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Kimmo Porkka - One of the best experts on this subject based on the ideXlab platform.
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Dasatinib and Navitoclax act synergistically to target NUP98-NSD1^+/FLT3-ITD^+ acute myeloid leukemia
Leukemia, 2019Co-Authors: Jarno L. Kivioja, Angeliki Thanasopoulou, Juerg Schwaller, Ashwini Kumar, Mika Kontro, Bhagwan Yadav, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors, Kimmo PorkkaAbstract:Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3 -ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3 -ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone ( P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors ( P = 0.029). Furthermore, NUP98-NSD1 ^+ /FLT3- ITD^+ patient cells were also very sensitive to BCL2-inhibitor Navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC_50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1 ^+ /FLT3- ITD^+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1 ^ - /FLT3- ITD^+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor Navitoclax in NUP98-NSD1 ^+ /FLT3- ITD^+ cells. Gene expression analysis supported the potential relevance of dasatinib and Navitoclax by revealing significantly higher expression of BCL2A1 , FGR , and LCK in NUP98-NSD1 ^+ /FLT3- ITD^+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib–Navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3- ITD.
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dasatinib and Navitoclax act synergistically to target nup98 nsd1 flt3 itd acute myeloid leukemia
Leukemia, 2019Co-Authors: Jarno L. Kivioja, Angeliki Thanasopoulou, Juerg Schwaller, Ashwini Kumar, Mika Kontro, Bhagwan Yadav, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors, Kimmo PorkkaAbstract:Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3-ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3-ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone (P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors (P = 0.029). Furthermore, NUP98-NSD1+/FLT3-ITD+ patient cells were also very sensitive to BCL2-inhibitor Navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1+/FLT3-ITD+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1-/FLT3-ITD+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor Navitoclax in NUP98-NSD1+/FLT3-ITD+ cells. Gene expression analysis supported the potential relevance of dasatinib and Navitoclax by revealing significantly higher expression of BCL2A1, FGR, and LCK in NUP98-NSD1+/FLT3-ITD+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib–Navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3-ITD.
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Targeting BCL-2, BCL-XL, BCL-W and MDM2 in B-Cell Acute Lymphoblastic Leukemia Is Highly Effective Ex Vivo
Blood, 2018Co-Authors: Helena Hohtari, Shady Adnan Awad, Olli Dufva, Swapnil Potdar, Caroline A. Heckman, Krister Wennerberg, Satu Mustjoki, Kimmo PorkkaAbstract:Abstract Despite the advances in the treatment of acute lymphoblastic leukemia (ALL), a major fraction of adult patients still succumb to leukemia- or treatment-related events. In particular, the outcome of elderly ALL patients remains dismal. Our aim was to discover new or repurposed drugs for B-cell ALL in a clinically relevant ex vivo drug sensitivity testing platform. We analyzed 19 primary B-ALL samples using a well-established drug sensitivity and resistance testing platform and a drug panel including 65 drugs in five different concentrations. The main drug classes were glucocorticoids, MDM2 antagonists, and inhibitors of BCR-ABL1, VEGFR, BCL-2, BCL-XL, BET, MEK, JAK, Aurora kinase, PI3K, MTOR, IGF1R, ERK, STAT3, STAT5, HSP90 and NAMPT proteins. The samples were viably frozen bone marrow (BM) mononuclear cells collected at diagnosis. The cohort included both Philadelphia-positive (Ph+) (n=10) and Ph-negative (Ph-) (n=9) patients with a median age of 43 years (range 22-68). Cell viability (CellTiter-Glo) was measured after plating and after a three-day incubation with the drugs. A drug sensitivity score (DSS) was calculated from the viability readouts, which takes into account the area under the dose response curve, measuring both drug efficacy and potency. DSS values >10 are considered effective and >20 highly effective. As an overall view of drug sensitivity, a