Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced Neoplasms

2002 ◽  
Vol 20 (19) ◽  
pp. 4074-4082 ◽  
Author(s):  
Antoinette R. Tan ◽  
Donna Headlee ◽  
Richard Messmann ◽  
Edward A. Sausville ◽  
Susan G. Arbuck ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Optimal Schedule ◽  
Maximum Tolerated Dose ◽  
Chemotherapeutic Agents ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Tumor Pain ◽  
Micromolar Range

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m2/d for 5 days; doses of 50 and 62.5 mg/m2/d for 3 days; and doses of 62.5 and 78 mg/m2/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses ≥ 52.5 mg/m2/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 μmol/L (range, 1.3 to 4.2 μmol/L), 3.2 μmol/L (range, 1.7 to 4.8 μmol/L), and 3.9 μmol/L (1.8 to 5.1 μmol/L), respectively. Twelve patients had stable disease for ≥ 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m2/d for 5 days, 50 mg/m2/d for 3 days, and 62.5 mg/m2/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.

Flavopiridol Treatment of Patients Aged 70 or Older with Refractory or Relapsed Chronic Lymphocytic Leukemia Is Feasible and Not Associated with Adverse Outcome When Compared to Younger Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1378-1378
Author(s):  
Deborah M Stephens ◽  
Amy S. Ruppert ◽  
Kristie A. Blum ◽  
Jeffrey A. Jones ◽  
Joseph M. Flynn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Age Groups ◽  
Lymphocytic Leukemia ◽  
Cyclin Dependent Kinase ◽  
Complex Karyotype ◽  
Younger Patients ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Significant Difference

Abstract Abstract 1378 Although the most rapidly growing portion of the United States population is the elderly (Yancik R and Ries L, Semin Oncol 2004), they are consistently underrepresented in cancer clinical trials (Hutchins L et al, N Engl J Med 1999). The incidence of chronic lymphocytic leukemia (CLL) is markedly increased in older people, with a median age at diagnosis of 72 years (Ries L et al, SEER Clinical Statistics Review 2008). In contrast, an age range of between 58 and 66 years has been noted in patients (pts) enrolled in key trials to evaluate the first-line treatment for CLL (Eichhorst B et al, Leuk Lymphoma 2009). Both fludarabine and chemoimmunotherapy with rituximab have not demonstrated much promise in the older subset of patients. Developing new therapeutics that have clinical benefit and also demonstrate feasibility of administration to this patient population is of great interest. Flavopiridol, is a pan-cyclin-dependent kinase inhibitor, that has demonstrated significant clinical activity in relapsed and refractory CLL pts including those with del(17p13.1)(Christian B et al, Clin Lymphoma Myeloma 2009). We sought to determine the feasibility and impact of treating patients over the age of 70 with flavopiridol by reviewing outcomes of two clinical trials using single-agent flavopiridol in patients with relapsed or refractory CLL at our institution (Byrd J et al, Blood 2007; Lin T et al, J Clin Oncol 2009). Pts were divided into categories based on age [≥70 years old (n = 21) and <70 years old (n = 95)]. Of the 21 pts aged 70 or older, all but one (95%) presented with Rai Stage III/IV compared with 76% of the younger pts (<70 years old; P = 0.07). Older age was also associated with complex karyotype (63% vs. 37%; P = 0.04). No significant difference was observed in response rates, with 43% of older pts achieving response vs. 47% of younger pts (P = 0.81). The estimated median progression free survival (PFS) for both age groups was 0.8 years (P = 0.9). In multivariable analyses, there remained no significant differences in response rates or PFS when controlling for treatment schedule, Rai stage and presence of complex karyotype (P = 0.76 and P = 0.89, respectively). Although overall survival tended to be worse in the older pts compared with the younger pts (estimated medians of 2.1 and 2.4 years, respectively), following adjustment for other variables in a multivariable analysis, this difference was no longer significant (P = 0.54, hazard ratio = 1.20 [95% CI: 0.7 – 2.1]). With respect to toxicities, no significant difference in occurrence of tumor lysis syndrome (TLS) or cytokine release syndrome (CRS) was observed between the two age groups, TLS occurred in 48% of older pts and 45% of younger pts (P = 1.00), while CRS occurred in 33% of older pts and 36% of younger pts (P = 1.00). As for infection, only 29% of older pts experienced this toxicity compared to 62% of younger pts (P = 0.007). In multivariable pharmacokinetic (PK) analyses of a patient subset (n=56), there were no significant associations observed between PK parameters and age when controlling for age, bilirubin level, alanine transaminase level, platelet count, white blood cell count, BUN, and 14 distinct single nucleotide polymorphisms. These data demonstrate that flavopiridol administration to older CLL patients is both feasible, acceptably tolerated, and has similar efficacy as compared to younger patients. Future development of treatment approaches with both single-agent and combination strategies of flavopiridol should be considered for older CLL patients. Disclosures: Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol is under investigation in CLL. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

