novartis: Consultancy, Research Funding, Speakers Bureau.
Catherine Dutreix - One of the best experts on this subject based on the ideXlab platform.
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simultaneous physiologically based pharmacokinetic pbpk modeling of parent and active metabolites to investigate complex cyp3a4 drug drug interaction potential a case example of Midostaurin
Drug Metabolism and Disposition, 2018Co-Authors: Helen Gu, Catherine Dutreix, Taoufik Ouatas, Sam Rebello, Lai Wang, Dung Yu Chun, Heidi J Einolf, Handan HeAbstract:Midostaurin (PKC412) is being investigated for the treatment of acute myeloid leukemia (AML) and advanced systemic mastocytosis (advSM). It is extensively metabolized by cytochrome P450 (CYP) 3A4 to form 2 major active metabolites, CGP52421 and CGP62221. In vitro and clinical drug-drug interaction (DDI) studies indicated that Midostaurin and its metabolites are substrates, reversible and time-dependent inhibitors, and inducers of CYP3A4. A simultaneous pharmacokinetic model of parent and active metabolites was initially developed by incorporating data from in vitro, preclinical, and clinical pharmacokinetic studies in healthy volunteers and in patients with AML or advSM. The model reasonably predicted changes in Midostaurin exposure after single-dose administration with ketoconazole (5.8-fold predicted vs 6.1-fold observed increase) and rifampicin (90% predicted vs 94% observed reduction) as well as changes in midazolam exposure (1.0 predicted vs 1.2 observed ratio) after daily dosing of Midostaurin for 4 days. The qualified model was then applied to predict the DDI effect with other CYP3A4 inhibitors or inducers and DDI potential with midazolam under steady-state conditions. The simulated midazolam AUC ratio of 0.54 and accompanying observed 1.9-fold increase in the CYP3A4 activity biomarker 4β-hydroxycholesterol indicated a weak-to-moderate CYP3A4 induction by Midostaurin and its metabolites at steady state in patients with advSM. In conclusion, a simultaneous parent-and-active-metabolite modeling approach allowed predictions under steady-state conditions that were not possible to achieve in healthy subjects. Furthermore, endogenous biomarker data enabled evaluation of the net effect of Midostaurin and its metabolites on CYP3A4 activity at steady state and increased confidence in DDI predictions.
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target interaction profiling of Midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth
Leukemia, 2016Co-Authors: Barbara Peter, Catherine Dutreix, Katharina Blatt, Gabriele Stefanzl, Emir Hadzijusufovic, Georg E Winter, Keiryn L Bennett, Gregor Eisenwort, Manuela Gridling, Gregor HoermannAbstract:Target interaction profiling of Midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth
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a phase 1 2 open label dose escalation study of Midostaurin in pediatric patients pts with relapsed or refractory r r acute leukemia final results of study itcc 024 cpkc412a2114
Blood, 2015Co-Authors: Michel C Zwaan, Catherine Dutreix, Stefan Soderhall, Benoit Brethon, Matteo Luciani, Carmelo Rizzari, D W Sternberg, Emmanuelle Besse, Franca Fagioli, Phoenix HoAbstract:Introduction Outcomes for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) have improved, but the prognosis for pts with R/R disease remains poor. Childhood AML and MLL-rearranged ALL (MLL r-ALL) often overexpress or have activating mutations in the FLT3 tyrosine kinase (TK). Midostaurin (PKC412) is an orally available TK inhibitor that targets FLT3, KIT, and other kinases. Data in adults for single-agent Midostaurin, including from studies CPKC412A2104 and CPKC412A2106, showed that 100 mg bid (≈ 60 mg/m2 bid) was adequately tolerated, elicited leukemic blast reduction, and inhibited FLT3 autophosphorylation. Here, we present the safety and preliminary clinical activity of Midostaurin in children with R/R acute leukemia. Methods In this multicenter dose-escalation study, children (3 mo to 2 y to Results This study enrolled 22 pts (7 at 30 mg/m2 bid [2 younger, 5 older]; 15 at 60 mg/m2 bid [9 younger, 6 older]) starting on Sep 21, 2009. The median age was 2 y (range, 0.5-17 y); 9 pts (9 older) had AML and 13 pts (11 younger, 2 older) had ALL. The dose-determining