Phase I dose-escalation and pharmacokinetic study of temozolomide (SCH 52365) for refractory or relapsing malignancies

Temozolomide, an oral cytotoxic agent with approximately 100% bioavailability after one administration, has demonstrated schedule-dependent clinical activity against highly resistant cancers. Thirty patients with minimal prior chemotherapy were enrolled in this phase I trial to characterize the drug's safety, pharmacokinetics and anti-tumour activity, as well as to assess how food affects oral bioavailability. To determine dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD), temozolomide 100–250 mg m−2 was administered once daily for 5 days every 28 days. The DLT was thrombocytopenia, and the MTD was 200 mg m−2 day−1. Subsequently, patients received the MTD to study how food affects the oral bioavailability of temozolomide. When given orally once daily for 5 days, temozolomide was well tolerated and produced a non-cumulative, transient myelosuppression. The most common non-haematological toxicities were mild to moderate nausea and vomiting. Clinical activity was observed against several advanced cancers, including malignant glioma and metastatic melanoma. Temozolomide demonstrated linear and reproducible pharmacokinetics and was rapidly absorbed (mean Tmax ~1 h) and eliminated (mean t1/2 = 1.8 h). Food produced a slight reduction (9%) in absorption of temozolomide. Temozolomide 200 mg m−2 day−1 for 5 days, every 28 days, is recommended for phase II studies. © 1999 Cancer Research Campaig

Structural Control on Downdip Locking Extent of the Himalayan Megathrust

Geologic reconstructions of the Main Himalayan Thrust in Nepal show a laterally extensive midcrustal ramp, hypothesized to form the downdip boundary of interseismic locking. Using a recent compilation of interseismic GPS velocities and a simplified model of fault coupling, we estimate the width of coupling across Nepal using a series of two-dimensional transects. We find that the downdip width of fault coupling increases smoothly from 70 to 90 km in eastern Nepal to 100–110 km in central Nepal, then narrows again in western Nepal. The inferred coupling transition is closely aligned with geologic reconstructions of the base of the midcrustal ramp in central and eastern Nepal, but in western Nepal, the data suggest that the location is intermediate between two proposed ramp locations. The result for western Nepal implies either an anomalous coupling transition that occurs along a shallowly dipping portion of the fault or that both ramps may be partially coupled and that a proposed crustal-scale duplexing process may be active during the interseismic period. We also find that the models require a convergence rate of 15.5 ± 2 mm/year throughout Nepal, reducing the geodetic moment accumulation rate by up to 30% compared with earlier models, partially resolving an inferred discrepancy between geodetic and paleoseismic estimates of moment release across the Himalaya