Phase I study of the CDK inhibitor dinaciclib (SCH 727965) in patients (pts) with relapsed/refractory CLL.

Flynn, Joseph M.; Jones, J. A.; Andritsos, Leslie A.; Blum, Kristie A.; Johnson, A. J.; Hessler, J; Wiley, Elizabeth; Heerema, NA; Poon, Jennifer; Small, Karen; Jou, Ying Ming; Zhang, D.; Statkevich, Paul; Mr, Grever; Bannerji, Rajat; Byrd, John C.

doi:10.1200/jco.2011.29.15_suppl.6623

Cited by 9 publications

(8 citation statements)

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“…CRS, manageable with steroids and not requiring treatment discontinuation, was observed in four patients. The RPTD of dinaciclib administered on this schedule to heavily pre-treated patients with CLL was found to be 14 mg/m 2 (72). A rapid decrease in Mcl-1 was noted, and DLTs included bacterial pneumonia and TLS requiring temporary dialysis at the 17 mg/m 2 dose.…”

Section: Selected Small-molecule Cdkis Under Investigation For Hemmentioning

confidence: 99%

“…High response rates (RRs) were observed, including in patients with extensive prior treatment, bulky disease or poor-risk cytogenetics (17p deletion). Common toxicities observed in these two trials included myelosuppression, nausea, vomiting, diarrhea, fatigue, hyperglycemia, hypocalcemia and elevated transaminases (71, 72). …”

Section: Selected Small-molecule Cdkis Under Investigation For Hemmentioning

confidence: 99%

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Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Bose¹,

Simmons²,

Grant³

2013

Expert Opinion on Investigational Drugs

129

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INTRODUCTION Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anti-cancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. AREAS COVERED A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. EXPERT OPINION In general, the anti-tumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad spectrum CDK inhibition will likely be required for most cancers.

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Section: Selected Small-molecule Cdkis Under Investigation For Hemmentioning

confidence: 99%

Section: Selected Small-molecule Cdkis Under Investigation For Hemmentioning

confidence: 99%

Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Bose¹,

Simmons²,

Grant³

2013

Expert Opinion on Investigational Drugs

129

View full text Add to dashboard Cite

show abstract

“…To date, this agent has advanced to several phase II studies with promising activity in chronic lymphocytic leukemia [29]. Other CDK inhibitors such as seliciclib, dinaciclib and AZD438 [30-32] show myelotoxicity, GI toxicity, fatigue, skin rash and electrolytes inbalance, with no neurological toxicity. Mechanisms for the ataxia/tremor observed with PHA-848125 in humans are not well defined.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies

et al. 2011

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Summary Purpose This phase I trial assessed the safety, maximally tolerated dose (MTD) and pharmacokinetics of TRKA/CDK inhibitor PHA-848125AC in adult patients with advanced/metastatic solid tumors. Patients and methods Patients with relapsed or refractory solid tumors, for which no standard therapy existed, were eligible. PHA-848125AC was administered orally in two schedules: daily for 7 consecutive days in 2-week cycles (i.e. 7 days on/7 days off q2wks; S1) or daily for 4 consecutive days a week for 3 weeks in 4-week cycles (i.e. 4 days on/3 days off × 3wks q4wks; S2). Result Thirty-seven patients were treated in this study, 22 in S1 and 15 in S2. The recommended phase II dose (RP2D) was 150 mg/day for either schedule. The dose-limiting toxicities (DLTs) in S1 included ataxia (Grade 2–4) and tremors (Grade 2–3). In S2, DLTs included tremors (Grade 2–3), elevated lipase (Grade 3), increased creatinine (Grade 2), and nausea and vomiting (Grade 3). These events were all reversible. In S2, out of 14 patients evaluable for efficacy, 2 patients with thymic carcinoma, showed partial response and stable disease was observed in 3 patients. Stable disease was observed in 6 out 14 patients evaluable for efficacy on S1. Drug pharmacokinetics demonstrated a half-life of approximately 33 h, and dose-proportionality with accumulation by a factor of 3 after repeated administrations. Conclusion The RP2D of PHA-848125AC was 150 mg/day on both schedules. Based on the responses noted in thymic carcinoma, a phase II study for patients with that disease is currently enrolling.

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“…Otherwise the drug was well tolerated with diarrhea and hematologic toxicity being most prominent. 58 Somewhat despite expectations, dinaciclib has not performed as well in a trial enrolling patients with indolent and large cell lymphoma, where only one partial response in a patient with diffuse large B-cell lymphoma was observed. Activity not meeting criteria for partial response was seen in 2 patients with follicular lymphoma and one patient with mantle cell lymphoma.…”

Section: Alternative and Emerging Targets: B-cell Receptor And Beyondmentioning

confidence: 99%

“…Dinaciclib was administered to five cohorts of patients with relapsed/refractory CLL (N=33) and an expansion cohort (N=16). 58 Recommended Phase II dose was established at 14 mg/m 2 on days 1, 8 and 15 of a 28-day cycle. PR was observed in 15/33 (45%) of all patients, including many who had prior fludarabine treatments and those with deletion 17p.…”

Section: Alternative and Emerging Targets: B-cell Receptor And Beyondmentioning

confidence: 99%

Targeted Therapy in Chronic Lymphocytic Leukemia: Past, Present, and Future

Danilov¹

2013

Clinical Therapeutics

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Background Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world. Recent advances in understanding the biology of B-cell malignancies resulted in the development of novel agents targeting key pro-survival pathways in the neoplastic B-cell. Objective The goal of this article was to summarize current literature on the emerging therapeutic approaches in CLL and B-cell malignancies. Methods A literature review was performed, identifying pathways and key clinical trials involving novel therapies in CLL with special emphasis on B-cell receptor targeting agents. Results Understanding the biology of B-cell receptor signaling pathway led to identification of novel molecular targets. Most notably, inhibitors of Bruton tyrosine kinase and phosphatidylinositide 3-kinase-δ have entered clinical trials and demonstrated high response rates in CLL, including high-risk disease. Cyclin-dependent kinase inhibitors may evolve into an alternative therapeutic approach in CLL. New drugs which target molecules within and outside of the B-cell receptor signaling pathway show promise in pre-clinical studies. Conclusions Both pre-clinical and early clinical trial results involving novel targeted therapies suggest that the standard treatment paradigm in CLL and B-cell malignancies will soon change. Particular attention should be paid to the BCR-targeting agents, whose favorable side effect profile may improve lives of the elderly patients with CLL.

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Phase I study of the CDK inhibitor dinaciclib (SCH 727965) in patients (pts) with relapsed/refractory CLL.

Cited by 9 publications

References 0 publications

Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Phase I study of the safety, tolerability and pharmacokinetics of PHA-848125AC, a dual tropomyosin receptor kinase A and cyclin-dependent kinase inhibitor, in patients with advanced solid malignancies

Targeted Therapy in Chronic Lymphocytic Leukemia: Past, Present, and Future

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