set included 17 pts. No DLTs occurred at 30 mg/m2 bid; thus, in each age group, the dose was escalated directly to 60 mg/m2 bid. One DLT (increased alanine aminotransferase [ALT]) occurred in a younger pt receiving 60 mg/m2 bid; no older pts had a DLT. The most common AEs regardless of study drug relationship (any grade/grade 3/4) were vomiting (68%/5%), pyrexia (41%/14%), and thrombocytopenia (41%/36%). Grade 3/4 AEs (particularly thrombocytopenia, elevated ALT, and anemia) were more common with the higher dose. Consistent with the safety profile of Midostaurin in adults, the most frequent drug-related any-grade AEs were vomiting (55%), nausea (32%), and diarrhea (18%). The MTD was not reached. Median OS was 3.7 mo (95% CI, 2.7-8.3 mo) in pts with AML and 1.4 mo (95% CI, 1.0-2.9 mo) in pts with ALL. All 5 on-treatment deaths (ie, death while on study drug or within Midostaurin demonstrated limited single-agent clinical activity in this study. Five pts (56% [95% CI, 21%-86%]) with AML achieved a clinical response. The best response was a morphological complete remission with incomplete count recovery on day 14. The pt remained in remission until stopping treatment on day 64, received a stem cell transplant (SCT) on day 76, and was alive at day 960 after completing the per-protocol survival follow-up. Three pts (23% [95% CI, 5%-54%]) with ALL achieved a clinical response; all were peripheral blood blast responses. All pts discontinued treatment; reasons were disease progression (64%), start of new cancer therapy (including SCT [18%]), withdrawn consent (14%), or AEs (5%). Median duration of exposure was 15.5 days (range, 3-64 days). Time-dependent PK and exposures of Midostaurin and its 2 active metabolites (CGP52421 and CGP62221) at the selected doses were similar to adult data. Conclusions Single-agent Midostaurin was adequately tolerated at 60 mg/m2 bid, the highest dose evaluated. Only limited clinical activity was demonstrated; thus, future trials in children with FLT3 -mutated AML should be in combination with established chemotherapies. The RDE of Midostaurin for such studies is 30 mg/m2 bid due to a higher frequency of grade 3/4 AEs in the 60 mg/m2 bid dose group and known toxicities of existing standard pediatric AML regimens. Disclosures Zwaan:Janssen: Research Funding; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Soderhall:Novartis: Other: Investigator in clinical trials within my duties or ordinary salary at the hospital; Merck: Other: Investigator in clinical trials within my duties or ordinary salary at the hospital. Sternberg:Novartis Oncology: Employment, Equity Ownership. Besse:Novartis: Employment. Dutreix:Novartis: Employment. Ho:Seattle Genetics (employment started after completion of involvement in presented study): Employment. Dufour:Pfizer: Consultancy.
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comparison of two endogenous biomarkers of cyp3a4 activity in a drug drug interaction study between Midostaurin and rifampicin
European Journal of Clinical Pharmacology, 2014Co-Authors: Catherine Dutreix, Sebastien Lorenzo, Yanfeng WangAbstract:Purpose Midostaurin, a multitargeted tyrosine kinase inhibitor, is primarily metabolized by CYP3A4. This Midostaurin drug–drug interaction study assessed the dynamic response and clinical usefulness of urinary 6β-hydroxycortisol to cortisol ratio (6βCR) and plasma 4β-hydroxycholesterol (4βHC) for monitoring CYP3A4 activity in the presence or absence of rifampicin, a strong CYP3A4 inducer.
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investigation into cyp3a4 mediated drug drug interactions on Midostaurin in healthy volunteers
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Catherine Dutreix, Johannes Roesel, Florence Munarini, Sebastien Lorenzo, Yanfeng WangAbstract:Purpose Midostaurin (PKC412), a multitargeted tyrosine kinase inhibitor that targets FMS-related tyrosine kinase 3 and KIT, is in clinical trials for the treatment for acute myeloid leukemia and advanced systemic mastocytosis. In vitro studies showed that Midostaurin is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) and that Midostaurin inhibits and/or induces the same enzyme. Here, we address the clinical relevance of CYP3A4-related drug–drug interactions with Midostaurin as either a “victim” or “perpetrator.”
