Cancer Chemotherapy and Pharmacology

Efficacy of immunotherapy, gut microbiota and impact of antibiotic use: are there confounding factors?

Qualitative and quantitative variations in liver function thresholds among clinical trials in cancer: a need for harmonization Abstract Purpose The liver is critically involved in drug metabolism pathways and the potential for hepatic toxicity is significant with specific cancer therapeutics. Variations in the definition of liver function thresholds that may generate heterogeneity of toxicity and efficacy outcomes across therapeutics trials in cancer require assessment. Methods A random sample of therapeutic trials in cancer (n = 500, general category), trials using hepatotoxic drugs (abiraterone, pazopanib: n = 181), trials using drugs metabolized by the liver (doxorubicin, vincristine: n = 606), and therapeutic trials in hepatic dysfunction (n = 49) were each identified on clinicaltrials.gov. Definitions of liver function thresholds and their distribution were collated and categorized in each group. Results A third of all trials listed on clinicaltrials.gov across the four categories failed to provide an explicit definition of liver function. Among trials with an explicit definition, a combination of bilirubin and transaminase levels was used in 33–64%, whereas a miscellaneous combination of definitions (in the general category consisting of 11 unique liver function parameters creating 17 unique combinations) was used 29–58% of the time across the four categories of studies. The Child–Pugh or National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were rarely employed (0–12% studies). Allowance for Gilbert’s disease in bilirubin thresholds was identified in only 6–23% studies and for liver metastases in 2–15% of studies. Conclusions There is a marked heterogeneity in the liver function definitions used across cancer clinical trials even when the potential for drug toxicity and altered drug metabolism is significant. Harmonization of criteria will streamline eligibility and mitigate variations in key outcomes across trials.

Stress resilience and survival among cancer patients: is there any absolute truth?

A single-center, open-label study investigating the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [ 14 C]-labeled idasanutlin and an intravenous tracer dose of [ 13 C]-labeled idasanutlin in a single cohort of patients with solid tumors Abstract Purpose Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic p53 activator with oral administration. To determine the need to conduct dedicated trial(s) for organ impairment on pharmacokinetic (PK) exposure and/or drug–drug interactions, a single dose of [14C]- and [13C]-labeled idasanutlin was evaluated. Methods This study was an open-label, non-randomized, single-center trial of idasanutlin to investigate the excretion balance, pharmacokinetics, metabolism, and absolute bioavailability of a single oral dose of [14C]-labeled idasanutlin and an IV tracer dose of [13C]-labeled idasanutlin in a single cohort of patients with solid tumors. After completing cycle 1 assessments, patients could have participated in an optional treatment extension of idasanutlin. Clinical endpoints were PK, and safety/tolerability. Results Co-administration of an oral dose of idasanutlin with an IV tracer dose revealed low systemic CL, a moderate Vd, and a moderate (40.1%) absolute bioavailability of idasanutlin. Idasanutlin and its major inactive metabolite, M4, were the major circulating moieties in plasma, and excretion of idasanutlin-associated radioactivity was primarily via the fecal route (91.5% of the dose), with negligible amounts recovered in urine, following oral administration. Conclusion The clinical implications of this study support the conclusion that renal impairment is unlikely to significantly impact exposure to idasanutlin and M4 metabolite, whereas a significant hepatic impairment may potentially alter exposure to the parent drug and/or metabolite(s). The potential for drug–drug interactions is low.

Treatment with selenium-enriched Saccharomyces cerevisiae UFMG A-905 partially ameliorates mucositis induced by 5-fluorouracil in mice Abstract Purpose Gastrointestinal mucositis is a major problem associated with cancer therapy. To minimize these deleterious effects, simultaneous administration of antioxidant components, such as selenium, can be considered. There is a growing interest in the use of yeasts because they are able to convert inorganic selenium into selenomethionine. In the present study, oral administration of Saccharomyces cerevisiae UFMG A-905 enriched with selenium was evaluated as an alternative in minimizing the side effects of 5FU-induced mucositis in mice. Methods Mice body weight, food consumption, faeces consistency and the presence of blood in faeces were assessed daily during experimental mucositis induced by 5-fluorouracil (5FU). Blood was used for intestinal permeability determination, and small intestine for oxidative stress, immunological and histopathological examination. Results The increased intestinal permeability observed with mucositis induction was partially reverted by S. cerevisiae and selenium-enriched yeast. Both treatments were able to reduce myeloperoxidase activity, but only selenium-enriched yeast reduced eosinophil peroxidase activity. CXCL1/KC levels, histopathological tissue damage and oxidative stress (lipid peroxidation and nitrite production) in the small intestine were reduced by both treatments; however, this reduction was always higher when treatment with selenium-enriched yeast was evaluated. Conclusions Results of the present study showed that the oral administration of S. cerevisiae UFMG A-905 protected mice against mucositis induced by 5-FU, and that this effect was potentiated when the yeast was enriched with selenium.

Development of cutaneous squamous cell carcinoma after prolonged exposure to pegylated liposomal doxorubicin and hand–foot syndrome: a newly recognized toxicity Abstract Pegylated liposomal doxorubicin (PLD) can be administered for prolonged periods with minimal toxicity. The risk of cutaneous squamous cell carcinoma (SCC) with this therapy has not been reported. We describe cutaneous SCC of the plantar foot in two patients exposed to high doses of PLD. A 50-year-old man with angiosarcoma received a total PLD dose of 1350 mg/m2 and developed cutaneous SCC of bilateral plantar feet. A 45-year-old woman with cutaneous T-cell lymphoma was treated with a total PLD dose of 1142 mg/m2 with subsequent diagnosis of cutaneous SCC of the right plantar foot. No risk factors for SCC of the plantar foot were identified in either patient. Cutaneous SCC is likely an unreported side effect of prolonged exposure to PLD. An extended duration of hand–foot syndrome from other anti-cancer drugs may also share this risk. Regular complete skin examination with early intervention for suspicious lesions is indicated in this patient population.

