Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia.

Eg5 (kinesin spindle protein) is a microtubule motor protein, essential for centrosome separation during mitosis. This Phase I/II, open-label, multicenter, two-part study investigated AZD4877, a potent Eg5 inhibitor, in patients with acute myeloid leukemia. Primary objectives were to determine the maximum tolerated dose (MTD) (part A), assess efficacy (part B) and determine the pharmacokinetic profile (parts A and B). Secondary objectives included assessment of safety and tolerability. AZD4877 was administered at a range of doses (2, 4, 7, 10, 13, 16 and 18 mg/day) as a 1-hour intravenous infusion on three consecutive days of a continuous 2-week schedule. The MTD in part A was defined as 16 mg/day based on dose-limiting stomatitis at 16 and 18 mg/day, hyperbilirubinemia at 16 mg/day and palmar-plantar erythrodysesthesia syndrome at 18 mg/day. Systemic exposure to AZD4877 generally increased with increasing dose whereas half-life was not dose dependent. No evaluable patients experienced a complete remission (CR) or CR with incomplete blood count recovery (CRi), demonstrating no evidence of AZD4877 efficacy in this population. Evidence of monoasters in all but the 4 mg/day dose group provided proof of mechanism for AZD4877. This study was terminated due to lack of efficacy. (ClinicalTrials.gov identifier NCT00486265).

Formation of methotrexate polyglutamates in purified myeloid precursor cells from normal human bone marrow.

Immature myeloid precursor cells were preferentially selected from normal human bone marrow by using immune rosette techniques that employed monoclonal antibodies against mature granulocytes, monocytes, T and B lymphocytes, and erythroid precursors (Mo5, M3, OKT3, B1, and EP1, respectively). We examined the formation, retention, and cytotoxic effects of methotrexate (MTX) polyglutamates (MTX-PGs) in these purified myeloid precursor cells. After 1- and 24-h exposures to MTX, with thymidine and deoxyinosine as rescue, the intracellular MTX-PG profile was examined by high-pressure liquid chromatography. Efflux patterns of MTX-PGs were also studied after additional 1- and 24-h incubations in drug-free media. Cytotoxic effects of retained MTX-PGs on bone marrow myeloid precursors were examined by colony formation in drug-free semisolid agar. Normal myeloid precursor cells converted MTX to MTX-PGs in a concentration- and time-dependent manner, preferentially retaining MTX-PGs with three to five glutamyl moieties. At low concentrations of MTX (1 microM), MTX-PG formation was insufficient to maintain saturation of the target enzyme dihydrofolate reductase after removal of drug from the incubation medium, and there was no decrease in myeloid colony formation. At higher concentrations of MTX (10 microM), formation of higher molecular weight polyglutamates was sufficient to allow for 24-h saturation of intracellular binding capacity after removal of extracellular drug and resulted in a 35% reduction in the formation of colony-forming units in culture. Comparison of MTX metabolism in normal bone marrow cells and the MTX-sensitive HL-60 human leukemia cell line showed twofold greater PG formation by these tumor cells after 24-h exposure to 1 or 10 microM MTX, and a marked (greater than 30-fold) increase in cytotoxicity for the HL-60 cells as compared with normal myeloid precursors, suggesting that the MTX polyglutamation may be important to its selective antitumor action.

Determinants of the sensitivity of human small-cell lung cancer cell lines to methotrexate.

We have characterized the determinants of methotrexate (MTX) responsiveness in eight patient-derived cell lines of small-cell lung cancer (SCLC). Clonogenic survival was correlated with factors known to affect sensitivity to drug. NCI-H209 and NCI-H128 were most drug sensitive, with drug concentrations required to inhibit clonogenic survival by 50% with less than 0.1 microM MTX. Six cell lines (NCI-H187, NCI-H345, NCI-H60, NCI-H524, NCI-H146, and NCI-N417D) were relatively drug resistant. In all cell lines studied, higher molecular weight MTX-polyglutamates (MTX-PGs) with 3-5 glutamyl moieties (MTX-Glu3 through MTX-Glu5) were selectively retained. Relative resistance to low (1.0 microM) drug concentrations appeared to be largely due to decreased intracellular metabolism of MTX. Five of the six resistant lines were able to synthesize polyglutamates at higher (10 microM) drug concentrations, although one resistant cell line (NCI-N417D) did not synthesize higher molecular weight MTX-PGs, even after exposure to 10 microM drug. Two cell lines with resistance to 10 microM MTX (NCI-H146 and NCI-H524) synthesized and retained higher molecular weight MTX-PGs in excess of binding capacity after exposure to 10 microM drug. However, the specific activity of thymidylate synthase in these cell lines was low. MTX sensitivity in patient-derived cell lines of SCLC requires the ability of cells to accumulate and retain intracellular drug in the form of polyglutamate metabolites in excess of dihydrofolate reductase, as well as a high basal level of consumption of reduced folates in the synthesis of thymidylate.

Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone.

The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration. Initial studies were performed in six rhesus monkeys with chronic indwelling Ommaya reservoirs. Following intraventricular administration of 0.2 mg of AZQ, elimination was monoexponential with half-lives of 32 and 39 min in ventricular and lumbar CSF, respectively. AZQ clearance (0.2 ml/min) was 5-fold greater than estimated CSF bulk flow, indicating that transcapillary passage and/or metabolism may be important clearance mechanisms for this drug. In spite of its rapid clearance from ventricular CSF, a substantial peak AZQ concentration was achieved in lumbar CSF (12 microM), which was 7 times higher than the peak ventricular CSF level (1.7 microM) achieved following i.v. AZQ administration (16 mg/sq m). Moreover, the mean area under the CSF concentration-time curve in ventricular CSF was 20-fold greater following intraventricular versus i.v. AZQ dosing, despite an 80-fold-lower dose. AZQ was not detectable in plasma (less than 0.06 microM) following intraventricular administration. No animals demonstrated clinical evidence of acute neurotoxicity. Subsequently, intraventricular AZQ was administered to a patient with refractory meningeal leukemia. Intraventricular AZQ (0.5 mg) resulted in a peak ventricular (56 microM) CSF level which was 80-fold higher than ventricular CSF levels achieved following systemic AZQ administration of a dose of 24 mg/sq m in humans. Moreover, intraventricular AZQ yielded substantial CSF levels without detectable plasma concentrations. These data suggest that intraventricular administration of AZQ is feasible and may have pharmacological advantages over systemic administration for the treatment of meningeal neoplasia.

Phase I and clinical pharmacology study of intravenous flavone acetic acid (NSC 347512).

We have conducted a Phase I and pharmacological study of flavone acetic acid, one of a series of novel flavonoids. The drug was administered i.v. weekly for 4 weeks, with a 2-week rest and then repeated. Flavone acetic acid was given initially in a 1-h infusion, but at the 3900-mg/m2 dose level, the infusion time was lengthened to 3 h. A total of 31 patients were treated with 9 different dose levels, ranging from 330 to 6400 mg/m2. Dose-limiting toxicity was acute hypotension that began after about one-third of each drug dose had been infused and rarely lasted more than a few minutes after the infusion was discontinued. In addition, subjective fatigue and asthenia causing unacceptable patient discomfort was dose limiting. A significant side effect noted that was not dose limiting was diarrhea during the infusion. This drug exhibited nonlinear pharmacokinetic behavior. Plasma levels exceeded 300 micrograms/ml during the infusion at the maximally tolerated dose. After the infusion ended the principal half-life was about 2 h. In 24-h urine collections 27% of the flavone acetic acid dose was recovered as intact drug and an additional 37% was recovered as a metabolite. The maximally tolerated dose determined in this study is 6400 mg/m2 given i.v. over 3 h.

Phase II and pharmacokinetic study of aziridinylbenzoquinone [2,5-diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone, diaziquone, NSC 182986] in high-grade gliomas.

2,5-Diaziridinyl-3,6-bis(carboethoxyamino)-1,4-benzoquinone (AZQ; Diaziquone, NSC 182986) is a rationally designed antitumor drug possessing sufficient lipid solubility to allow penetration into the central nervous system. Thirty-one patients with high-grade glioma and progressive disease following radiation, with or without previous chemotherapy, have been treated with 144 cycles of drug, consisting of 20 mg/sq m given as an i.v. infusion on Days 1 and 8 of a 28-day cycle. Responses were measured by serial computer tomography scanning. Of the 28 evaluable patients, 6 (21%) had limited improvement (10 to 40% reduction in tumor size) on computer tomography scan, 10 (36%) had disease stabilization, and 12 (43%) had progressive disease. The drug was well tolerated clinically, with little acute toxicity. The major toxicity was myelosuppression, which appeared cumulative, using this dose regimen. AZQ was measurable in both tumor tissue and tumor cyst fluid in patients on therapy. Plasma samples taken during the period of infusion confirm that 50% or more of the total AZQ exposure occurs during the infusion period. AZQ behaves as intended by design and demonstrates activity in this poor-prognosis group of patients.