heatmap and dendrograms from DSS values are shown in Figure 1A. As expected, most patients were sensitive to glucocorticoids and tyrosine kinase inhibitors (TKIs) showed efficacy in Ph+ ALL. In addition, two Ph-negative patients were sensitive to TKIs, suggesting a Philadelphia-like disease. Drugs that showed pan-ALL efficacy included BCL-2 family inhibitors, idasanutlin (MDM2 inhibitor), luminespib (HSP90 inhibitor), daporinad (NMPRT inhibitor) and plicamycin (antineoplastic antibiotic). For the other drugs, only individual patients showed sensitivity, in line with the diverse molecular background of ALL. Strikingly, 17/19 (89%) of patients in our cohort were highly sensitive (DSS>20) to Navitoclax (a BCL-2, BCL-XL and BCL-W inhibitor), whereas the BCL-2-specific inhibitor venetoclax was effective only in a distinct subset of patients (Figure 1B). 6/19 (32%) of patients were highly sensitive (DSS>20) to venetoclax and represented all risk classes based on age, white blood cell counts and karyotype, but interestingly, all were Ph-negative. Overall, response to venetoclax correlated with response to Navitoclax (Spearman, r=0.85; P<0.0001). To examine differential gene expression of anti-apoptotic proteins between Ph+ and Ph- patients, we analyzed microarray gene expression data from ArrayExpress public database (www.ebi.ac.uk/arrayexpress, E-MTAB-5035). The analyzed cohort included 96 Ph- and 41 Ph+ adult B-ALL patients. Ph-negative samples were characterized with higher BCL-2 expression, whereas Ph-positive samples showed higher BCL-W expression and a trend to higher BCL-XL expression (Figure 1C). Thus, lack of venetoclax efficacy ex vivo in Ph-positive ALL indicated dependence on BCL-W and BCL-XL, as also reflected in the gene expression analyses. Inhibitors of BCL-2, such as Navitoclax and venetoclax, potently induce apoptosis in a variety of cancer cells. Both inhibitors showed promising efficacy in our B-ALL samples. Dose-limiting thrombocytopenia has limited the use of Navitoclax in solid tumors. However, in our assay Navitoclax showed more uniform potency, particularly in Ph+ samples suggesting a rational combination with tyrosine kinase inhibitors. Similar to conventional cytotoxic agents used in ALL, a therapeutic window may exist for safe use of Navitoclax in acute leukemia. In conclusion, targeting the multidomain anti-apoptotic proteins (BCL-2, BCL-XL, BCL-W, MCL-1) and TP53 with MDM2, possibly in combination, is a promising strategy for improving outcome of adult B-ALL. Figure 1. Figure 1. Disclosures Hohtari: Incyte: Research Funding. Heckman:Novartis: Research Funding; Celgene: Research Funding; Orion Pharma: Research Funding. Wennerberg:Novartis: Research Funding. Mustjoki:Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Porkka:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.
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BCL2-Inhibitors Target a Major Group of Newly-Diagnosed and Relapsed/Refractory Acute Myeloid Leukemia Ex Vivo
Blood, 2015Co-Authors: Mika Kontro, Samuli Eldfors, Caroline A. Heckman, Krister Wennerberg, Muntasir Mamun Majumder, Alun Parsons, Tea Pemovska, Olli Kallioniemi, Kimmo PorkkaAbstract:BACKGROUND: BCL-2 family members play a critical role in the regulation of apoptosis. BCL-2 and BCL-XL promote cell survival by preventing mitochondrial apoptotic pore formation. BH3 mimetic drugs such as venetoclax (ABT-199) promote apoptosis by inhibiting BCL-2 while Navitoclax (ABT-263) inhibits both BCL-2 and BCL-XL. In AML, the expression of anti-apoptotic proteins is highly variable. In a recent study venetoclax showed single-agent activity in 6/12 AML cell lines and 20/25 patient samples. (Pan et al. Cancer Disc 2014). The samples with complex cytogenetics were largely resistant. Sensitivity correlated with increased BCL-2 protein levels and negatively correlated with BCL-XL and MCL-1 protein levels. We aimed to expand these data to both newly diagnosed and relapsed AML patients and to isolate biomarkers for patient selection. METHODS: We assessed the ex vivo sensitivity of fresh leukemic cells from 16 diagnosed and 36relapsed/refractory AML patient samples to venetoclax (25 samples) and Navitoclax (52 samples). Exome sequencing was performed on 32 samples and gene expression of BCL2 family members (BCL-2, BCL-XL, MCL-1, BIK, BAX, BAK1, BID, BCL2L12, BIM, BCL2A1, PUMA