TAK-228 (formerly MLN0128), an investigational dual TORC1/2 inhibitor plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies.

PURPOSE: This phase I trial evaluated the safety, pharmacokinetic profile, and antitumor activity of investigational oral TORC1/2 inhibitor TAK-228 plus paclitaxel, with/without trastuzumab, in patients with advanced solid malignancies. METHODS: Sixty-seven patients received TAK-228 6-40 mg via three dosing schedules; once daily for 3 days (QDx3d QW) or 5 days per week (QDx5d QW), and once weekly (QW) plus paclitaxel 80 mg/m2 (dose-escalation phase, n = 47) and with/without trastuzumab 2 mg/kg (expansion phase, n = 20). Doses were escalated using a modified 3 + 3 design, based upon dose-limiting toxicities in cycle 1. RESULTS: TAK-228 pharmacokinetics exhibited dose-dependent increase in exposure when dosed with paclitaxel and no apparent differences when administered with or 24 h after paclitaxel. Dose-limiting toxicities were dehydration, diarrhea, stomatitis, fatigue, rash, thrombocytopenia, neutropenia, leukopenia, and nausea. The maximum tolerated dose of TAK-228 was determined as 10-mg QDx3d QW; the expansion phase proceeded with 8-mg QDx3d QW. Overall, the most common grade ≥3 drug-related toxicities were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable patients, eight achieved partial response and six had stable disease lasting ≥6 months. CONCLUSION: TAK-228 demonstrated a safety profile consistent with other TORC inhibitors and promising preliminary antitumor activity in a range of tumor types; no meaningful difference was noted in the pharmacokinetics of TAK-228 when administered with or 24 h after paclitaxel. These findings support further investigation of TAK-228 in combination with other agents including paclitaxel, with/without trastuzumab, in patients with advanced solid tumors. CLINICALTRIALS. GOV IDENTIFIER: NCT01351350.

A phase IB trial of the oral MEK inhibitor trametinib (GSK1120212) in combination with everolimus in patients with advanced solid tumors.

BACKGROUND: This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity. PATIENTS AND METHODS: A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle. RESULTS: Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%). CONCLUSIONS: This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.

Phase I study of weekly paclitaxel in combination with pazopanib and lapatinib in advanced solid malignancies.

BACKGROUND: We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics. METHODS: Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate. RESULTS: Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months). CONCLUSIONS: Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

The mechanics of landing when stepping down in unilateral lower-limb amputees.

BACKGROUND: The ability to successfully negotiate stairs and steps is an important factor for functional independence. While work has been undertaken to understand the biomechanics of gait in lower-limb amputees, little is known about how amputees negotiate stairs and steps. This study aimed to determine the mechanics of landing in unilateral lower-limb amputees when stepping down to a new level. A secondary aim was to assess the effects of using a shank-mounted shock-absorbing device (Tele-Torsion Pylon) on the mechanics of landing. METHODS: Ten unilateral amputees (five transfemoral and five transtibial) and eight able-bodied controls performed single steps down to a new level (73 and 219 mm). Trials were repeated in amputees with the Tele-Torsion Pylon active and inactive. The mechanics of landing were evaluated by analysing peak limb longitudinal force, maximal limb shortening, lower extremity stiffness, and knee joint angular displacement during the initial contact period, and limb and ankle angle at the instant of ground-contact. Data were collected using a Vicon 3D motion analysis system and two force platforms. FINDINGS: Amputees landed on a straightened and near vertical limb. This limb position was maintained in transfemoral amputees, whereas in transtibial amputees knee flexion occurred. As a result lower extremity stiffness was significantly greater in transfemoral amputees compared to transtibial amputees and able-bodied controls (P<0.001). The Tele-Torsion Pylon had little effect on the mechanics of landing in transtibial amputees, but brought about a reduction in lower extremity stiffness in transfemoral amputees (P<0.05). INTERPRETATION: Amputees used a stepping strategy that ensured the direction of the ground reaction force vector was kept anterior of the knee joint centre. Using a Tele-Torsion Pylon may improve the mechanics of landing during downward stepping in transfemoral amputees.

