Myke R. Green

Update on aurora kinase targeted therapeutics in oncology

Introduction: Mammalian cells contain three distinct serine/threonine protein kinases with highly conserved catalytic domains, including aurora A and B kinases that are essential regulators of mitotic entry and progression. Overexpression of aurora A and/or B kinase is associated with high proliferation rates and poor prognosis, making them ideal targets for anticancer therapy. Disruption of mitotic machinery is a proven anticancer strategy used by multiple chemotherapeutic agents. Numerous small molecule inhibitors of the aurora kinases have been discovered and tested in vivo and in vitro, with a few currently in Phase II testing. Areas covered: This review provides the reader with updated results from both preclinical and human studies for each of the aurora kinase inhibitors (AKIs) that are currently being investigated. The paper also covers in detail the late breaking and Phase I data presented for AKIs thereby allowing the reader to compare and contrast individual and class-related effects of AKIs. Expert opinion: While the successful development and approval of an AKI for anticancer therapy remains unresolved, preclinical identification of resistant mechanisms would help in designing better early phase clinical trials where relevant combinations may be evaluated prior to Phase II testing. The authors believe that aurora kinases are important anticancer targets that operate in collaboration with other oncogenes intimately involved in uncontrolled tumor proliferation and by providing a unique, targeted and complimentary anticancer mechanism, expand the available armamentarium against cancer.

Targeting immune checkpoints in unresectable metastatic cutaneous melanoma: a systematic review and meta‐analysis of anti‐CTLA‐4 and anti‐PD‐1 agents trials

Anti‐cytotoxic T lymphocyte‐associated antigen‐4 (CTLA‐4) and anti‐programmed cell death‐1 (PD‐1) inhibitors have been shown to significantly improve survival in patients with metastatic cutaneous melanoma. However, there was some heterogeneity as well as some variation in the degree of benefit across studies. We reviewed randomized trials and performed a meta‐analysis to determine the efficacy and safety of immune checkpoint inhibitors in comparison with conventional regimens. Eligible studies were limited to randomized controlled trials comparing anti‐CTLA‐4 or anti‐PD‐1 inhibitors to chemotherapy or vaccination treatment in adult patients with unresectable cutaneous metastatic melanoma. Progression‐free survival (PFS) rate at 6 months was 28.5% versus 17.7% (RR: 0.84, 95% CI: 0.76–0.93), overall survival (OS) rate at 1 year was 51.2% versus 38.8% (RR: 0.72, 95% CI: 0.59–0.88), and overall response rate (ORR) at 6 months was 29.6% versus 17.7% (RR: 0.85, 95% CI: 0.76–0.95) favoring immune check point inhibitors over chemotherapies or vaccination. Immune check point inhibitors were associated with more frequent immune‐related adverse events at 13.7% versus 2.4% of treated patients (RR: 6.74, 95% CI: 4.65–9.75). Subgroup analyses demonstrated significant PFS (RR: 0.92 vs. 0.74, P < 0.00001) and ORR (RR: 0.95 vs. 0.76, P = 0.0004) improvement with anti‐PD‐1 treatment compared to anti‐CTLA‐4 when each of them was compared to control treatments. Collectively, these results demonstrate that immune checkpoint inhibitors have superior outcomes compared to conventional chemotherapies or vaccination, and support the results of recent randomized trials that showed superior outcomes with anti‐PD‐1 agents over ipilimumab in unresectable metastatic cutaneous melanoma patients.

Management of toxicities associated with high-dose interleukin-2 and biochemotherapy.

High-dose interleukin-2, administered as a single agent or in combination with antineoplastic agents, known as biochemotherapy, holds the promise of durable remissions for patients with metastatic renal cell carcinoma and metastatic melanoma. The toxicities arising from high-dose interleukin-2-based therapies affect every organ system, causing significant acute morbidity. Administration of high-dose interleukin-2-based therapies requires specialized care and knowledge because of the severity and uniqueness of toxicities compared with the toxicities encountered with other forms of anticancer therapy. However, the toxicities of high-dose interleukin-2-based therapies are predictable and manageable by vigilant monitoring and appropriate supportive care protocols. To maximize outcomes, both acute and delayed toxicities require vigilant monitoring and adroit symptom management. This review details the pathophysiology, monitoring parameters, and management strategies for patients receiving high-dose interleukin-2-based therapy, with a focus on new and important management principles.