and BAD) was determined on 31 samples by qRT-PCR. Samples from primary cells of healthy individuals (n=10), and CMML (n=7) or CLL (n=2) patients were used as controls. Drug sensitivity was determined over a 10,000-fold concentration range (1-10 000 nM). A leukemia-specific drug sensitivity score (sDSS) derived from area under the dose response curve calculations was used as the efficacy variable by comparing leukemia results with those from normal bone marrow cells (Bhagwan et al., Sci Rep 2014, Pemovska et al., Cancer Disc 2014). RESULTS: Compared to healthy controls, CMML samples were largely non-sensitive, whereas CLL samples were highly sensitive to BCL-2 inhibitors ex vivo. The AML samples exhibited heterogeneous responses. 15/25 (60%) of AML samples were sensitive to venetoclax and 35/52 (67%) to Navitoclax. Both diagnostic (12 of 16 samples, 75%) and relapsed/refractory samples (24 of 36 samples, 64%) were sensitive to Navitoclax. Similarly, 6/7 (86%) of diagnostic samples and 9/18 (50%) of relapsed/refractory samples were sensitive to venetoclax. We observed responses to venetoclax and Navitoclax in each patient to be similar, although Navitoclax showed efficacy at lower concentrations: in 25 samples tested with both agents, mean sDSS values were lower in Navitoclax-treated samples (paired t-test, p=0.02). All except one patient sample exhibited a difference in resistance between the two drugs showing sensitivity to Navitoclax but not to venetoclax. We observed responses across all mutational profiles, including samples with mutations to FLT3 -ITD, NPM1, TP53, NRAS and IDH1 and IDH2, as well as in samples with complex karyotypes. Intriguingly, three of four samples with mutated TP53 exhibited sensitivity to BCL2 inhibition. No single mutation predicted sensitivity or resistance. At the RNA level, no statistical correlation between BCL2 or BCL-XL expression for BCL2 inhibitor response was observed. Instead we observed high levels of beta-2-microglobulin (B2M) mRNA expression in BCL2 inhibitor-resistant samples with a strong negative correlation to Navitoclax sensitivity (r=-0.60, P=0.0008). DISCUSSION: We did not observe BCL2 and BCL-XL mRNA expression to be optimal predictors for BCL2 inhibitor response. On the other hand, we observed high expression of B2M mRNA expression in resistant samples suggesting that it could serve as a biomarker for sensitivity to BCL2 inhibitors. The high B2M expression has been previously linked to poor prognosis in solid tumors and in AML (Albitar et al., Leukemia 2007). In cell line models B2M leads to phosphorylation and inactivation of proapototic protein BAD (Nokura et al., J Urol 2007). This may affect the balance between pro- and antiapoptotic proteins and thus offer a escape route from BCL2 inhibition. To conclude, we observed BCL2 inhibition to be effective ex vivo in over half of all AML samples, tested both in primary and relapsed/refractory state as well as across different subgroups defined by AML driver mutations. Of the potential biomarkers that were assessed, B2M was the best mRNA-level indicator for anti-BCL-2 drug efficacy. Disclosures Off Label Use: BCL2 inhibitors are not approved for the treatment of AML. Heckman:Celgene: Honoraria, Research Funding; Pfizer: Research Funding. Porkka:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Pfizer: Honoraria.
Hao Xiong - One of the best experts on this subject based on the ideXlab platform.
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Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of Navitoclax (ABT-263) induced thrombocytopenia
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax. Methods Data from 256 patients who received oral Navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of Navitoclax treatment. Results The PD model was able to describe a slight downward trend of platelet counts over the long-term Navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies. Conclusions We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial Navitoclax administration and long-term decline of platelets after continuous administration of Navitoclax.
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Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of Navitoclax (ABT-263) induced thrombocytopenia.
Cancer chemotherapy and pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax.