scholarly journals Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

2013 ◽  
Vol 51 (3) ◽  
pp. T61-T74 ◽  
Author(s):  
Prasenjit Dey ◽  
Rodrigo P A Barros ◽  
Margaret Warner ◽  
Anders Ström ◽  
Jan-Åke Gustafsson
Keyword(s):  
Small Molecules ◽  
Kinase Inhibitor ◽  
Anxiety And Depression ◽  
Pharmaceutical Companies ◽  
Biological Processes ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Key Pathways ◽  
Insight Into

Estrogen and its receptors (ERs) influence many biological processes in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancies, ERβ usually is a tumor suppressor and ERα is an oncogene. ERβ regulates genes in several key pathways including tumor suppression (p53, PTEN); metabolism (PI3K); survival (Akt); proliferation pathways (p45Skp2, cMyc, and cyclin E); cell-cycle arresting factors (p21WAF1, cyclin-dependent kinase inhibitor 1 (CDKN1A)), p27Kip1, and cyclin-dependent kinases (CDKs); protection from reactive oxygen species, glutathione peroxidase. Because they are activated by small molecules, ERs are excellent targets for pharmaceuticals. ERα antagonists have been used for many years in the treatment of breast cancer and more recently pharmaceutical companies have produced agonists which are very selective for ERα or ERβ. ERβ agonists are being considered for preventing progression of cancer, treatment of anxiety and depression, as anti-inflammatory agents and as agents, which prevent or reduce the severity of neurodegenerative diseases.

Risk Factors for Tumor Lysis Syndrome (TLS) In Patients with Chronic Lymphocytic Leukemia (CLL) Treated with the Cyclin Dependent Kinase Inhibitor, Flavopiridol.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1386-1386
Author(s):  
Kristie A. Blum ◽  
Amy S. Ruppert ◽  
Jennifer A. Woyach ◽  
Jeffrey A. Jones ◽  
Leslie Andritsos ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Multivariable Analysis ◽  
Female Gender ◽  
Stage I ◽  
Stage Iii ◽  
Cyclin Dependent Kinase ◽  
Bulky Disease ◽  
Cyclin Dependent Kinase Inhibitor

