Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer.

PURPOSE: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer. PATIENTS AND METHODS: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. RESULTS: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m2 paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. CONCLUSIONS: Alternating sequential palbociclib/paclitaxel in patients with Rb+ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb+ breast cancer regardless of subtype; efficacy trials are warranted.

Effect of Gemcitabine and nab-Paclitaxel With or Without Hydroxychloroquine on Patients With Advanced Pancreatic Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Autophagy is a mechanism of treatment resistance to chemotherapy that has a role in the maintenance of pancreatic cancer. Hydroxychloroquine sulfate (HCQ) is an inhibitor of autophagy that inhibits the fusion of the autophagosome to the lysosome. OBJECTIVE: To determine whether HCQ improves overall survival at 1 year in combination with gemcitabine hydrochloride and nab-paclitaxel (GA) among patients with metastatic pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS: Open-label, phase 2 randomized clinical trial conducted between March 18, 2013, and November 16, 2017, at the University of Pennsylvania, HonorHealth, and The Johns Hopkins University among 112 patients with previously untreated metastatic or advanced pancreatic ductal adenocarcinoma, Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate marrow and organ function. All efficacy analyses were performed for the intention-to-treat population. INTERVENTIONS: Patients were randomized in a 1:1 ratio to receive GA with or without HCQ. All patients received standard doses of GA, and those randomized to receive HCQ were treated continuously with 600 mg orally twice daily. MAIN OUTCOME AND MEASURE: Overall survival at 1 year. RESULTS: A total of 112 patients (45 women and 67 men; median age, 65 years; range, 43-86 years) were enrolled; 55 were randomized to receive GA plus HCQ, and 57 to receive GA. Overall survival at 12 months was 41% (95% CI, 27%-53%) in the HCQ group and 49% (95% CI, 35%-61%) in the non-HCQ group. Median progression-free survival was 5.7 months (95% CI, 4.0-9.3 months) in the HCQ group and 6.4 months (95% CI, 4.5-7.6 months) in the non-HCQ group. Median overall survival was 11.1 months (95% CI, 9.0-14.2 months) in the HCQ group and 12.1 months (95% CI, 9.3-15.5 months) in the non-HCQ group. Overall response rate was 38.2% (n = 21) in the HCQ group and 21.1% (n = 12) in the non-HCQ group (P = .047). Treatment-related grade 3 or 4 adverse events that differed between the HCQ and non-HCQ groups were neutropenia (23 of 54 [42.6%] vs 12 of 53 [22.6%]), anemia (2 of 54 [3.7%] vs 9 of 53 [17.0%]), fatigue (4 of 54 [7.4%] vs 0), nausea (5 of 54 [9.3%] vs 0), peripheral neuropathy (7 of 54 [13.0%] vs 3 of 53 [5.7%]), visual changes (3 of 54 [5.6%] vs 0), and neuropsychiatric symptoms (3 of 54 [5.6%] vs 0). CONCLUSIONS AND RELEVANCE: The addition of HCQ to block autophagy did not improve the primary end point of overall survival at 12 months. These data do not support the routine use of GA plus HCQ for metastatic pancreatic cancer in the absence of a biomarker. However, improvement seen in the overall response rate with HCQ may indicate a role for HCQ in the locally advanced setting, where tumor response may permit resection. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01506973.

The kinetics of thermal instability in nanocrystalline silver and the effect of heat treatment on the antibacterial activity of nanocrystalline silver dressings.

The kinetics of nanocrystalline silver dressing heat treatment was investigated via isothermal heat treatments at 90 degrees C, 100 degrees C, and 110 degrees C lasting 2-50h. Bactericidal efficacy of the dressings was measured via log reductions, while bacteriostatic longevity was determined via plate-to-plate transfer corrected zones of inhibition. Morphological evolution of the dressing was studied by X-ray diffraction, scanning electron microscopy, and X-ray photoelectron spectroscopy, while changes in heat flow were measured by differential scanning calorimetry. Increasing temperature increased the rate at which dressing bactericidal activity and bacteriostatic longevity decreased. Once changes in dressing properties began, they occurred nonlinearly with time. The earliest biological, chemical, and physical indicators of altered dressing properties were loss of bacteriostatic longevity, silver-oxygen bonds, and fine features, respectively. An early change in heat flow appeared to be responsible for these indicators, while a later change corresponded to rapid grain growth occurring after a critical crystallite size (approximately 30 nm) was reached. The grain growth exponent was determined to be 2.8 for temperatures of 100-110 degrees C, with an activation energy of 177 kJ/mol, suggesting that normal grain growth occurred, with volume and/or grain boundary diffusion as the dominant forms of diffusion. The thermal instability of nanocrystalline silver should be accounted for during production, storage, and use of dressings. The properties required for nanosilver antimicrobial efficacy demonstrated in this study, as well as its thermal instability, should be taken into consideration for the development of nanosilver products in the future.