Other tyrosine kinase inhibitors in clinical trials

2012 ◽  
pp. 40-48
Author(s):  
Maria Debiec-Rychter ◽  
Sebastian Bauer
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors

Osteoarticular Pain after Discontinuation of Tyrosine Kinase Inhibitors (TKI): A French Cohort

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 137-137 ◽  
Author(s):  
Marc G Berger ◽  
Bruno Pereira ◽  
Charlotte Oris ◽  
Sandrine Saugues ◽  
Pascale Cony-Makhoul ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Medical History ◽  
Board Of Directors ◽  
Tyrosine Kinase Inhibitors ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Duration Of Treatment ◽  
Advisory Committees ◽  
History Of

Abstract Context: The Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) increasing dramatically the survival of CML patients and leading to a residual disease with a sustained and deep molecular response. In this subset of very good responder patients, the attempts of stopping treatment in different clinical trials were successfully achieved without relapse. The Swedish team in the EURO-SKI protocol already reported cases of musculoskeletal pain occurring after cessation of TKI (Richter et al., JCO, 2014). Since several clinical trials regarding TKI discontinuation have been also run in France, we decided to retrospectively collect data using the pharmacovigilance system of the different Trials collected prospectively. Method: 428 patients from STIM2 (n=204) and EURO-SKI (n=224) trials were systematically analyzed from the case report from each trial. For the EURO-SKI only French patients were included. Statistical analysis was performed using Stata 13 software (StataCorp LP, College Station, TX, US). Comparisons between the independent groups were realized using the Chi-squared or Fisher's exact tests for categorical variables, and using Student t-test or Mann-Whitney test for quantitative. Multivariate analyses were performed to take into account adjustment on covariates fixed according to univariate results and clinically relevance. Results: Among the 428 patients the main characteristics were as follow i,e; 208 (48.6%) men and 220 (51.4%) women, with a median age of 77.5 years (24-93). Sokal scores (n=449) were low in 187 (41.6%) patients, intermediate in 188 (41.9%) patients and high in 74 (16.5%) patients. A withdrawal TKI syndrome (WS) was reported for 102 (23.8%) patients (100 after imatinib and 2 after nilotinib). 2). The WS consists in bone and articular pains and arthritis and affects the upper limbs, shoulders and cervical rachis, with a grade 1 or 2 in most patients and grade 3 in 22% of patients . The prevalence of WS depends on the trials, 34.8% in EURO-SKI group and 13.8% in STIM2 group (p<0.001). The WS was treated by non-steroidal anti-inflammatory drugs, corticosteroids or by local infiltration. The median duration of WS was 7 months (range: 3-30 months, 24 exploitable cases). We did not observe any difference between WS group and the group without painful syndrome in terms of sex ratio (p=0.92), age (p=0.33), sokal score (p=0.15), BCR-ABL transcript (p=0.42) or duration of CML (p=0.24). However the median duration of TKI therapy appeared longer in this subgroup (median: 88.8 months vs 79.8 months (p=0.02). There was no biological inflammatory syndrome and the results of medical imaging were inconclusive. However, a medical history of osteoarticular pains or disease appeared as predisposing to withdrawal syndrome (22.9% in WS group vs 9.8% in control group; p=0.002). Finally the two factors, duration of treatment and medical history were confirmed using multivariate analysis (RR=1.73 and 1.76 respectively). Among 19 exploitable cases suffering CML relapse and requiring further TKI treatment, pain disappeared in 7 patients (37%) within a median period of 3.5 weeks. Conclusion: About 23% of patients who stopped TKIs experienced a TKI WS and all TKI seems to be concerned. The predisposing factors were a medical history of osteoarticular pain or disease, and the duration of treatment. So patients and physicians should be aware and recommendations should be proposed for patients who have treated longtime with a history of arthritis. Disclosures Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: 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, Research Funding, Speakers Bureau. Rousselot:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

OP449, a Novel SET Antagonist, Is Cytotoxic To Leukemia Cells and Enhances Efficacy Of Tyrosine Kinase Inhibitors In Drug-Resistant Myeloid Leukemias

