Phase Ib Trial of Phenformin in Patients with V600-mutated Melanoma Receiving Dabrafenib and Trametinib.

PURPOSE: Preclinical studies show that activation of AMP kinase by phenformin can augment the cytotoxic effect and RAF inhibitors in BRAF V600-mutated melanoma. We conducted a phase Ib dose-escalation trial of phenformin with standard dose dabrafenib/trametinib in patients with metastatic BRAF V600-mutated melanoma. EXPERIMENTAL DESIGN: We used a 3+3 dose-escalation design which explored phenformin doses between 50 and 200 mg twice daily. Patients also received standard dose dabrafenib/trametinib. We measured phenformin pharmacokinetics and assessed the effect of treatment on circulating myeloid-derived suppressor cells (MDSC). RESULTS: A total of 18 patients were treated at dose levels ranging from 50 to 200 mg twice daily. The planned dose-escalation phase had to be cancelled because of the COVID 19 pandemic. The most common toxicities were nausea/vomiting; there were two cases of reversible lactic acidosis. Responses were seen in 10 of 18 patients overall (56%) and in 2 of 8 patients who had received prior therapy with RAF inhibitor. Pharmacokinetic data confirmed drug bioavailability. MDSCs were measured in 7 patients treated at the highest dose levels and showed MDSC levels declined on study drug in 6 of 7 patients. CONCLUSIONS: We identified the recommended phase II dose of phenformin as 50 mg twice daily when administered with dabrafenib/trametinib, although some patients will require short drug holidays. We observed a decrease in MDSCs, as predicted by preclinical studies, and may enhance immune recognition of melanoma cells. SIGNIFICANCE: This is the first trial using phenformin in combination with RAF/MEK inhibition in patients with BRAF V600-mutated melanoma. This is a novel strategy, based on preclinical data, to increase pAMPK while blocking the MAPK pathway in melanoma. Our data provide justification and a recommended dose for a phase II trial.

Developing guidance for feeding tube administration of oral medications.

BACKGROUND: Drug administration through feeding tubes presents many challenges to the healthcare provider. There is little information available on medications than can be delivered safely when crushed and what efforts can be implemented to minimize clogging the feeding tube. Our institution requested a comprehensive examination of all oral medications for the feeding tube route. METHODS: This report is a synopsis of the physical evaluation of 323 different oral medications for their appropriateness for feeding tube administration with distal site in either the stomach or jejunum. A worksheet was created for each medication. This document contained a review of the chemical and physical properties that would contribute to delivery of the medication. Each medication was then studied for the degree of disintegration, pH, osmolality, and potential to form clogs. For drugs that needed to be crushed, the volume of water needed to dissolve the drug, time for that process, and volume needed to rinse the tube after administration was also studied. RESULTS: The results of this review are summarized in a table and based on a composite of the documents cited, tests conducted, and author's judgements based all the data collected. Thirty-six medications were identified as inappropriate for feeding tube administration, and an additional 46 medications were identified as inappropriate for direct jejunal administration. CONCLUSION: The information produced by this study will enable clinicians to make informed choices in selecting, compounding, and rinsing medications through feeding tubes. Using the template provided, they will be able to evaluate a drug not studied here for potential issues in feeding tube administration.

Keratinocytes coordinate inflammatory responses and regulate development of secondary lymphedema.

Epidermal changes are histological hallmarks of secondary lymphedema, but it is unknown if keratinocytes contribute to its pathophysiology. Using clinical lymphedema specimens and mouse models, we show that keratinocytes play a primary role in lymphedema development by producing T-helper 2 (Th2) -inducing cytokines. Specifically, we find that keratinocyte proliferation and expression of protease-activated receptor 2 (PAR2) are early responses following lymphatic injury and regulate the expression of Th2-inducing cytokines, migration of Langerhans cells, and skin infiltration of Th2-differentiated T cells. Furthermore, inhibition of PAR2 activation with a small molecule inhibitor or the proliferation inhibitor teriflunomide (TF) prevents activation of keratinocytes stimulated with lymphedema fluid. Finally, topical TF is highly effective for decreasing swelling, fibrosis, and inflammation in a preclinical mouse model. Our findings suggest that lymphedema is a chronic inflammatory skin disease, and topically targeting keratinocyte activation may be a clinically effective therapy for this condition.

A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

TGF-ß1 mediates pathologic changes of secondary lymphedema by promoting fibrosis and inflammation.