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mechanism based pharmacokinetic pharmacodynamic meta analysis of Navitoclax abt 263 induced thrombocytopenia
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax.
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Effect of rifampin on the pharmacokinetics, safety and tolerability of Navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer.
Journal of clinical pharmacy and therapeutics, 2014Co-Authors: Jianning Yang, Alison M. Graham, Kyle D. Holen, Rajendra Pradhan, L. S. Rosen, Hao XiongAbstract:Summary What is known and objective Navitoclax, a first-in-class small molecule Bcl-2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4. Drugs that affect CYP3A4 may therefore have an impact on the pharmacological profile of Navitoclax. This study evaluated the effects of co-administration of a potent CYP3A4 inducer rifampin on the pharmacokinetic and safety profiles of Navitoclax. Methods This open-label, fixed-sequence, 2-period study was performed in twelve subjects with non-haematologic or haematologic malignancy that was relapsed or refractory to standard therapy. A 7-day washout period separated the two treatment periods. On Study Day 1 and Day 8, subjects received a single 250 mg oral dose of Navitoclax. Rifampin 600 mg was administrated once daily (QD) on Study Day 4 through Day 10. Blood samples for Navitoclax assay were collected prior to dosing (0 h) and at a series of time points through 72 h after dosing on Study Day 1 and Day 8. Results and discussion Co-administration of a single 250 mg dose of Navitoclax with 600 mg QD doses of rifampin had a negligible effect on the maximum plasma concentration (Cmax) of Navitoclax [ratio of geometric least square means: 0·84 (90% CI: 0·61–1·16)] but moderately decreased the area under the plasma concentration–time curve (AUC) of Navitoclax [ratio of geometric least square means: 0·59 (90% CI: 0·44–0·80)]. Rifampin did not affect the half-life of Navitoclax. Co-administration of rifampin did not appear to significantly change the safety profile of Navitoclax in the limited number of patients evaluated in this study. What is new and conclusion Co-administration Navitoclax with rifampin moderately decreased Navitoclax AUC, which could be partly due to the induction effect of rifampin on CYP3A4. Further assessment on the mechanism of drug interaction is warranted.
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studying Navitoclax a targeted anticancer drug in healthy volunteers ethical considerations and risk benefit assessments and management
Anticancer Research, 2014Co-Authors: Hao Xiong, Kyle D. Holen, Rajendra Pradhan, Rod A. Humerickhouse, Adel Nada, Andrew Krivoshik, James W. Rhodes, Gary Gordon, Walid M. AwniAbstract:BACKGROUND Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying Navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of Navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.
Kyle D. Holen - One of the best experts on this subject based on the ideXlab platform.
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Safety, efficacy, and pharmacokinetics of Navitoclax (ABT-263) in combination with irinotecan: results of an open-label, phase 1 study.
Cancer chemotherapy and pharmacology, 2015Co-Authors: Anthony W. Tolcher, Jianning Yang, Todd A. Busman, Patricia Lorusso, Jennifer Arzt, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal, Jeffrey F. Waring, Kyle D. HolenAbstract:Purpose The oral Bcl-2 inhibitor Navitoclax demonstrated activity in solid and hematologic malignancies as monotherapy and in combination with other cytotoxic agents in preclinical and early clinical studies. We evaluated the safety, pharmacokinetics (PK), and antitumor activity of Navitoclax plus irinotecan.
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Safety, efficacy, and pharmacokinetics of Navitoclax (ABT-263) in combination with erlotinib in patients with advanced solid tumors
Cancer chemotherapy and pharmacology, 2015Co-Authors: Anthony W. Tolcher, Kyle D. Holen, Todd A. Busman, Patricia Lorusso, Jennifer Arzt, Guinan Lian, Niki S. Rudersdorf, Carol Ann Vanderwal, Whitney P. Kirschbrown, Lee S. RosenAbstract:Purpose Navitoclax (ABT-263), a novel, oral Bcl-2 inhibitor, enhances the antitumor effects of chemotherapy in vitro by lowering the apoptotic threshold. This phase I study (NCT01009073) evaluated the safety, pharmacokinetics, and preliminary antitumor activity of Navitoclax combined with erlotinib in patients with advanced solid tumors.
