Purpose Naturally occurring tumor suppressor microRNA-34a (miR-34a) downregulates the expression of >30 oncogenes across multiple oncogenic pathways, as well as genes involved in tumor immune evasion, but is lost or under-expressed in many malignancies. This first-inhuman, phase I study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics, and clinical activity of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumors. Patients and Methods Adult patients with solid tumors refractory to standard treatment were enrolled in a standard 3+3 dose escalation trial. MRX34 was given intravenously twice weekly (BIW) for three weeks in 4-week cycles. Results Forty-seven patients with various solid tumors, including hepatocellular carcinoma (HCC; n=14), were enrolled. Median age was 60 years, median prior therapies was 4 (range, 1–12), and most were Caucasian (68%) and male (57%). Most common adverse events (AEs) included fever (all grade %/G3 %: 64/2), fatigue (57/13), back pain (57/11), nausea (49/2), diarrhea (40/11), anorexia (36/4), and vomiting (34/4). Laboratory abnormalities included lymphopenia (G3 %/G4 %: 23/9), neutropenia (13/11), thrombocytopenia (17/0), increased AST (19/4), hyperglycemia (13/2), and hyponatremia (19/2). Dexamethasone premedication was required to manage infusion-related AEs. The MTD for non-HCC patients was 110 mg/m2, with two patients experiencing dose-limiting toxicities of G3 hypoxia and enteritis at 124 mg/m2. The half-life was >24 h, and Cmax and AUC increased with increasing dose. One patient with HCC achieved a prolonged confirmed PR lasting 48 weeks, and four patients experienced SD lasting ≥4 cycles. Conclusion MRX34 treatment with dexamethasone premedication was associated with acceptable safety and showed evidence of antitumor activity in a subset of patients with refractory advanced solid tumors. The MTD for the BIW schedule was 110 mg/m2 for non-HCC and 93 mg/m2 for HCC patients. Additional dose schedules or MRX34 have been explored to improve tolerability.

BackgroundThe combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model.ObjectiveTo establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed.Patients and MethodsBEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed.ResultsCommon toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr.ConclusionsThe combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug–drug interactions when these two drugs are administered together.Clinicaltrials.gov: NCT01508104 Electronic supplementary materialThe online version of this article (doi:10.1007/s11523-017-0482-9) contains supplementary material, which is available to authorized users.

Commercially available physical activity monitors provide clinicians an opportunity to obtain oncology patient health measures to an unprecedented degree. These devices can provide objective and quantifiable measures of physical activity, which are not subject to errors or bias of self-reporting or shorter duration of formal testing. Prior work on so-called quantified-self data was based on older-generation, research-grade accelerometers, which laid the foundation for consumer-based physical activity monitoring devices to be validated as a feasible and reliable tool in patients with cancer. Physical activity monitors are being used in chronic conditions including chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, and obesity. Differing demographics, compounded with higher symptom and treatment burdens in patients with cancer, imply that additional work is needed to understand the unique strengths and weaknesses of physical activity monitors in this population. Oncology programs can systematically implement these tools into their workflows in an adaptable and iterative manner. Translating large amounts of data collected from an individual physical activity monitoring device into clinically relevant information requires sophisticated data compilation and reduction. In this article, we summarize the characteristics of older- and newer-generation physical activity monitors, review the validation of physical activity monitors with respect to health-related quality-of-life assessments, and describe the current role of these devices for the practicing oncologist. We also highlight the challenges and next steps needed for physical activity monitors to provide relevant information that can change the current state of oncology practice.