Eligible patients (enrollment target, n = 170) will be randomized at a 1 1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily).
In contrast, where heterogeneity is limited, as in some leukemias (e.g., APL), single-agent administration often leads to better treatment outcomes if not curative results.
Although the combination was never administered in reverse order, topotecan and IF did not appear to interact pharmacokinetically in the studied combination regimen, since the observed pharmacokinetics were similar to those after single-agent administration.
For example in three-dimensional cell cultures of BRAF mutant melanoma the combination of BRAF and AKT3 directed siRNAs demonstrated significantly higher reduction of tumour growth compared with weak growth inhibition by single-agent administration (Cheung et al, 2008).
After single-agent administration in preclinical models, rapid regrowth of the viable tumour rim is observed, which obtains its nutrients from the surrounding normal tissue and blood supply (Salmon and Siemann, 2007).
The strategy to hit multiple aspects of signalling pathways, thought to be key to ovarian cancer control of growth and survival, proved to be more effective than single-agent administration in most but not all of the tumours studied.
Although paclitaxel has demonstrated efficacy in phase III trials in the first-line setting (Paridaens et al, 2000; Sledge et al, 2003), the optimal dose schedule for single-agent administration has not been fully established.
Similar results were observed in a phase I study of the experimental epidermal growth factor receptor tyrosine kinase inhibitor EKB-569, in which 5-fluorouracil exposure was increased approximately two-fold when capecitabine was given in combination with EKB-569 compared with single-agent administration (Laheru et al, 2008).
Our data suggests that, at least for this type of tumour driven by activation of the PI3K and mTOR pathway, single-agent administration of drugs that suppress these pathways would be effective at shrinking tumours and inhibiting their growth, but would not cause complete regression.
Population pharmacokinetic parameters of topotecan were similar to previously reported parameter estimates obtained using a population approach (Gallo et al, 2000) and a standard two-stage analysis (Wall et al, 1992; van Warmerdam et al, 1995) after single-agent administration of 0.5 2.0 mg m−2 topotecan in the daily times five schedule.
This feasibility study was designed to evaluate the tolerability, safety, and efficacy of single agent long-term administration of S-1 chemotherapy following three cycles of DOC plus CDDP in patients with completely resected stage II or IIIA NSCLC.