Horst Schran - One of the best experts on this subject based on the ideXlab platform.
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dose and time dependent pharmacokinetics of Midostaurin in patients with diabetes mellitus
The Journal of Clinical Pharmacology, 2008Co-Authors: Yanfeng Wang, Peter Graf, James Kisicki, Horst SchranAbstract:: Midostaurin is a novel potent inhibitor of both protein kinase C and the major receptor for vascular endothelial growth factor involved in angiogenesis, presenting a rationale for its use in diabetic retinopathy. This study evaluated the safety and pharmacokinetics of Midostaurin following multiple oral doses of Midostaurin for 28 days at 4 dose levels (25 mg bid, 50 mg bid, 75 mg bid, 75 mg tid), as well as a single oral 100-mg dose in patients with diabetes mellitus (n = 9-13 per dose cohort). Pharmacokinetic parameters were determined on days 1 and 28 based on the plasma concentrations of Midostaurin and its metabolites, CGP62221 and CGP52421. The plasma exposures (C(max) and AUC(0-tau)) of Midostaurin and metabolites increased less than proportionally over the dose range of 25 to 100 mg, showing a 2.2-fold increase after the first dose. Midostaurin concentrations increased during the first 3 to 6 days of dosing, then declined with time (by 30%-50%) until a steady state was achieved, representing an average accumulation factor (R) of 1.7. CGP62221 showed a similar concentration-time pattern as Midostaurin (R = 2.5), but CGP52421 accumulated significantly (R = 18.8). A high-fat meal was found to significantly increase the C(max) and AUC(0-12 h) of Midostaurin by 1.5-fold (P = .04) and 1.8-fold (P = .01), respectively, compared with taking the drug after an overnight fast. Midostaurin administered at 50 to 225 mg/day appeared to be generally safe in this group of patients. The most common treatment-related adverse events (eg, loose stools, nausea, vomiting, and headache) were found to be dose related, and the frequency increased markedly above the 150-mg/day dose level.
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a mechanism based population pharmacokinetic model for characterizing time dependent pharmacokinetics of Midostaurin and its metabolites in human subjects
Clinical Pharmacokinectics, 2008Co-Authors: Yanfeng Wang, Horst SchranAbstract:Background and objective: Midostaurin, a novel potent inhibitor of protein kinase C enzyme and class III receptor tyrosine kinases, including Fms-like tyrosine kinase-3 (FLT3) and c-KIT, shows time-dependent pharmacokinetics in human subjects, presumably due to enzyme auto-induction. The purpose of this study was to develop a mechanism-based population pharmacokinetic model to describe the plasma concentration profiles of Midostaurin and its metabolites and to characterize the time course of auto-induction.
Giridharan Ramsingh - One of the best experts on this subject based on the ideXlab platform.
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phase i study of cladribine cytarabine granulocyte colony stimulating factor clag regimen and Midostaurin and all trans retinoic acid in relapsed refractory aml
International Journal of Hematology, 2014Co-Authors: Giridharan Ramsingh, Peter Westervelt, Ali Mcbride, Keith Stockerlgoldstein, Mark A Fiala, Geoffrey L Uy, Amanda F Cashen, John F Dipersio, Camille N AbboudAbstract:We conducted a phase I study using Midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose-limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of Midostaurin achieved therapeutic levels with no significant interaction between Midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and Midostaurin in FLT3-ITD AML, this combination warrants further investigation.