BACKGROUND: Secondary lymphedema is a common complication of cancer treatment, and previous studies have shown that the expression of transforming growth factor-beta 1 (TGF-ß1), a pro-fibrotic and anti-lymphangiogenic growth factor, is increased in this disease. Inhibition of TGF-ß1 decreases the severity of the disease in mouse models; however, the mechanisms that regulate this improvement remain unknown. METHODS: Expression of TGF-ß1 and extracellular matrix molecules (ECM) was assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL). The effects of TGF-ß1 inhibition using neutralizing antibodies or a topical formulation of pirfenidone (PFD) were analyzed in mouse models of lymphedema. We also assessed the direct effects of TGF-ß1 on lymphatic endothelial cells (LECs) using transgenic mice that expressed a dominant-negative TGF-ß receptor selectively on LECs (LECDN-RII ). RESULTS: The expression of TGF-ß1 and ECM molecules is significantly increased in BCRL skin biopsies. Inhibition of TGF-ß1 in mouse models of lymphedema using neutralizing antibodies or with topical PFD decreased ECM deposition, increased the formation of collateral lymphatics, and inhibited infiltration of T cells. In vitro studies showed that TGF-ß1 in lymphedematous tissues increases fibroblast, lymphatic endothelial cell (LEC), and lymphatic smooth muscle cell stiffness. Knockdown of TGF-ß1 responsiveness in LECDN-RII resulted in increased lymphangiogenesis and collateral lymphatic formation; however, ECM deposition and fibrosis persisted, and the severity of lymphedema was indistinguishable from controls. CONCLUSIONS: Our results show that TGF-ß1 is an essential regulator of ECM deposition in secondary lymphedema and that inhibition of this response is a promising means of treating lymphedema.

Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

PURPOSE: Intratumorally injected Clostridium novyi-NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi, replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation. PATIENTS AND METHODS: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi-NT across 6 dose cohorts (1 × 104 to 3 × 106 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose. RESULTS: Among 24 patients, a single intratumoral injection of C. novyi-NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 106 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (n = 2) and grade 4 gas gangrene (n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (n = 1), limb abscess (n = 1), soft-tissue infection (n = 1), respiratory insufficiency (n = 1), and rash (n = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. C. novyi-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. CONCLUSIONS: Single intratumoral injection of C. novyi-NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi-NT in humans.

ASPEN Safe Practices for Enteral Nutrition Therapy [Formula: see text].

Enteral nutrition (EN) is a valuable clinical intervention for patients of all ages in a variety of care settings. Along with its many outcome benefits come the potential for adverse effects. These safety issues are the result of clinical complications and of process-related errors. The latter can occur at any step from patient assessment, prescribing, and order review, to product selection, labeling, and administration. To maximize the benefits of EN while minimizing adverse events requires that a systematic approach of care be in place. This includes open communication, standardization, and incorporation of best practices into the EN process. This document provides recommendations based on the available evidence and expert consensus for safe practices, across each step of the process, for all those involved in caring for patients receiving EN.

Quality Control Analytical Methods: Method Validation.

To properly determine the accuracy of a pharmaceutical product or compounded preparation, tests must be designed specifically for that evaluation. The procedures selected must be verified through a process referred to as method validation, an integral part of any good analytical practice. The results from a method validation procedure can be used to judge the quality, reliability, and consistency of analytical results. The purpose of this article is to deliver the message of the importance of validation of a pharmaceutical product or compounded preparation and to briefly discuss the results of a lack of such validation.

PFAT5 and the Evolution of Lipid Admixture Stability.

PFAT5 is defined by United States Pharmacopeia Chapter 729 as follows: the "percentage of fat residing in globules larger than 5 µm (PFAT5) for a given lipid injectable emulsion [is] not to exceed 0.05%." The unstable aggregates are trapped in lungs, liver, and the reticuloendothelial system. Large particles will accumulate in pulmonary capillaries, which are between 4 and 9 µm in diameter. Over the years, there has been an evolution of methods to characterize and define intravenous fat emulsion (IVFE) stability when combined as a total nutrient admixture (TNA). Many studies have claimed IVFE stability measuring mean particle size, zeta potential, and visual checks. Interestingly, none of the studies that claimed the TNA as stable identified an unstable one through testing. This report reviews those parameters and shows they were not a valid measure of lipid stability. The PFAT5 parameter has emerged as the only validated measure of lipid stability. There are clinical consequences of using lipids that exceed the PFAT5 limit. This parameter is applicable to both manufactured and compounded lipid preparations. The clinician should be aware of the limitations of much of the literature concerning the lipid stability assessment. More stability studies are needed using PFAT5 to identify the actual limits of TNA compounding.

Osmolality, pH, and compatibility of selected oral liquid medications with an enteral nutrition product.

