Phase I study of the checkpoint kinase 1 inhibitor GDC-0575 in combination with gemcitabine in patients with refractory solid tumors.

BACKGROUND: Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic properties of GDC-0575 alone and in combination with gemcitabine. Antitumor activity and Chk1 pathway modulation were assessed. PATIENTS AND METHODS: In this phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose. Patients in arm 2 received either i.v. gemcitabine 1000 mg/m2 (arm 2a) or 500 mg/m2 (arm 2b), followed by GDC-0575 (45 or 80 mg, respectively, as RP2D). Stage II enrolled disease-specific cohorts. RESULTS: Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were Eastern Cooperative Oncology Group PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No pharmacokinetic drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were four confirmed partial responses, three occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2. CONCLUSION: GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine; however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary antitumor activity was observed but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine. CLINICAL TRIAL NUMBER: NCT01564251.

Measurement of IR laser backscatter spectra from sulfuric acid and ammonium sulfate aerosols.

An optical system employing a tunable carbon dioxide laser has been used to investigate backscatter signatures of aerosols as a function of wavelength. Submicron sulfuric acid or ammonium sulfate aerosols are produced with a vapor-condensation aerosol generator. The aerosol is contained in a 1-m long windowless aerosol chamber, and laser radiation backscattered from the irradiated aerosol is collected and measured as the laser is tuned from 9.2 to 10.8 microm. The volume backscatter coefficient is calculated from the lidar equation to yield the theoretical IR spectrum of the aerosol. The measured spectral signature is compared with the theoretical signature, which is computed from Mie theory. Backscatter signatures show excellent agreement with calculated signatures. The spectral signature of ammonium sulfate is readily distinguished from that of sulfuric acid for the conditions of the experiment. Because of vapor pressure characteristics of sulfuric acid, it is possible to concentrate the acid in the generator over time and look for a change in the acid concentration in the aerosol. Not only has this concentration process been observed optically, but under these experimental conditions the acid concentration in the aerosol can be determined by observing backscatter at just two wavelengths.

Measurement of average atmospheric temperature using a CO(2) laser radar.

A single-ended CO(2) lidar system has been used to measure the average temperature over a path between the lidar and the foothills located 5 km away. The CO(2) lidar was used to measure the ratio of transmission of the P(38) to the P(20) lines in the 10-microm band of CO(2). This ratio of transmission is directly related to temperature. Good correlation was obtained between the lidar-measured temperature and the thermometermeasured values.

Single-ended measurement of infrared extinction using lidar.

The goal of this study was to investigate the feasibility of single-ended measurement of the total extinction coefficient using an ir lidar system. Extinction was measured using a CO(2) laser radar system at four wavelengths near 10.3 microm. The measured results agree with theoretical estimates of extinction over a wide range. Single-ended measurements of extinction appear feasible to a horizontal range of 10 km using commercially available components. The system could potentially generate extinction data in a 3-D grid, enabling one to determine ir transmission between any two points in the field.

Remote measurement of ethylene using a CO(2) differential-absorption lidar.

Ethylene has been monitored with a single-ended CO(2) lidar using topographical scattering. Foliage on the foothills 5 km away provided the backscattered signal. Interference due to water vapor was found to be equivalent to 7.6 ppb of ethylene, and this correction was applied to the data. The total measurement uncertainty was found to average 1.6 ppb. The lidar-measured concentrations agree with point monitor samples over a wide range of ambient concentrations.

Remote measurement of HCI, CH(4), and N(2)O using a single-ended chemical-laser lidar system.

The applicability of the high energy discretely tuned DF laser for remote measurement of HCl, CH(4), and N(2)O has been investigated. A single-ended or monostatic lidar system using radiation backscattered from topographical targets was tested. Selective absorption of the backscattered signal was used to infer concentration of gaseous species. Good agreement was obtained between the lidar measurements and the concentrations determined by in situ measurements in the remotely positioned sample chamber. The lowest measurable material concentration for each gas was inferred from random fluctuations in the measured concentration. Sensitivity of the existing system to HCl, CH(4), and N(2)O was found to be 0.05 ppm-km, 6.0 ppm-km, and 0.24 ppm-km, respectively. An N(2)O plume was also measured in the open atmosphere between the lidar system and a foliage target to demonstrate system capabilities under typical field conditions. Performance predictions indicate that total burden and range-resolved species concentration measurements are feasible to a range of 10 km or more with commercially available components.