A phase I and pharmacokinetic study of diamminecyclobutane-dicarboxylatoplatinum (NSC 241240).

Carboplatin (CBDCA; NSC 241240) is a second-generation platinum coordination compound which in preclinical testing was found to be less nephrotoxic and emetogenic than cis-diamminedichloroplatinum (CDDP), while retaining a broad spectrum of antitumor activity. We have conducted a Phase I trial of CBDCA in 38 patients with advanced carcinoma. The drug was given without hydration as a 24-hr constant i.v. infusion on Day 1 of a 28-day cycle. Seventy-five cycles of CBDCA were administered in eight dose levels ranging from 20 to 320 mg/sq m. Dose-limiting toxicity was myelosuppression, primarily thrombocytopenia, occurring between Days 14 and 28 of the cycle. Myelosuppression was first observed at a dose of 240 mg/sq m and became dose-limiting at 320 mg/sq m, which is the recommended dose for Phase II trial. Other toxicities included nausea and vomiting and reversible renal failure seen in two patients with low normal pretreatment creatinine clearances. No consistent changes were seen on serial audiograms. Plasma concentrations of total and ultrafilterable platinum were measured by flameless atomic absorption spectrophotometry. Following cessation of the infusion, a half-life of 170 +/- 34 min (S.D.) was found for CBDCA-derived ultrafilterable platinum. In vitro clonogenic assay of a CDDP-sensitive human ovarian cancer cell line using clinically achievable drug concentrations suggests that prolonged infusions of CBDCA may be more cytotoxic than bolus administration. In this study, minimal responses were seen in two patients with ovarian carcinoma who had failed previous combination chemotherapy including CDDP. In addition, three patients with refractory metastatic breast cancer responded to CBDCA (two minimal responses and one partial response) with remission durations averaging 3 months. CBDCA behaves as predicted by preclinical studies with different toxicities from CDDP and apparent activity in breast cancer.

A phase I and pharmacokinetic study of dihydro-5-azacytidine (NSC 264880).

5,6-Dihydro-5-azacytidine (DHAC; NSC 264880) is an analogue of 5-azacytidine that does not possess the hydrolytically unstable 5,6-imino bond of the parent compound. Thus, unlike 5-azacytidine, DHAC is stable in aqueous solution and may be administered by prolonged i.v. infusion, potentially avoiding acute toxicities associated with bolus administration of 5-azacytidine. In this study, patients with advanced cancer were treated with DHAC administered as a 24-h constant i.v. infusion every 28 days. Treatment began at a dose of 1 g/sq m and was escalated to the maximum-tolerated dose of 7 g/sq m, where the limiting toxicity was pleuritic chest pain. Other toxicities included nausea and vomiting, which were not limiting. There was no evidence for myelosuppression, nephrotoxicity, or hepatotoxicity. DHAC was measured in plasma, urine, and ascites by a sensitive and specific reverse-phase high-performance liquid chromatography assay capable of detecting 50 ng of drug per ml. Steady-state plasma levels were achieved with 8 h and ranged from 10.0 to 20.5 micrograms of DHAC per ml at the maximum-tolerated dose. Total-body clearance of 311 +/- 76 ml/min/sq m and postinfusion half-lives between 1 and 2 h were observed. Between 8 and 20% of the administered dose was excreted unchanged in urine. While ascites DHAC levels in a patient with ovarian cancer were comparable to plasma levels, postinfusion elimination was slower from this compartment than from plasma. No correlation was observed between DHAC plasma levels and duration or intensity of dose-limiting pleuritic chest pain. One patient with progressive Hodgkin's lymphoma demonstrated stabilization of disease for seven treatment cycles, and two patients with aggressive lymphoma demonstrated dramatic, although transient, disease responses. A dose of 7 g/sq m is recommended for Phase II trials of DHAC using this schedule.

Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs.

Calcium channel blockers (CCBs) such as verapamil and nitrendipine are capable of increasing drug sensitivity in resistant murine and human tumor cells. This finding has potential value in the treatment of acquired drug resistance in human malignancies. Thus, we tested the ability of CCBs of two different structural classes to enhance the toxicity of doxorubicin (DOX), vinblastine (VBL), and vincristine (VCR) for normal myeloid and macrophage colony formation (marrow colony forming units-granulocyte-monocyte [CFU-GM]). Drug effects on colony formation from 35 normal volunteer marrows and from seven patient marrows in the recovery phase after cytotoxic chemotherapy were determined. No enhancement of toxicity was mediated by verapamil or nitrendipine when these drugs were co-incubated with the cytotoxic drugs for one hour or 24 hours before plating marrow cells in a semisolid agar system.

Reversible acute pulmonary edema due to uncontrolled hyperglycemia in diabetic individuals with renal failure.

On eight separate occasions, four functionally anephric diabetic patients (on maintenance hemodialysis) experienced episodes of severe hyperglycemia with acute interstitial and alveolar pulmonary edema demonstrated clinically and by chest x-ray without electrocardiographic or enzymatic evidence of an acute myocardial lesion. Three patients had normal stress 201T1 scanning. The fourth patient, who experienced three such episodes, had normal coronary angiograms and only a mild elevation of the left-ventricular end-diastolic pressure. Clinical and chest x-ray improvement were immediate following insulin therapy and control of hyperglycemia, without phlebotomy or dialysis. Since these episodes were observed during a 1-yr period, this syndrome may be more common than suspected. It is concluded that in functionally anephric diabetic individuals: (1) pulmonary edema can be precipitated by uncontrolled diabetes; (2) endogenous fluid shifts may contribute to the cause of acute pulmonary edema; (3) clinical and radiologic improvement can be achieved with adequate insulin therapy; and (4) blood glucose levels should be monitored and controlled in diabetic patients with renal failure.

Enrichment of myeloid progenitor cells from normal human bone marrow using an immune-rosette technique.

In this study we have developed methods for purification of myeloid progenitor cells (CFU-Cs) from normal human bone marrow cells. Bone marrow aspirates were obtained from volunteers, and mononuclear cells (MNCs) were separated by Ficoll-Hypaque gradient centrifugation. T- and B-lymphocytes, monocytes, mature granulocytes, and erythroid precursors were eliminated by an immune-rosette technique using a panel of murine monoclonal antibodies and immunoglobulin (Ig)-coated sheep red blood cells (SRBCs). MNCs were treated with OKT3, B1, M3, Mo5, and EP1 monoclonal antibodies, which are reactive with T cells, B cells, monocytes, granulocytes, and erythroid precursors, respectively. Antibody-treated MNCs were incubated with SRBCs that had been coated with goat antirabbit IgG F(ab')2 and rabbit antimouse Ig for immune rosetting. Rosetted cells were then separated from nonrosetted cells in Ficoll-Hypaque. Nonrosetted cells were, in the second step, treated with an OKIa1 monoclonal antibody and again separated into an Ia+ and Ia- cell fraction by the same manner; 39% +/- 19.2% (mean +/- 1 SD, range 16.3%-75.4%) of CFU-Cs (colonies plus clusters) were recovered in the OKT3-, B1-, M3-, Mo5-, EP1- cell fraction, and the number of CFU-Cs grown in semisolid agar was 149.6 +/- 73.0 (64.0-309.0)/10(4) plated cells in this purified fraction, representing an enrichment of 14.2 +/- 6.4 (6.0-27.3)-fold when compared with unseparated marrow cell fractions. CFU-Cs were enriched 17.7 +/- 8.6 (6.1-28.3)-fold in the Ia+ cell fraction. These purified myeloid precursors would be of value for in-depth studies of the interactions between hematopoietic progenitor cells and regulatory factors that influence their proliferation and differentiation and also of drug metabolism and determinants of cytotoxicity.

Impact of fatigue on quality of life in oncology patients.