Optimising absorption of posaconazole

Posaconazole, a triazole antifungal agent with proven efficacy for prophylaxis and treatment of fungal infections, is often limited by poor absorption. We report on five consecutive patients who received posaconazole along with a care bundle intended to increase absorption by addressing gastric pH, co‐administration with food, dividing doses and avoiding drug interactions. Each patient yielded multiple robust posaconazole serum concentrations. No patient experienced breakthrough fungal infection while receiving posaconazole. The posaconazole care bundle administered to oncology patients is feasible and may optimise posaconazole absorption.

Posaconazole serum level on day 2 predicts steady state posaconazole serum level.

To the Editor: Posaconazole has demonstrated superiority versus alternate antifungal agents in patients with acute myelogenous leukemia or myelodysplastic syndrome receiving intensive remission induction chemotherapy. Significant interpatient and intrapatient variations in serum level suggest benefit to therapeutic drug monitoring (TDM). Posaconazole TDM is controversial due, in part, to length of time to reach steady state and protracted time to process posaconazole serum samples. Data derived from computer simulations indicate that steady state posaconazole serum level may be predicted by the serum level obtained 3–5 hours after posaconazole administration on day 2. This simulation found that steady state posaconazole serum levels were double the day 2 serum level. Predicting the steady state serum level by extrapolating day 2 posaconazole serum level has not been investigated in humans. After obtaining institutional review board approval, 16 patients were included from December 2009 through June 2011. This cohort included 14 patients with acute myelogenous leukemia, 1 patient with acute leukemic transformation of chronic myelomonocytic leukemia, and 1 patient with acute lymphoblastic leukemia. The median age was 59 years (range, 19–81 years) with 9 male and 7 female patients. All patients received intensive remission induction chemotherapy for acute leukemia in combination with posaconazole prophylaxis. After completion of anthracycline administration, posaconazole 200 mg per os 3 times daily was administered in combination with adjuvant modalities to optimize absorption, as previously described. Day 2 posaconazole serum levels were obtained 3–5 hours after administration of fourth consecutive dose, and day 7 levels were obtained as a trough before morning dose. Serum posaconazole levels were assayed by solid-phase extraction highperformance liquid chromatography at the Fungus Testing Laboratory (San Antonio, TX). The precision of this assay is adjusted per curve by using high, medium, and low controls against each sample to derive a coefficient of determination. The lower limit of detection for this assay is 0.125 mg/mL, and the upper limit is 5 mg/mL. All 16 patients were evaluable. The median day 2 posaconazole serum level was 0.41 mg/mL (range, 0.23–0.81 mg/mL), and median day 7 posaconazole serum level was 0.99 mg/mL (range, 0.32– 2.26 mg/mL) (Table 1). The median increase in serum level from days 2 to 7 is 195% (range, 110%–398%). Median adherence to posaconazole bundle was 90% (range, 80%–100%). No patients (0%) experienced a decrease in serum posaconazole levels from days 2 to 7. Twelve patients (75%) experienced

Therapeutic Drug Monitoring and Dose Adjustment of Posaconazole Oral Suspension in Adults With Acute Myeloid Leukemia.

170% increase in serum posaconazole level from days 2 to 7. Nine patients (56%) obtained a day 7 posaconazole serum level >0.7 mg/mL. No patients (0%) discontinued therapy due to intolerance of posaconazole or adjuvant modalities, and all patients (100%) demonstrated complete adherence to posaconazole and adjuvant modalities. Five calendar days (median; range, 5–8 days) passed between drawing the serum level and obtaining the result for each posaconazole serum level, irrespective of which day level drawn. Day 2 posaconazole serum level results were available on day 7 (median; range, 7–9 days) of posaconazole dosing, which is 5 days sooner than results of day 7 serum level. The median time from study entry (day of first dose of posaconazole) to obtaining results of day 7 serum posaconazole level was 12 days (range, 11–14 days). All 9 patients (100%) who obtained a posaconazole serum level >0.7 mg/mL on day 7 remained free of fungal infections throughout duration of neutropenia and the first 100 days after start of posaconazole. By contrast, of the 7 patients who did not obtain a posaconazole serum level >0.7 mg/mL on day 7, 1 patient (6%) was radiographically diagnosed with fungal pneumonia on day 78 after start of posaconazole. Currently only available as an oral suspension, posaconazole is an important member of the antifungal armamentarium, possessing broad spectrum of antifungal activity. Despite data demonstrating improved clinical outcomes, including overall survival, versus