Olanzapine-containing antiemetic therapy for the prevention of carboplatin-induced nausea and vomiting Abstract Purpose There remains an unmet clinical need for the control of chemotherapy-induced nausea and vomiting (CINV), particularly in the prevention of nausea and the delayed phase control. We evaluated the efficacy and safety of antiemetic therapy with olanzapine, a neurokinin-1 receptor antagonist, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist and dexamethasone in patients receiving carboplatin-containing chemotherapy. Olanzapine inhibits signalling via multiple neurotransmitter receptors involved in CINV. Methods Chemotherapy-naïve patients with lung cancer who received carboplatin-containing chemotherapy were enrolled in this phase-II study. Patients received olanzapine, aprepitant, a 5-HT3 receptor antagonist and dexamethasone. The primary endpoint was the complete response rate (no vomiting and no rescue therapy) during 120 h after administration of chemotherapy agents. Results Thirty-three patients received olanzapine-containing antiemetic therapy. The overall complete response rate was 93.3% (95% confidence interval, 80.4–98.3%). The frequency of nausea was 15.2% in the delayed phase and 18.2% in the overall phase. Somnolence was observed in 16 patients. Conclusion Adding olanzapine to antiemetic therapy with aprepitant, a 5-HT3 receptor antagonist and dexamethasone improved CINV control in patients receiving carboplatin-containing chemotherapy.

A phase 2 study to assess the pharmacokinetics and pharmacodynamics of CPX-351 and its effects on cardiac repolarization in patients with acute leukemias Abstract Purpose Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization. Methods Twenty-six adults with acute leukemia were treated with CPX-351 for 1–2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline. Results Mean QTcF changes were < 10 ms at all time points. No clinically meaningful effects on heart rate, QRS interval, PR interval, or QTcB were observed. Estimated mean half-lives for total cytarabine and daunorubicin were > 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea. Conclusions The cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin. Trial registration Clinicaltrials.gov identifier: NCT02238925.

Pharmacokinetics and safety of lobaplatin plus etoposide in Chinese men older than 65 years with extensive-stage small cell lung cancer: a phase II clinical trial Abstract Purpose This phase II, multicenter, single arm clinical study was first performed to evaluate the therapeutic efficacy and safety of the regimen—a combination of lobaplatin (LBP) and etoposide (VP-16)—and investigate the pharmacokinetics of LBP in Chinese men older than 65 years with extensive-stage small cell lung cancer (SCLC). Methods Patients older than 65 were treated with the combination of LBP and VP-16 for 4–6 cycles through intravenous drip. The initial dose of VP-16 was 100 mg/m2/day for d1-d3 in each 21-day cycle, while LBP was administrated for d1 in each cycle based on creatinine clearance (Ccr), 20 mg/m2 for Ccr < 60 mL/min; 25 mg/m2 for 60 ≤ Ccr < 80 mL/min and 30 mg/m2 for Ccr ≥ 80 mL/min. Efficacy, safety and pharmacokinetics were evaluated to confirm the therapeutic effect. Results Thirteen elderly patients were enrolled and three patients were discontinued. The median progress-free survival was 129 days and the median overall survival was 238 days, which caused a significantly prolonged survival rate of 38.5% and a higher disease control rate of 80%. Most frequent adverse events were mild to moderate containing leukopenia, neutropenia, anemia, nausea and anorexia. Pharmacokinetic analysis revealed that there is no significant difference between LP-D1 and LP-D2 at the same dosage level. With the dosage increasing, the elimination clearance showed a slowing tendency, especially for 30 mg/m2 group. Conclusions LBP (20, 25, 30 mg/m2) in combination with VP-16 (100 mg/m2) could inhibit the elderly SCLC disease process, prolong their survival time and reduce adverse reactions via preliminary assessment and provide guidance for further investigation.

Orally administered salecan ameliorates methotrexate-induced intestinal mucositis in mice Abstract Purpose Methotrexate (MTX) is a widely used cancer chemotherapy agent. The efficacy of MTX is often limited by serious side effects, such as intestinal mucositis. The aim of this study was to evaluate the protective effect of water-soluble β-glucan salecan on MTX-induced intestinal toxicity in mice. Methods Intestinal mucositis was induced in C57BL/6 mice by intraperitoneal injection of MTX for two consecutive days. Mice were orally administrated with saline or salecan for 6 days before MTX injection and continued to the end of the study. Several histological and biochemical parameters were measured in the jejunum. Results Orally administration of salecan improved the severity of intestinal mucositis in a dose-dependent manner, as evidenced by the well-maintained mucosal architecture and body weight in salecan-treated groups. Salecan treatment inhibited MTX-induced oxidative stress and effectively scavenged free radicals both in vitro and in vivo. Metabolomics analysis revealed that salecan treatment reversed the intestinal metabolic profiling changes in mice with MTX-induced mucositis. Salecan treatment modulated the innate immunity through the regulation of TLR and Dectin1 expression in the jejunum, thus protecting mice from MTX-induced intestinal damage. Conclusions Salecan has potential advantages in the treatment of MTX-induced intestinal mucositis, and its protective effect is mainly attributed to its antioxidant and immunomodulatory properties.