The gait initiation process in unilateral lower-limb amputees when stepping up and stepping down to a new level.

BACKGROUND: Unilateral lower-limb amputees lead with their intact limb when stepping up and with their prosthesis when stepping down; the gait initiation process for the different stepping directions has not previously been investigated. METHODS: Ten unilateral amputees (5 transfemoral and 5 transtibial) and 8 able-bodied controls performed single steps up and single steps down to a new level (73 and 219 mm). Duration, a-p and m-l centre of mass and centre of pressure peak displacements and centre of mass peak velocity of the anticipatory postural adjustment and step execution phase were evaluated for each stepping direction by analysing data collected using a Vicon 3D motion analysis system. FINDINGS: There were significant differences (in the phase duration, peak a-p and m-l centre of pressure displacement and peak a-p and m-l centre of mass velocity at heel-off and at foot-contact) between both amputee sub-groups and controls (P<0.05), but not between amputee sub-groups. These group differences were mainly a result of amputees adopting a different gait initiation strategy for each stepping direction. INTERPRETATION: Findings indicate the gait initiation process utilised by lower-limb amputees was dependent on the direction of stepping and more particularly by which limb the amputee led with; this suggests that the balance and postural control of gait initiation is not governed by a fixed motor program, and thus that becoming an amputee will require time and training to develop alternative neuromuscular control and coordination strategies. These findings should be considered when developing training/rehabilitation programs.

The 'redefinition of death' debate: western concepts and western bioethics.

Biomedicine is a global enterprise constructed upon the belief in the universality of scientific truths. However, despite huge scientific advances over recent decades it has not been able to formulate a specific and universal definition of death: In fact, in its attempt to redefine death, the concept of death appears to have become immersed in ever increasing vagueness and ambiguity. Even more worrisome is that bioethics, in the form of principlism, is also endeavouring to become a global enterprise by claiming neutrality. It appears that the discourse within both disciplines have similarly manipulated the boundaries of death to include the "dying". This paper argues that the redefinition of death debate in biomedicine reveals a concept of personhood which is profoundly western in origin and which is in accordance to the concept adhered to within principlism. Biomedicine and bioethics do not appear to acknowledge the limitations of their own world view and hence lack an understanding of their applicability and appropriateness in diverse social and cultural contexts; a situation which adds credence to claims as to the hegemonic and imperialistic nature of all such global enterprises.

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors.

Vinorelbine (Navelbine) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m2. Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m2. Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m2 on days 1 and 8 and mitoxantrone 10 mg/m2 on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.

Orofacial granulomatosis: a diagnostic problem for the unwary and a management dilemma. Case reports.

Orofacial granulomatosis is a condition that may be difficult to diagnose for those unfamiliar with the entity. This paper describes two cases and addresses the presentation, pathogenesis and treatment. The clinical recognition of this condition is important as is the subsequent investigation by an appropriate specialist. Management of patients needs to take into account the results of further investigations, the patient's expectations, and the severity of the condition.

Vinorelbine: a new antineoplastic drug for the treatment of non-small-cell lung cancer.

OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, and dosage and administration guidelines for vinorelbine in the treatment of non-small-cell lung cancer (NSCLC). DATA SOURCES: A MEDLINE search (1989-1995) using the terms vinorelbine and Navelbine was conducted. Additional unpublished data were provided by Glaxo Wellcome Drug Information. STUDY SELECTION AND DATA EXTRACTION: The articles chosen for inclusion all appeared in peer-reviewed journals. Pertinent abstracts, as judged by the authors, were also included. DATA SYNTHESIS: Vinorelbine is a new semisynthetic vinca alkaloid approved by the Food and Drug Administration for the first-line treatment of patients with advanced NSCLC. The drug demonstrated a broad spectrum of antitumor activity in preclinical studies and produced dose-limiting neutropenia in Phase I trials. In Phase II studies, an overall response rate of approximately 30% was reported with single-agent vinorelbine. Furthermore, in large, multicenter, randomized Phase III trials, treatment with vinorelbine alone and in combination with cisplatin resulted in improved survival compared with controls. The drug was well tolerated, with granulocytopenia being the most commonly reported adverse effect. However, the incidence of fever and hospitalization associated with this granulocytopenia was exceptionally low. The recommended dose is 30 mg/m2 weekly administered by intravenous injection or infusion. CONCLUSIONS: As no specific chemotherapy regimen has previously been regarded as standard therapy for advanced NSCLC, vinorelbine is a promising new treatment for this patient population. It has been shown in several randomized, controlled trials to increase survival without compromising quality of life.

