A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours

Schöffski, Patrick; Awada, Ahmad; Dumez, Herlinde; Gil, Thierry; Bartholomeus, S.; Wolter, Pascal; Taton, Martine; Fritsch, Holger; Glomb, Patricia; Munzert, Gerd

doi:10.1016/j.ejca.2011.11.001

Cited by 145 publications

(144 citation statements)

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“…Volasertib showed a moderate plasma clearance (897 mL/min; geometric coefficient of variation 43%) and a large volume of distribution (6130 L; geometric coefficient of variation 42%). Volasertib pharmacokinetics in combination with LDAC were similar to those obtained earlier for volasertib monotherapy, 26 suggesting no effect of cytarabine on the pharmacokinetics of volasertib. Further, the exposure to cytarabine following s.c. …”

Section: Pharmacokineticssupporting

confidence: 66%

“…There was an increase in hematologic AEs, as expected, from the antimitotic mode of action and from data of the phase 1 study of volasertib in patients with advanced solid tumors. 26 The time interval between cycles was somewhat longer in responding patients after LDAC 1 volasertib Response by ELN genetic group, n (%) Response by BM blast count, n (%)…”

Section: Discussionmentioning

confidence: 99%

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Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Döhner

Lübbert

Fiedler

et al. 2014

Blood

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Key Points• Volasertib plus low-dose cytarabine increased the response rate and improved survival in AML patients ineligible for intensive treatment.• Volasertib plus low-dose cytarabine resulted in responses across all AML genetic subgroups and had a clinically manageable safety profile.Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC 1 volasertib 350 mg IV days 1 1 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC 1 volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P 5 .052). Responses in the LDAC 1 volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC 1 volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P 5 .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P 5 .047). LDAC 1 volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 1 90. This study was

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Section: Pharmacokineticssupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Döhner

Lübbert

Fiedler

et al. 2014

Blood

Self Cite

208

163

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“…1,[7][8][9][10][11][12][13][14][15][16][17][18][19] In particular, BI 2536 and BI 6727 are the most intensively investigated Plk1 inhibitors. [20][21][22][23][24][25] Poloxin, the first reported non-peptidic inhibitor of the PBD of Plk1, shows its specificity and anti-proliferative activity in vitro as well as in vivo. [15][16][17] While the preclinical data of Plk1 inhibitors are encouraging, the clinical results are rather less inspiring, showing limited anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

et al. 2013

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“…BI 2536, 46 BI 6727 47 and GSK461364 48 showed antitumor activity and stabilized disease in a subset of patients with advanced solid tumors, with manageable and reversible toxicity. Based on our results, it is plausible that PLK1-targeting drugs may also have therapeutic potential in childhood ALL.…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

et al. 2013

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This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. ABSTRACTinhibitor highly selective for PLK1 and the first orally administered selective PLK1 inhibitor entering phase I clinical trials 25 (clinicaltrials.gov identifier: NCT01014429). This study shows the potential of PLK1-targeting therapeutics in the treatment of childhood ALL, and indicates their value for further clinical evaluation. Methods Cell linesCell lines (DSMZ, Braunschweig, Germany) were cultured in RPMI+Glutamax with pen-strep, fungizone (Life Technologies, Bleiswijk, The Netherlands) and 10% or 20% fetal calf serum (Integro, Zaandam, The Netherlands), at 37ºC and 5% CO 2 .

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A phase I, dose-escalation study of the novel Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours

Cited by 145 publications

References 13 publications

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy

Polo-like kinase 1 inhibitors, mitotic stress and the tumor suppressor p53

Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells

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