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Effect of rifampin on the pharmacokinetics, safety and tolerability of Navitoclax (ABT-263), a dual inhibitor of Bcl-2 and Bcl-XL , in patients with cancer.
Journal of clinical pharmacy and therapeutics, 2014Co-Authors: Jianning Yang, Alison M. Graham, Kyle D. Holen, Rajendra Pradhan, L. S. Rosen, Hao XiongAbstract:Summary What is known and objective Navitoclax, a first-in-class small molecule Bcl-2 family inhibitor, is metabolized in vitro by the hepatic microsomal cytochrome P450 (CYP) enzymes CYP3A4. Drugs that affect CYP3A4 may therefore have an impact on the pharmacological profile of Navitoclax. This study evaluated the effects of co-administration of a potent CYP3A4 inducer rifampin on the pharmacokinetic and safety profiles of Navitoclax. Methods This open-label, fixed-sequence, 2-period study was performed in twelve subjects with non-haematologic or haematologic malignancy that was relapsed or refractory to standard therapy. A 7-day washout period separated the two treatment periods. On Study Day 1 and Day 8, subjects received a single 250 mg oral dose of Navitoclax. Rifampin 600 mg was administrated once daily (QD) on Study Day 4 through Day 10. Blood samples for Navitoclax assay were collected prior to dosing (0 h) and at a series of time points through 72 h after dosing on Study Day 1 and Day 8. Results and discussion Co-administration of a single 250 mg dose of Navitoclax with 600 mg QD doses of rifampin had a negligible effect on the maximum plasma concentration (Cmax) of Navitoclax [ratio of geometric least square means: 0·84 (90% CI: 0·61–1·16)] but moderately decreased the area under the plasma concentration–time curve (AUC) of Navitoclax [ratio of geometric least square means: 0·59 (90% CI: 0·44–0·80)]. Rifampin did not affect the half-life of Navitoclax. Co-administration of rifampin did not appear to significantly change the safety profile of Navitoclax in the limited number of patients evaluated in this study. What is new and conclusion Co-administration Navitoclax with rifampin moderately decreased Navitoclax AUC, which could be partly due to the induction effect of rifampin on CYP3A4. Further assessment on the mechanism of drug interaction is warranted.
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studying Navitoclax a targeted anticancer drug in healthy volunteers ethical considerations and risk benefit assessments and management
Anticancer Research, 2014Co-Authors: Hao Xiong, Kyle D. Holen, Rajendra Pradhan, Rod A. Humerickhouse, Adel Nada, Andrew Krivoshik, James W. Rhodes, Gary Gordon, Walid M. AwniAbstract:BACKGROUND Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying Navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of Navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.
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A phase I clinical trial of Navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors
Investigational new drugs, 2014Co-Authors: James M. Cleary, Jianning Yang, Alison M. Graham, Herbert Hurwitz, Alberto J. Montero, C. Franklin, Mack Mabry, Todd Busman, Caio Max S. Rocha Lima, Kyle D. HolenAbstract:Purpose: To investigate the safety, optimal dosing, pharmacokinetics and clinical activity of a regimen of Navitoclax (ABT-263) combined with gemcitabine in patients with solid tumors. Experimental Design: Patients with solid tumors for which gemcitabine was deemed an appropriate therapy were enrolled into one of two different dosing schedules (21-day dosing schedule: Navitoclax administered orally on days 1–3 and 8–10,; and gemcitabine 1,000 mg/m2 on days 1 and 8; 28-day dosing schedule: Navitoclax administrated orally on days 1–3, 8–10, and 15–17; and gemcitabine 1,000 mg/m2 on days 1, 8 and 15). Navitoclax doses were escalated from 150 to 425 mg. An expanded safety cohort was conducted for the 21-day dosing schedule at the maximum tolerated dose (MTD) of Navitoclax. Results: Forty-six patients were enrolled at three U.S. centers. The most common adverse events included: hematologic abnormalities (thrombocytopenia, neutropenia, and anemia), liver enzyme elevations (ALT and AST), and gastrointestinal disturbances (diarrhea, nausea, and vomiting). Dose-limiting toxicities (DLTs) observed in cycle 1 were grade 4 thrombocytopenia (2 patients), grade 4 neutropenia (1 patient), and grade 3 AST elevation (2 patients). The MTD of Navitoclax was 325 mg co-administered with gemcitabine 1,000 mg/m2 for the 21-day schedule. No clinically significant pharmacokinetic drug–drug interactions were observed. There were no objective responses. Stable disease, reported at the end of cycle 2, was the best response in 54 % of evaluable patients (n = 39). Conclusions: The combination of Navitoclax 325 mg with gemcitabine 1,000 mg/m2 was generally well tolerated and exhibited a favorable safety profile in patients with advanced solid tumors.