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phase i study of cladribine 2 chlorodeoxyadenosie cytarabine and g csf based induction therapy clag with atra all trans retinoic acid and Midostaurin for relapsed refractory aml
Blood, 2011Co-Authors: Giridharan Ramsingh, Peter Westervelt, Ali Mcbride, Keith Stockerlgoldstein, Geoffrey L Uy, Amanda F Cashen, John F Dipersio, Andrew Sprau, Camille N AbboudAbstract:Abstract 3609 Patients with relapsed or refractory AML have poor outcomes after conventional salvage chemotherapy with long-term remissions likely only with allogeneic stem cell transplantation. Hence, there is a need for better treatment options for these patients. Since it is known that multiple pathways are dysregulated in AML, combination therapy that targets multiple pathways may improve remission rates. The combination of salvage chemotherapy (CLAG), a multi-targeted tyrosine kinase inhibitor (Midostaurin) and a differentiation inducing agent (ATRA) was investigated in patients with relapsed refractory AML in this study, to assess its tolerability and to identify the maximum tolerated dose (MTD) of Midostaurin in the combination. Midostaurin is a multi-targeted kinase inhibitor that has been shown to inhibit FLT-3 (FMS like tyrosine kinase 3) mutations and wild type and other molecular targets thought to be important for the pathogenesis of AML including VEGFR-1, PDGFR, c-kit, H-ras, K-ras and MDR. FLT-3 mutations are seen in about 25–30% of patients with AML and is associated with poor long term survival. FLT-3 is highly expressed even in patients without FLT-3 mutations making FLT-3 a promising target in AML. In vitro studies have suggested that ATRA induces differentiation not only in AML-M3 but also in AML other than AML-M3. In AML cell lines ATRA has been shown to increase sensitivity to cytarabine. Addition of ATRA to induction therapy has shown to produce superior results in AML patients over 60 years of age. Here we conducted this single institutional phase I trial with the combination of Midostaurin, ATRA and CLAG in patients with relapsed refractory AML. Patients ≥ 18 years of age with relapsed/refractory AML were included in the study. The treatment regimen consisted of CLAG (cladribine 5 mg/m 2 IV days 2–6, cytarabine 2 g/m 2 IV days 2–6, GCSF 300 mcg SC days 1–6), ATRA 15 mg/m 2 PO days 7–20, Midostaurin 25 mg (cohort 1) or 50 mg (cohort 2) PO BID days 7–20. Response was assessed by a bone marrow examination done at day 28–45. A total of 11 patients were enrolled in the study (4 in cohort 1 and 7 in cohort 2) of which 9 (3 in cohort 1 and 6 in cohort 2) were evaluable for the planned end points. The median age was 52 years (range 32–71) and male: female ratio was 45:55. FLT-3 mutation was positive in 6 patients, negative in 1 and unknown in the rest. 4 patients had complex karyotype cytogenetics. 7 patients were in enrolled at first relapse, 2 at second relapse and 2 after refractory disease following the first induction therapy. The ECOG performance score was 0 for all enrolled patients. No dose limiting toxicities was observed in either cohort. Grade 3/4 hematological toxicity was seen in 100% of patients as expected. Grade 3/4 non-hematological toxicity was seen in 2 patients: 1 patient died of pulmonary hemorrhage which was attributed to severe thrombocytopenia and another patient developed grade 4 hyperglycemia. No significant hepatotoxicity occurred in our two dosing cohorts with Midostaurin and ATRA likely as echinocandins were used instead of azoles for antifungal therapy. Overall 3/9 (33.3%) evaluable patients achieved complete remission/ complete remission with incomplete count recovery. Five patients died, 4 of progressive disease and one from pulmonary hemorrhage. The levels of Midostaurin and ATRA were measured at pretreatment, 1 hour, 4 hours, 8 hours, 12 hours, 7 days, 14 days and 20 days on treatment. The median levels of Midostaurin were 2150 ng/ml (range 641–7210) in the 25 mg cohort and 1820 ng/ml (range 850–8930) in the 50 mg cohort. In summary CLAG+ Midostaurin+ATRA regimen has an acceptable toxicity profile for relapsed refractory AML and the MTD of Midostaurin defined in this trial is 50 mg. Additional phase 2 studies to assess the effectiveness of this regimen in relapsed refractory AML are warranted. Disclosures: Off Label Use: The purpose of the study is to investigate the use of Midostaurin and ATRA in relapsed refractory AMl in compbination with chemotehrapy. Westervelt: Novartis: Speakers Bureau. Abboud: novartis: Consultancy, Research Funding, Speakers Bureau.