Background.
AZD1480 is a novel agent that inhibits Janus‐associated kinases 1 and 2 (JAK1 and JAK2). The primary objective of this phase I study was to investigate the safety and tolerability of ...AZD1480 when administered as monotherapy to patients with solid tumors.
Methods.
Thirty‐eight patients with advanced malignancies were treated at doses of 10–70 mg once daily (QD) and 20–45 mg b.i.d.
Results.
Pharmacokinetic (PK) analysis revealed rapid absorption and elimination with minimal accumulation after repeated QD or b.i.d. dosing. Exposure increased in a dose‐dependent manner from 10–50 mg. Maximum plasma concentration (Cmax) was attained ∼1 hour after dose, and t1/2 was ∼5 hours. Pharmacodynamic analysis of circulating granulocytes demonstrated maximum phosphorylated STAT3 (pSTAT3) inhibition 1–2 hours after dose, coincident with Cmax, and greater pSTAT3 inhibition at higher doses. The average pSTAT3 inhibition in granulocytes at the highest dose tested, 70 mg QD, was 56% (standard deviation: ±21%) at steady‐state drug levels. Dose‐limiting toxicities (DLTs) consisted of pleiotropic neurologic adverse events (AEs), including dizziness, anxiety, ataxia, memory loss, hallucinations, and behavior changes. These AEs were generally reversible with dose reduction or treatment cessation.
Conclusions.
Whether the DLTs were due to inhibition of JAK‐1/2 or to off‐target effects is unknown. The unusual DLTs and the lack of clinical activity led to discontinuation of development.
摘要
背景. AZD1480是抑制Janus相关激酶‐1和‐2（JAK1和JAK2）的新型药物。本项I期研究的主要目的是调查AZD1480单药治疗实体瘤患者的安全性和耐受性。
方法: 共38例晚期癌症患者接受AZD1480治疗，剂量为10 ∼ 70mg每日1次（QD）或20 ∼ 45mg每日2次（BID）。
结果. 药代动力学（PK）分析显示AZD1480QD或BID重复给药后迅速吸收和排泄，仅有极少在体内累积。10 ∼ 50 mg剂量之间的药物暴露水平增加呈剂量依赖性。给药约1h后达到血浆峰浓度（Cmax），而半衰期（t1/2）约为5h。循环粒细胞的药效学分析证实AZD1480给药后1 ∼ 2 h对磷酸化STAT3（pSTAT3）的抑制效应最强，与Cmax出现时间一致，且剂量越高pSTAT3抑制效应越强。给药剂量最大（即70 mg QD）时，稳态药物浓度下粒细胞pSTAT3的平均抑制程度为56%（标准差：±21%）。剂量限制性毒性（DLT）包括多种表现的神经系统不良事件（AE），如头晕、焦虑、共济失调、失忆、幻觉和行为改变。随着剂量减小或治疗中止，这些AE通常可逆。
结论.DLT究竟是由JAK‐1/2抑制还是脱靶效应引起仍未可知。非常规的DLT事件和临床疗效不足导致了药物研发的中止。
To evaluate the proposed cancer-related fatigue (CRF) diagnostic criteria in a sample of cancer survivors. More accurate prevalence estimates of CRF may result in improved diagnosis and management of ...one of the most common symptoms associated with cancer and its treatment.
Three hundred seventy-nine individuals who had been treated with chemotherapy, either alone or in combination with radiation therapy, were surveyed. Patients were asked background questions about their current condition, their medical history, and the frequency of fatigue during their chemotherapy. Additionally, patients who reported experiencing fatigue at least a few days each month during treatment were asked a series of questions about the impact of fatigue on their daily functioning.
One hundred forty-one (37%) individuals reported at least 2 weeks of fatigue in the previous month. Of the respondents who had received their last treatment more than 5 years ago, 33% still reported at least a 2-week period of fatigue in the month before the interview. Evaluation of the proposed criteria revealed that 17% of respondents met at least two criteria for CRF.