Jarno L. Kivioja - One of the best experts on this subject based on the ideXlab platform.
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Dasatinib and Navitoclax act synergistically to target NUP98-NSD1^+/FLT3-ITD^+ acute myeloid leukemia
Leukemia, 2019Co-Authors: Jarno L. Kivioja, Angeliki Thanasopoulou, Juerg Schwaller, Ashwini Kumar, Mika Kontro, Bhagwan Yadav, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors, Kimmo PorkkaAbstract:Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3 -ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3 -ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone ( P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors ( P = 0.029). Furthermore, NUP98-NSD1 ^+ /FLT3- ITD^+ patient cells were also very sensitive to BCL2-inhibitor Navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC_50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1 ^+ /FLT3- ITD^+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1 ^ - /FLT3- ITD^+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor Navitoclax in NUP98-NSD1 ^+ /FLT3- ITD^+ cells. Gene expression analysis supported the potential relevance of dasatinib and Navitoclax by revealing significantly higher expression of BCL2A1 , FGR , and LCK in NUP98-NSD1 ^+ /FLT3- ITD^+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib–Navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3- ITD.
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dasatinib and Navitoclax act synergistically to target nup98 nsd1 flt3 itd acute myeloid leukemia
Leukemia, 2019Co-Authors: Jarno L. Kivioja, Angeliki Thanasopoulou, Juerg Schwaller, Ashwini Kumar, Mika Kontro, Bhagwan Yadav, Muntasir M. Majumder, Komal K. Javarappa, Samuli Eldfors, Kimmo PorkkaAbstract:Acute myeloid leukemia (AML) with co-occurring NUP98-NSD1 and FLT3-ITD is associated with unfavorable prognosis and represents a particularly challenging treatment group. To identify novel effective therapies for this AML subtype, we screened patient cells and engineered cell models with over 300 compounds. We found that mouse hematopoietic progenitors co-expressing NUP98-NSD1 and FLT3-ITD had significantly increased sensitivity to FLT3 and MEK-inhibitors compared to cells expressing either aberration alone (P < 0.001). The cells expressing NUP98-NSD1 alone had significantly increased sensitivity to BCL2-inhibitors (P = 0.029). Furthermore, NUP98-NSD1+/FLT3-ITD+ patient cells were also very sensitive to BCL2-inhibitor Navitoclax, although the highest select sensitivity was found to SRC/ABL-inhibitor dasatinib (mean IC50 = 2.2 nM). Topoisomerase inhibitor mitoxantrone was the least effective drug against NUP98-NSD1+/FLT3-ITD+ AML cells. Of the 25 significant hits, four remained significant also compared to NUP98-NSD1-/FLT3-ITD+ AML patients. We found that SRC/ABL-inhibitor dasatinib is highly synergistic with BCL2-inhibitor Navitoclax in NUP98-NSD1+/FLT3-ITD+ cells. Gene expression analysis supported the potential relevance of dasatinib and Navitoclax by revealing significantly higher expression of BCL2A1, FGR, and LCK in NUP98-NSD1+/FLT3-ITD+ patients compared to healthy CD34+ cells. Our data suggest that dasatinib–Navitoclax combination may offer a clinically relevant treatment strategy for AML with NUP98-NSD1 and concomitant FLT3-ITD.
Rod A. Humerickhouse - One of the best experts on this subject based on the ideXlab platform.