Fatigue is the most commonly reported symptom in cancer patients and has a profound effect on patient quality of life (QOL). The Fatigue-1 and Fatigue-2 surveys performed by the Fatigue Coalition have shown that fatigue occurs on a consistent basis in approximately three quarters of patients treated for cancer. Fatigue-2 study results show that fatigue is associated with significant physical, emotional, psychologic, and social consequences, with virtually every aspect of daily life being affected. Patients also report that fatigue interferes with both their own and their caregivers' careers and economic status. Fatigue-2 documented a significant communication gap between patient and physician regarding fatigue and nonspecific physician responses to patient reports. This finding suggests that patients may benefit from physician initiation of discussion of the causes and treatments of fatigue and from physician education regarding available treatment modalities. Additional research is needed to elucidate the nature of fatigue in cancer patients. Algorithms for the differential diagnosis and treatment of cancer fatigue need to be developed and implemented to assist in timely recognition and management.

Patient, caregiver, and oncologist perceptions of cancer-related fatigue: results of a tripart assessment survey. The Fatigue Coalition.

Although fatigue is the most common symptom reported by cancer patients and has serious adverse effects on quality of life, it remains poorly understood. A survey was designed to characterize the epidemiology of cancer-related fatigue from the perspectives of the patient, primary caregiver, and oncologist. A telephone survey included 419 cancer patients recruited from 100,000 randomly selected households nationwide. Patients provided access to 200 primary caregivers (usually family members) who were also interviewed by telephone. In a separate mail survey, 197 of 600 randomly sampled oncologists (unrelated to the patients) responded to a questionnaire that assessed perceptions and attitudes concerning fatigue in cancer patients who had received chemotherapy or radiotherapy and their caregivers. The median patient age was 65 years, and the principal cancer diagnoses were breast (females) and genitourinary (males). Fifty-nine percent of the patients had received chemotherapy, 63% radiation therapy, and 24% both; 20% of patients received their last treatment within 6 weeks, 31% within 7 weeks to 1 year, and 49% more than 1 year ago. More than three quarters of patients (78%) experienced fatigue (defined as a general feeling of debilitating tiredness or loss of energy) during the course of their disease and treatment. Thirty-two percent experienced fatigue daily, and 32% reported fatigue significantly affected their daily routines. Caregivers reported observing fatigue in 86% of the index patients, and oncologists perceived that 76% of their patients experienced fatigue. Although oncologists believed that pain adversely affected their patients to a greater degree than fatigue (61% v 37%), patients felt that fatigue adversely affected their daily lives more than pain (61% v 19%). Most oncologists (80%) believed fatigue is overlooked or undertreated, and most patients (74%) considered fatigue a symptom to be endured. Fifty percent of patients did not discuss treatment options with their oncologists, and only 27% reported that their oncologists recommended any treatment for fatigue. When used, treatments for fatigue were generally perceived by patients and caregivers to be successful. These data confirm the high prevalence and adverse impact of cancer-related fatigue, although it is seldom discussed and infrequently treated. For patients and oncologists, improving the quality of life of cancer patients requires a heightened awareness of fatigue, a better understanding of its impact, and improve communication and familiarity with interventions that can reduce its debilitating effects.

[Fatigue syndrome caused by malignant tumor. An increasing priority in patient care]. / La sindrome da affaticamento da tumore maligno. Una crescente priorità nell'assistenza ai pazienti.

As oncologists have become more effective in alleviating pain, nausea and depression, fatigue has emerged as the most important symptom suffered by cancer patients. Indeed, the current literature suggests that fatigue is currently the most important untreated symptom in cancer medicine. In recent surveys of patients and their caregivers, fatigue is more important for the quality of life than pain, nausea or depression. Yet these same surveys confirm that oncologists underestimate the importance of cancer related fatigue. This may be partly because patients often do not fully share the full nature of their concerns. When patients do raise the issue of fatigue, the physicians' recommendations are often non specific. However, recent research has shown that fatigue is not inevitable and untreatable, but a symptom amenable to differential diagnosis and specific intervention. Like pain, fatigue is intrinsically a subjective problem where the doctor relies on the patient's reporting. Weakness, exhaustion, lethargy and asthenia are all used as functional descriptions of fatigue. While these are descriptive terms, clinical research in the measurement and alleviation of fatigue requires reproducible measurement tools. Several studies already exist and have begun to explore this important area of symptom management.