The prevalence of diagnosable CRF in the individuals in this sample, most of whom had completed treatment more than 1 year ago, was 17%-lower than expected based on previous reports that have used less-strict criteria. In a sizable number of people, CRF persists well beyond active treatment and should be a focus of intervention. Although they will require replication in other samples and clinical validation, these formal diagnostic criteria can be a step toward common language and a better understanding of the severity range and persistence of CRF.
Purpose. This survey was designed to confirm the prevalence and duration of fatigue in the cancer population and to assess its physical, mental, social, and economic impacts on the lives of patients ...and caregivers.
Patients and Methods. A 25‐minute telephone interview was completed with 379 cancer patients having a prior history of chemotherapy. Patients were recruited from a sample of 6,125 households in the United States identified as having a member with cancer. The median patient age was 62 years, and 79% of respondents were women. Patients reporting fatigue at least a few times a month were asked a series of questions to better describe their fatigue and its impact on quality of life.
Results. Seventy‐six percent of patients experienced fatigue at least a few days each month during their most recent chemotherapy; 30% experienced fatigue on a daily basis. Ninety‐one percent of those who experienced fatigue reported that it prevented a “normal” life, and 88% indicated that fatigue caused an alteration in their daily routine. Fatigue made it more difficult to participate in social activities and perform typical cognitive tasks. Of the 177 patients who were employed, 75% changed their employment status as a result of fatigue. Furthermore, 65% of patients indicated that their fatigue resulted in their caregivers taking at least one day (mean, 4.5 days) off work in a typical month. Physicians were the health care professionals most commonly consulted (79%) to discuss fatigue. Bed rest/ relaxation was the most common treatment recommendation (37%); 40% of patients were not offered any recommendations.
Conclusions. Cancer‐related fatigue is common among cancer patients who have received chemotherapy and results in substantial adverse physical, psychosocial, and economic consequences for both patients and caregivers. Given the impact of fatigue, treatment options should be routinely considered in the care of patients with cancer.
The RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life ...that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors.
This study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m
or dacarbazine 1000 mg/m
administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A.
A total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity DLT events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine.
The combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors.
ClinicalTrials.gov NCT00600496; registered 8 July 2009.
Fatigue is a complex, multifactorial disorder with physical, mental, and psychological dimensions that has been associated with diminished quality of life (QOL) in patients with cancer. The ...prevalence and severity of fatigue, however, has only recently been studied systematically. Two national surveys commissioned by The Fatigue Coalition, a multidisciplinary group of medical practitioners, researchers, and patient advocates, whose mission is to study the importance of fatigue for patients with cancer and their caregivers, have assessed the prevalence, severity, and QOL consequences of fatigue in patients with cancer. The most recent survey, initiated in 1998, sought to confirm and extend observations on the prevalence and impact of fatigue in patients with cancer as part of an initiative to develop guidelines for the differential diagnosis and treatment of fatigue. The FATIGUE 2 study probed the emotional, social, physical, and economic impact of fatigue on patients with cancer and their caregivers. Patient perceptions of the professional response to cancer‐related fatigue were also assessed. The key findings of these surveys are reviewed. 2000;5(suppl 2): 9‐12
Learning Objectives
After completing this course, the reader will be able to:
Differentiate between cytotoxic and molecularly‐targeted drug development in terms of drug discovery, mechanism of ...action, pharmacological effect, and specificity.
Define the primary objectives of phase I, II, and III clinical trials of cytotoxic and molecularly targeted anticancer agents.
