Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m(2) was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m(2)); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m(2), which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m(2))/gemcitabine 800 mg/m(2) d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types

Firms cash management, adjustment cost and its impact on firms’ speed of adjustment-A cross country analysis

We investigate the firms’ specific attributes that determine the difference in speed of adjustment (SOA) towards the cash holdings target in the Scandinavian countries: Denmark, Norway and Sweden. We examine whether Scandinavian firms maintain an optimal level of cash holdings and determine if the active cash holdings management is associated with the firms’ higher SOA and lower adjustment costs. Our findings substantiate that a higher level of off-target cost induces professional managers to rebalance their cash level towards the optimal balance of cash holdings. Our results reveal that Scandinavian firms accelerate SOA towards cash targets primarily for the precautionary motive. Moreover, our results show that SOA is heterogeneous across Scandinavian firms based on adjustment cost and deviate cash holdings towards the target mainly with the support of internal financing. Furthermore, our empirical findings show that the SOA of Norwegian firms is significantly higher than the Danish and Swedish firms

Effect of short-term immersion of Kappaphycus alvarezii (Doty) Doty in high nitrogen on the growth, nitrogen assimilation, carrageenan quality, and occurrence of “ice-ice” disease

Short-term immersion of Kappaphycus alvarezii (Doty) Doty in a high-nitrogen-containing medium was tested to increase growth, improve the quality of carrageenan, and decrease “ice-ice” disease occurrence. Tank-reared Kappaphycus were used as explants. Growth, nitrogen assimilation, carrageenan quality, and occurrence of ice-ice disease of enriched (E/N) K. alvarezii were determined. E/N and un-enriched (control) K. alvarezii were planted inside net cages in the sea. Nitrogen assimilation was monitored to determine if nitrogen was incorporated in the tissues after 12 h. Total thallus nitrogen of K. alvarezii doubled after immersion in high nitrogen. Growth rate and carrageenan yield of E/N K. alvarezii were significantly higher than those of the control. Gel strengths of E/N and the control were not significantly different. Ice-ice disease occurrence was significantly higher in the control than the enriched seaweeds. Short-term immersion of K. alvarezii in a high-nitrogen medium before outplanting increased growth rate and decreased the occurrence of “ice-ice”.Acknowledgement is due to the Australian Centre for International Agricultural Research (ACIAR SMAR/2008/025)