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2511-2511 ◽  
Author(s):  
Anupriya Agarwal ◽  
Ryan J. Meckenzie ◽  
Raffaella Pippa ◽  
Christopher A. Eide ◽  
Jessica Oddo ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Growth ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Lines ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Combination Index ◽  
Leukemia Cells ◽  
Pp2a Activity

Abstract Background The SET oncoprotein, an inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia cells, preventing PP2A from performing its regulatory role in deactivating signaling proteins by dephosphorylation. Restoration of PP2A activity in both chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cells to normal levels through shRNA-mediated knockdown of SET results in reduced leukemogenesis. Given the central role of PP2A and SET in regulating various kinase-dependent and -independent downstream signaling pathways, we evaluated the efficacy of SET antagonism in CML and AML cell lines as well as primary patient cells using OP449, a novel, specific, cell-penetrating SET antagonist. Results Treatment of human and murine CML cells with OP449 resulted in dose-dependent increase in PP2A activity and selective inhibition of cell growth (IC50: 0.60 to 1.11 μM), while parental Ba/F3 cells exhibited no measurable cytotoxicity. OP449-mediated decrease in the viability of leukemia cells was significantly rescued by co-treatment with okadaic acid, a PP2A inhibitor, confirming efficacy is mediated through PP2A activation. OP449 was also 3 to 8-fold more potent than FTY720 (a known activator of PP2A) and induced dephosphorylation/degradation of BCR-ABL1, AKT, and STAT5. Importantly, OP449 demonstrated activity against the ABL1 tyrosine kinase inhibitor-resistant BCR-ABL1T315I mutant and the BCR-ABL1E255V/T315I compound mutant (IC50: 1.62 and 1.97 μM, respectively). Consistent with cell line findings, OP449 also inhibited growth of primary cells from CML blastic phase patients harboring either wildtype BCR-ABL1 or BCR-ABL1T315I while normal CD34+ cells exhibited minimal effect. Further, treatment of CML cell lines and primary CD34+ CML cells with OP449 in combination with the ABL1 tyrosine kinase inhibitors showed significantly increased cytotoxicity as compared to each compound alone. For example, treatment of primary CD34+ CML cells with 2.5 μM OP449 or 200 nM nilotinib alone each resulted in a 50% reduction in colony formation, while combination of OP449 and nilotinib at these concentrations reduced colony formation by approximately 87%, suggesting synergistic reduction of clonogenicity (combination index: 0.195). Similar to our findings in CML cells, OP449 increased PP2A activity and suppressed growth in a dose-dependent manner in AML cell lines and primary patient samples harboring various different genetic lesions including FLT3-ITD, CSF1R overexpression, NRASQ61L, and JAK3A572V. Additionally, synergistic inhibition of these cells was observed when OP449 was combined with relevant tyrosine kinase inhibitors and chemotherapy. For example, treatment of MOLM-14 cells (FLT3-ITD) with 2.5 μM OP449 or 1 nM AC220 alone reduced cell viability by 58% and 75%, respectively; combined treatment reduced cell growth 96% (combination index: 0.723). Similarly, treatment of HL-60 cells (NRASQ61L) with 1 μM OP449 or 250 nM cytarabine alone reduced cell viability by 40% and 60%, respectively, whereas combined treatment led to a 94% reduction in viability (combination index: 0.630). Mechanistically, AML patient samples showed significantly increased SET expression compared to normal CD34+ cells, and treatment of AML cells with OP449 reduced phosphorylation of downstream ERK, STAT5, AKT and S6 ribosomal protein signaling. Finally, to evaluate OP449 antitumor efficacy in vivo, we tested OP449 (5 mg/kg intraperitoneally every 3 days) in xenograft mice bearing human HL-60 cell derived tumors. OP449 significantly inhibited tumor growth measured over time and resulted in a >2-fold reduction in tumor burden at the end of the experiment compared to vehicle-treated controls (Day 18: 1.14±0.06 g vs. 0.45±0.08 g, respectively; p<0.001). These results demonstrate the in vivo efficacy of OP449 in a murine leukemia model. Conclusions SET antagonism is selectively cytotoxic to CML and AML cells harboring various genetic lesions and drug-resistant mutations. Our results demonstrate that combined targeting of SET and tyrosine kinases provides more efficient and selective inhibition of leukemia cell growth for a broad range of oncogenic lesions as compared to normal cells. Taken together, our findings suggest a novel therapeutic paradigm of SET antagonism in combination with tyrosine kinase inhibitors for the treatment of CML and AML patients with drug resistance. Disclosures: Agarwal: Oncotide Pharmaceuticals: Research Funding. Tyner:Incyte Corporation: Research Funding. Vitek:Oncotide Pharmaceuticals: Employment. Christensen:Oncotide Pharmaceuticals: Employment. Druker:Ambit Biosciences: Consultancy, PI or co-investigator on Novartis clinical trials. OHSU and Dr. Druker have a financial interest in MolecularMD. OHSU has licensed technology used in some of these clinical trials to MolecularMD. Potential conflicts of interest are managed by OHSU., PI or co-investigator on Novartis clinical trials. OHSU and Dr. Druker have a financial interest in MolecularMD. OHSU has licensed technology used in some of these clinical trials to MolecularMD. Potential conflicts of interest are managed by OHSU. Other; Bristol-Myers Squibb/Novartis: Currently PI or co-I on Novartis & Bristol-Myers Squibb clinical trials. His institution has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead. He does not derive salary, nor does his lab Other; Oncotide Pharmaceuticals: Research Funding, Subaward from NIH STTR, Subaward from NIH STTR Other.