Compare the end points used in clinical trials for cytotoxic agents to the proposed end points for target‐based (cytostatic) agents.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
Anticancer drug discovery has shifted from an empiric random screening directed approach to a more rational and mechanistic, target‐based approach, which reflects our rapidly expanding knowledge of the pathogenesis of a variety of forms of cancer at the molecular level, providing new targets for drug discovery and development. The clinical development of target‐based anticancer drugs will require fundamental changes to the traditional clinical trial design and end points that have been used for conventional cytotoxic drugs. In the phase I and II settings, traditional end points (toxicity and response) may not be suitable for more selective, cytostatic target‐based agents, and these end points may be replaced by biological or pharmacokinetic end points to define the optimal doses and the therapeutic effects of these drugs on their targets. For phase III trials, measurable clinical benefit will continue to be the primary end point. As our understanding of the complex pathways and networks controlling cell signaling, proliferation, and cell death expands, we must learn how and when to use agents to target specific steps in malignant transformation and proliferation, and we must adapt clinical trial design to test the clinical utility of this promising new class of anticancer drugs.
This article endeavors to clarify the current requirements and status of regulatory approval for chemoprevention (risk reduction) drugs and discusses possible improvements to the regulatory pathway ...for chemoprevention. Covering a wide range of topics in as much depth as space allows, this report is written in a style to facilitate the understanding of nonscientists and to serve as a framework for informing the directions of experts engaged more deeply with this issue. Key topics we cover here are as follows: a history of definitive cancer chemoprevention trials and their influence on the evolution of regulatory assessments; a brief review of the long-standing success of pharmacologic risk reduction of cardiovascular diseases and its relevance to approval for cancer risk reduction drugs; the use and limitations of biomarkers for developing and the approval of cancer risk reduction drugs; the identification of individuals at a high(er) risk for cancer and who are appropriate candidates for risk reduction drugs; business models that should incentivize pharmaceutical industry investment in cancer risk reduction; a summary of scientific and institutional barriers to development of cancer risk reduction drugs; and a summary of major recommendations that should help facilitate the pathway to regulatory approval for pharmacologic cancer risk reduction drugs.
This editorial invites readers to weigh in on whether The Oncologist should expend the considerable effort and expense to produce a peer‐reviewed, searchable venue for publishing the results of all ...well‐executed cancer trials that fail to meet positive endpoints.
Genistein (5,7,4'-trihydroxyisoflavone), an isoflavinoid found in soy beans, has been identified as potentially causal for the low incidence of metastatic prostate cancer (PCa) in certain countries. ...Although genistein-induced PCa cell adhesion has been identified as a possible causative mechanism, direct growth inhibition by genistein has been reported and also could be causal. If in vivo growth inhibition was significant, then growth inhibition should occur at concentrations attained with dietary consumption, the mechanism of growth inhibition should be relevant to PCa, and genistein (a broad-spectrum in vitro protein-tyrosine kinase inhibitor) should have relatively specific kinase inhibitory effects in vivo. These considerations were investigated by measuring growth inhibitory activity in a variety of PCa cell lines. Growth inhibitory effects were shown not to occur with concentrations below the low micromolar range (i.e., 3 logs above that attained in serum). In-depth mechanistic studies with the PC3-M metastatic variant cell line demonstrated that growth inhibition was independent of genistein's estrogenic effects. Genistein was shown to decrease the viability of nonadherent cells, suggesting a lack of dependence on cell adhesion for growth inhibition. However, important molecular and kinetic differences between genistein's effects on growth in adherent versus nonadherent cells were identified. Specific suppression of focal adhesion kinase activity (without global decreases in phosphotyrosine) was shown to precede induction of apoptosis, which was responsible for growth inhibition in adherent cells. These findings do not support an in vivo growth inhibitory role by genistein consumed in quantities associated with a soy-based diet. They do, however, identify genistein as a potential therapeutic agent for PCa and as a tool with which to study the control of apoptosis in PCa.
This editorial cites SEMATECH, a company formed by collaboration between industry and government in the semiconductor manufacturing field, as an example of how the public and private sectors might ...begin to work together in the all‐important area of biomarkers in cancer drug development.
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