Combination capecitabine and bevacizumab in the treatment of metastatic hepatic epithelioid hemangioendothelioma

Background: Prophylaxis with posaconazole, an extended-spectrum triazole antifungal, has been shown to increase overall survival in adults with acute myeloid leukemia receiving intensive remission induction chemotherapy. A paucity of data exists evaluating therapeutic drug monitoring and subsequent dose adjustment based on serum concentrations in humans. Methods: An observational study was performed in 29 adult patients with acute myeloid leukemia who initially received posaconazole oral suspension 200 mg 3 times daily and required ≥1 dose adjustment because of steady-state posaconazole serum concentration <0.7 mcg/mL. Four dosing schemas were compared simultaneously. Patient records were reviewed to collect patient-related and medication-related factors that may affect serum concentrations. Results: Thirty-five percent of patients experienced subtherapeutic posaconazole serum concentrations with prophylactic dosing of posaconazole oral suspension. Increasing the dose and/or schedule of posaconazole oral suspension led to attainment of goal posaconazole serum concentrations in all groups. However, patients who received 400 mg orally 3 times daily experienced the least significant increase in serum concentration and remained subtherapeutic, despite doubling the posaconazole daily dose. Toxicities were similar to baseline within all groups. Increasing the dose and/or frequency of posaconazole oral suspension led to an increase in systemic exposure and did not appreciably increase incidence of toxicities. Conclusions: Patients receiving posaconazole oral suspension that experience subtherapeutic posaconazole serum concentrations may benefit from increasing the frequency to 200 mg orally 4 times daily or dose to 300 mg orally 3 times daily.

Syndrome of inappropriate antidiuretic hormone secretion caused by high-dose bolus interleukin-2 therapy for metastatic melanoma.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, often misdiagnosed vascular neoplasm with clinical behaviors that range from indolent to highly aggressive. Even when the appropriate diagnosis is achieved, the best treatment for HEHE has not been defined or standardized, further complicating the care of these patients. We present a diagnostically challenging case of HEHE where we utilized capecitabine and bevacizumab as another novel treatment option.

Posaconazole for the Treatment of Oropharyngeal Candidiasis, Including Triazole-Resistant Disease, in HIV-positive Patients

Melanoma is a relatively common cancer and is often associated with a dire prognosis once diagnosed as metastatic. Immunomodulatory therapy with high-dose bolus interleukin-2 may provide durable responses, albeit in a small subset of those afflicted with metastatic melanoma. High-dose interleukin-2 is well-known to cause substantial toxicities, both acute and delayed. We report on a single case of syndrome of inappropriate antidiuretic hormone secretion in a patient with metastatic melanoma with metastases to the lung and liver which was associated with high-dose bolus interleukin-2 therapy.

Oxaliplatin-induced neuropathy: a tale of two electrolytes.

Oropharyngeal candidiasis is a common affliction in HIV-positive patients worldwide. Although the incidence has decreased with the advent of potent antiviral combinations, it continues to be a cause of significant morbidity. Historically, fluconazole or itraconazole was the treatment of choice for oropharyngeal candidiasis, but increasing incidence of resistance and high recurrence rates mandate the use of alternative therapies. Posaconazole, a broad-spectrum second-generation triazole antifungal agent, has been studied in both first-line and salvage settings for treatment of oropharyngeal candidiasis. Posaconazole is well-tolerated, yields high response rates and demonstrates durable response rates with long-term use. This review will provide state-of-the-art knowledge of pharmacology and therapeutics of posaconazole focusing on the indication for oropharyngeal candidiasis in HIV-positive patients.