Evaluation of intravenous ketorolac administered by bolus or infusion for treatment of postoperative pain. A double-blind, placebo-controlled, multicenter study.

BACKGROUND: Ketorolac is a nonsteroidal analgesic that may provide postoperative analgesia without opioid-related side effects. This double-blind, randomized, multicenter study evaluated the analgesic efficacy and safety of intravenous ketorolac in 207 patients during the first 24 h after major surgery. METHODS: Subjects were assigned to receive one of three analgesic regimens: a ketorolac infusion, ketorolac boluses, or placebo. All subjects had access to intravenous morphine via patient-controlled analgesia (PCA). Evaluations included PCA morphine used, pain assessment (categorical pain intensity scores and visual analogue pain scores), pain relief (categorical pain relief scores), sedation, presence of adverse events, and overall rating of regimens by study observers and patients. RESULTS: Patients in the ketorolac infusion group (but not the ketorolac bolus group) used less morphine (average 33 mg) than did the placebo group (44 mg) (P = 0.009). Significant differences favoring both ketorolac groups were seen in the pain intensity and the categorical pain relief scores at various time points during the study. At the termination of the study, compared with the placebo group, categorical pain intensity scores were lower in the ketorolac bolus group; visual analogue pain scores were lower in both ketorolac groups; and pain relief scores were higher in the ketorolac bolus group. The incidence of vomiting was significantly greater in the placebo group (27%) than in the ketorolac infusion group (12%) or bolus group (9%) (P = 0.032 and P = 0.005, respectively). The incidence of postoperative fever was 10% in the ketorolac bolus group and 25% in the placebo group (P = 0.013). Study observers noted less nursing difficulty while caring for patients in the ketorolac infusion group (P = 0.015). Study observers and patients in both ketorolac groups reported statistically significant overall drug superiority compared with placebo. CONCLUSIONS: It is concluded that intravenous boluses or infusions of ketorolac in conjunction with PCA morphine provide effective, safe analgesia after major surgery and improve on the response to PCA morphine alone.

Morphine and ibuprofen compared using the cold pressor test.

The analgesic efficacy of single doses of oral morphine sulphate solution (10 mg) and ibuprofen 600 mg was compared in 12 volunteers using a double-blind, double-dummy, placebo-controlled design on the cold pressor experimental pain model. Measurement of pain intensity was made before medication and then at 30, 60, 90, 120 and 180 min; blood samples were taken at these times for measurement of morphine and glucuronide metabolites by radioimmunoassay. Sessions were at least 5 days apart. Correlations were sought between analgesic effect and plasma concentrations of either morphine or morphine-6-glucuronide. Morphine produced significant reduction in both peak pain intensity and area under the pain intensity curve compared with placebo; the threshold time was significantly increased by morphine compared with placebo. Ibuprofen was statistically indistinguishable from placebo on all three measures of analgesia. Analgesic effect and plasma concentrations of morphine showed significant correlation (P = 0.053). The study confirmed reports of the opiate sensitivity of the cold pressor model, and the apparent insensitivity of the model to non-steroidal anti-inflammatory drugs.

Analgesia following femoral neck surgery. Lateral cutaneous nerve block as an alternative to narcotics in the elderly.

In a prospective controlled randomised trial on patients undergoing operative repair of fractured neck of femur via a lateral incision, the postoperative analgesic requirements of one group of patients who received a lateral cutaneous nerve block were compared with a second group who received no block. The former group were found to need significantly less intramuscular pethidine in the first 24 hours, and 44% required no supplementary analgesia whatsoever during this period. The time to first dose of opioid in the remainder was greatly increased. No untoward sequelae associated with the nerve block were seen.