When selecting medication for feeding tube administration, the liquid formulation is selected, so as to avoid obstructions that may occur from incompletely crushing a solid dosage form. Liquid medications can present issues of intolerance and compatibility when administered via a feeding tube. A predictor of intolerance is the liquid's osmolarity, and a predicator of compatibility is the liquid's pH value. This study examines 62 liquid formulations for their osmolality, pH, and physical compatibility with enteral nutrition (EN) formulas. These medications were selected as being the most commonly dispensed liquid medications from our outpatient pharmacy department. This study measures osmolality using freezing point depression. Depending on the dose, the osmotic load of a liquid medication may cause cramping and diarrhea. The pH value is predictive of potential interactions with the EN formula. Many drugs are weak bases and require acidic vehicles for optimal stability. The acidic liquids are especially reactive with enteral formulas that contain intact proteins. The result of this interaction can result in an occlusion of the feeding tube as the proteins form a gel-like clog. This study combined the liquid medication directly with the EN formula to determine the potential for feeding tube occlusion. Some drugs formed a solid mass in the test tube immediately, whereas others only presented granules, which may later contribute to obstructing the feeding tube. The prescriber should be aware of the potential impact of their choice in formulation, both in terms of the gastrointestinal tolerance and potential for interaction with coadministered nutrition.

ARN-509: a novel antiandrogen for prostate cancer treatment.

Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.

Warfarin bioavailability with feeding tubes and enteral formula.

BACKGROUND: Earlier literature showed reduced efficacy of warfarin when co-administered with enteral nutrition formulas through feeding tubes. This study used an in vitro model for gastric administration of warfarin through a feeding tube to evaluate potential causes for reduced warfarin absorption when administered through feeding tubes. METHODS: There were 2 phases of the study. The first phase used an artificial stomach model with or without the infusion of enteral nutrition formula. Warfarin was added to the contents either directly into the vessel or passed through a feeding tube. Warfarin tablet dissolution was compared to the injectable formulation, which served as a control. The second phase used chopped feeding tube material added to beakers containing warfarin in increasing amounts. RESULTS: Warfarin injection and tablet formulations showed decreased solubility when combined with acid. The warfarin solubility was higher when enteral formula was added. Warfarin concentration dropped by 35% when the drug was passed through a feeding tube, as opposed to added directly to the flask.In the second study, the warfarin levels were lower in the beakers containing feeding tubes. Doubling the amount of warfarin added did not raise levels to that of the initial dissolved. Doubling the amount of feeding tube material further reduced the concentration dissolved. CONCLUSIONS: Feeding-tube administration compromises the total amount of warfarin reaching patients. It appears, from this in vitro study, that the mechanism of the interaction of warfarin may be a result of direct binding to the feeding tube.

Recommendations for compounding medications for feeding tube administration.

There are no commercially available liquid medications that are formulated for feeding tube administration. The goal and indication of orally administered medications formulated in liquids is for pediatric patients or patients with limited ability to swallow tablets. Pharmacists who are considering compounding medications for feeding tube administration must be aware of the many issues involved in preparing drugs for this purpose. Many of these issues are discussed in this article. Also included in this article are reviews of some the literature involving the issues in co-administering nutrition by the same route.

Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously.

PURPOSE: To evaluate the safety, pharmacokinetics, and biological activity of suberoylanilide hydroxamic acid (SAHA) administered by 2-h i.v. infusion in patients with advanced cancer. EXPERIMENTAL DESIGN: SAHA was administered for 3 days every 21 days in part A and 5 days for 1-3 weeks in part B. Dose escalation proceeded independently in patients with solid tumor and hematological malignancies (part B only). Pharmacokinetic studies were performed along with assessment of acetylated histones in peripheral blood mononuclear cells and tumor tissues. RESULTS: No dose-limiting toxicities were observed in 8 patients enrolled in part A (75, 150, 300, 600, and 900 mg/m(2)/day). Among 12 hematological and 17 solid tumor patients enrolled in part B (300, 600, and 900 mg/m(2)/day), therapy was delayed > or = 1 week for grade 3/4 leukopenia and/or thrombocytopenia in 2 of 5 hematological patients at 600 mg/m(2)/day x 5 days for 3 weeks. The maximal-tolerated dose was 300 mg/m(2)/day x 5 days for 3 weeks for hematological patients. One solid patient on 900 mg/m(2)/day x 5 days for 3 weeks developed acute respiratory distress and grade 3 hypotension. The cohort was expanded to 6 patients, and no additional dose-limiting toxicities were observed. Mean terminal half-life ranged from 21 to 58 min, and there was dose-proportional increase in area under the curve. An accumulation of acetylated histones in peripheral blood mononuclear cells up to 4 h postinfusion was observed at higher dose levels. Posttherapy tumor biopsies showed an accumulation of acetylated histones by immunohistochemistry. Four (2 lymphoma and 2 bladder) patients had objective tumor regression with clinical improvement in tumor related symptoms. CONCLUSIONS: Daily i.v. SAHA is well tolerated, inhibits the biological target in vivo, and has antitumor activity in solid and hematological tumors.