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Safety and efficacy of Navitoclax, a BCL-2 and BCL-XL inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study.
Leukemia & lymphoma, 2020Co-Authors: Sven De Vos, Rod A. Humerickhouse, John P. Leonard, Jonathan W. Friedberg, Jasmine Zain, Kieron Dunleavy, John Hayslip, John Pesko, Wyndham H. WilsonAbstract:Navitoclax, a novel BCL-2 and BCL-XL inhibitor, demonstrated promising antitumor activity in the dose-escalation part of a phase 1/2a study (NCT00406809) in lymphoid tumors. Herein, we report the continued safety and efficacy results of the phase 2a portion. Twenty-six adult patients with relapsed/refractory follicular lymphoma (n = 11, Arm A) and other relapsed/refractory lymphoid malignancies (n = 15, Arm B) were enrolled. Navitoclax administration schedule consisted of a 150-mg 7-day lead-in dose followed by 250-mg daily dosing with the option to further increase to 325 mg after 14 days if the 250-mg dose was tolerated. All patients experienced at least 1 treatment-related adverse event (TRAE). Seventeen (65.4%) patients reported grade 3/4 TRAEs; thrombocytopenia (38.5%) and neutropenia (30.8%) were the most common. Two patients reported serious AEs; none were fatal (no deaths occurred within 30 days of last dose of study drug). The objective response rate (complete and partial) was 23.1% (6/26; Arm A: 9.1%, Arm B: 33.3%). Median progression-free survival and time to progression were identical: 4.9 months (95% CI: 3.0, 8.2); median overall survival: 24.8 months (95% CI could not be computed). Navitoclax monotherapy has an acceptable safety profile and meaningful clinical activity in a minority of patients with relapsed/refractory lymphoid malignancies.
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Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of Navitoclax (ABT-263) induced thrombocytopenia
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax. Methods Data from 256 patients who received oral Navitoclax (dose range 10–475 mg) as a 14/21-day schedule or a continuous once daily (QD) schedule were used to construct the model using NONMEM. The PK model was a two-compartmental model with a lag-time and a transit compartment in absorption. The PD model was a semi-physiological model that comprised a progenitor cell compartment, three transition compartments representing the maturation chain in the bone marrow and a peripheral blood compartment. Compared with the previously published models, the model established in this analysis applied a different feedback mechanism and introduced a new concept of progenitor cell “pool”, which describes a large pool of platelet progenitor cells at the beginning of Navitoclax treatment. Results The PD model was able to describe a slight downward trend of platelet counts over the long-term Navitoclax treatment as observed in around 8 % of the patients and the initial drop in platelets seen in our Phase 1/2a studies. Conclusions We have developed a new semi-physiological platelet model for describing fast drop of platelets after initial Navitoclax administration and long-term decline of platelets after continuous administration of Navitoclax.
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Mechanism-based pharmacokinetic/pharmacodynamic meta-analysis of Navitoclax (ABT-263) induced thrombocytopenia.
Cancer chemotherapy and pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax.
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mechanism based pharmacokinetic pharmacodynamic meta analysis of Navitoclax abt 263 induced thrombocytopenia
Cancer Chemotherapy and Pharmacology, 2014Co-Authors: Aksana Kaefer, Jianning Yang, Peter Noertersheuser, Sven Mensing, Rod A. Humerickhouse, Walid M. Awni, Hao XiongAbstract:Objective Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor and promotes apoptosis. Thrombocytopenia is a primary dose-limiting toxicity of Navitoclax which exhibited a distinct time profile in circulating platelets from that caused by traditional chemotherapies. A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the pharmacokinetic of Navitoclax as well as the time course of the platelet counts in cancer patients receiving Navitoclax.
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studying Navitoclax a targeted anticancer drug in healthy volunteers ethical considerations and risk benefit assessments and management
Anticancer Research, 2014Co-Authors: Hao Xiong, Kyle D. Holen, Rajendra Pradhan, Rod A. Humerickhouse, Adel Nada, Andrew Krivoshik, James W. Rhodes, Gary Gordon, Walid M. AwniAbstract:BACKGROUND Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying Navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of Navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.