Abstract Abstract 1386 Background: Hyperacute TLS, defined as a rise in uric acid, potassium, lactate dehydrogenase (LDH), and/or phosphate that occurs within 4.5 hours and peaks 24–48 hours after flavopiridol, has been described in up to 40% of pts with CLL treated with this agent. Methods: A retrospective analysis of 116 pts with relapsed or refractory CLL treated with single agent flavopiridol at the Ohio State University on phase I or II protocols was conducted to determine predictive factors for TLS. Pts received flavopiridol 30–50 mg/m2 bolus + 30–50 mg/m2 4-hour continuous IV infusion (CIVI) on days 1, 8, 15, and 22 every 35 days or days 1, 8, and 15 every 28 days. Results: In 116 pts, the median age was 60 (range, 31–84), median number of prior therapies was 4 (range, 1–14), 69% pts were male, 79% were Rai stage III-IV, 53% had bulky disease ≥ 10 cm, 52% had splenomegaly, and 69% had del(17p) and/or del(11q). Median pre-treatment laboratory values included B2-microglobulin (B2M) 4.4 (range, 0.8–14.9), absolute lymphocyte count (ALC) 7134/mm3 (range, 0–266,310), white blood cell count (WBC) 13,950/mm3 (range, 1,300-314,500), and LDH 199 U/L (range, 102–654). The incidence of TLS was 46% (95% CI: 36%-55%), with 14 of 53 pts (26%) with TLS requiring dialysis. In univariable analyses using logistic regression, variables associated with the occurrence of TLS were female gender (p<0.001), number of prior therapies (p<0.001), Rai stage III-IV (p<0.001), bulky disease ≥ 10 cm (p<0.001), splenomegaly (p=0.04), del(11q) (p=0.03), ALC (p=0.004), WBC (p<0.001), B2M (p<0.001), and LDH (p=0.003). 72% of females, 36% of males, 59% pts with lymphadenopathy ≥ 10 cm, 31% pts with lymphadenopathy < 10 cm, 55% pts with del(11q), and 35% pts with del(17p) developed TLS. Median B2M and WBC values in pts without TLS were 3.1 and 8,300/mm3 compared to 5.3 and 27,000/mm3 in pts with TLS, respectively. In a multivariable analysis using limited backwards selection (Table 1), female gender, bulky adenopathy ≥ 10 cm, WBC, and B2M were significantly associated with TLS (p<0.05). Notably, only 3 of 24 pts with Rai stage I/II disease developed TLS, and the small numbers of Rai stage I-II pts precluded the use of this variable in the multivariable analysis. Therefore, the multivariable analysis was restricted to pts with Rai stage III/IV (n=92), and the same 4 variables in Table 1 remained significantly associated with TLS. TLS occurred in all pts (n=8) with WBC > 150,000/mm3, 75% pts with WBC 100–150,000, and 38% pts with WBC < 100,000/mm3. TLS rates were 74% and 19% in pts with B2M above and below the median (4.4), respectively. In a secondary analysis, we examined if peak flavopiridol and its glucoronide metabolite (flavo-G) levels correlated with TLS or gender. In a subset of 85 pts with available data, flavo-G levels were associated with TLS (p=0.001), but this was independent of pt gender. When peak flavo-G levels were distributed into quartiles, 50% women in the lowest quartile developed TLS compared to 93% in the highest quartile. Likewise, 14% of men with the lowest flavo-G levels developed TLS as opposed to 57% in the highest quartile. With respect to pt outcomes, 49% with TLS and 44% without TLS responded to flavopiridol. In a multivariable model controlling for number of prior treatments, cytogenetic risk group, Rai stage, age, and gender, response rates were not significantly different (p=0.34) in patients with and without TLS. However, overall survival (OS) and progression-free survival (PFS) were inferior in pts with TLS (p=0.03 and p=0.04, respectively). Eighty-six pts have died, including 13 of 14 pts with TLS who required dialysis. For pts with TLS that did not require dialysis, OS was not significantly different (p=0.88), although PFS was still worse in this subgroup (p=0.03, Figure 1). Conclusions: Female pts and pts with B2M ≥ 4.4, WBC ≥ 100,000/mm3, or bulky adenopathy ≥ 10 cm were at highest risk and should be monitored for hyperacute TLS with flavopiridol. TLS does not appear to be predictive of response or improved PFS in pts receiving flavopiridol. Supported by NCI K23 CA109004, NCI U01 CA076576, NCI N01 CM62207, LLS SCOR 7080-06, and the D. Warren Brown Foundation. Disclosures: Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol is under investigation in CLL.

scholarly journals The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of differentiating neuroblastoma cells.

1996 ◽  
Vol 16 (4) ◽  
pp. 1335-1341 ◽  
Author(s):  
W Poluha ◽  
D K Poluha ◽  
B Chang ◽  
N E Crosbie ◽  
C M Schonhoff ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Neuronal Differentiation ◽  
Kinase Inhibitor ◽  
Cyclin E ◽  
Neuroblastoma Cells ◽  
Protein Kinase Activity ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Differentiated Cells

We are employing recent advances in the understanding of the cell cycle to study the inverse relationship between proliferation and neuronal differentiation. Nerve growth factor and aphidicolin, an inhibitor of DNA polymerases, synergistically induce neuronal differentiation of SH-SY5Y neuroblastoma cells and the expression of p21WAF1, an inhibitor of cyclin-dependent kinases. The differentiated cells continue to express p21WAF1, even after removal of aphidicolin from the culture medium. The p21WAF1 protein coimmunoprecipitates with cyclin E and inhibits cyclin E-associated protein kinase activity. Each of three antisense oligonucleotides complementary to p21WAF1 mRNA partially blocks expression of p21WAF1 and promotes programmed cell death. These data indicate that p21WAF1 expression is required for survival of these differentiating neuroblastoma cells. Thus, the problem of neuronal differentiation can now be understood in the context of negative regulators of the cell cycle.

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