Adjuvant Tyrosine Kinase Inhibitors in Treatment of Renal Cell Carcinoma: A Meta-Analysis of Available Clinical Trials

2019 ◽  
Vol 17 (2) ◽  
pp. e339-e344 ◽  
Author(s):  
Francesco Massari ◽  
Vincenzo Di Nunno ◽  
Veronica Mollica ◽  
Jeffrey Graham ◽  
Lidia Gatto ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Tyrosine Kinase Inhibitors ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Meta Analysis

Tyrosine kinase inhibitors: From rational design to clinical trials

2001 ◽  
Vol 21 (6) ◽  
pp. 499-512 ◽  
Author(s):  
Peter Traxler ◽  
Guido Bold ◽  
Elisabeth Buchdunger ◽  
Giorgio Caravatti ◽  
Pascal Furet ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Rational Design ◽  
Kinase Inhibitors

Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia: A review

2021 ◽  
pp. 107815522110383
Author(s):  
Donald C Moore
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Clinical Activity ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Pubmed Database ◽  
Bruton Tyrosine Kinase ◽  
American Society

Objective The objective of this review is to evaluate the available evidence for the Bruton tyrosine kinase inhibitors in the treatment of Waldenström macroglobulinemia. Data sources A search of the PubMed database was conducted using the following search terms: ibrutinib, PCI-32765, acalabrutinib, ACP-196, zanubrutinib, BGB-3111, and Waldenström macroglobulinemia. Prospective clinical trials evaluating the efficacy and safety of ibrutinib, acalabrutinib, and zanubrutinib in patients with Waldenström macroglobulinemia were evaluated. Abstracts from the American Society of Hematology and American Society of Clinical Oncology annual meetings were reviewed as well as the prescribing information for each drug. Data summary The first-generation Bruton tyrosine kinase inhibitor ibrutinib received Food and Drug Administration approval for Waldenström macroglobulinemia in 2015; this was the first drug approved for this rare condition. Ibrutinib has been evaluated as monotherapy and in combination with rituximab for the treatment of Waldenström macroglobulinemia. Since then, second-generation Bruton tyrosine kinase inhibitors, acalabrutinib and zanubrutinib, have been evaluated in prospective clinical trials for the treatment of Waldenström macroglobulinemia. All three agents have demonstrated high overall response rates and durable responses. Conclusion Bruton tyrosine kinase inhibitors have demonstrated significant clinical activity in the treatment of Waldenström macroglobulinemia, both in treatment naïve as well as the relapsed/refractory patient populations.

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