Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study.

BACKGROUND: This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers. METHODS: Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1). RESULTS: A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies. CONCLUSION: Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience. CLINICAL TRIAL NUMBER: 2006-003772-35.

Phase I dose-escalation study of brostallicin, a minor groove binder, in combination with cisplatin in patients with advanced solid tumors.

PURPOSE: Brostallicin is a DNA minor groove binder which shows enhanced antitumor activity in cells which are resistant to several anticancer agents due to their high glutathione S-transferase (GST)/glutathione content. Phase I and II clinical trials of single-agent brostallicin have shown that myelotoxicity is the dose-limiting toxicity (DLT), while hints of antitumor activity were mainly observed in soft tissue sarcoma. Preclinical studies showing a more than additive antitumor effect of the cisplatin-brostallicin combination paved the way to clinical combination studies. In particular, we set up the first clinical combination study of brostallicin and cisplatin in patients with advanced solid tumors. This study was to be followed by a phase II study in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). METHODS: Escalating doses of brostallicin were administered in combination with a fixed dose of cisplatin (75 mg/m(2)) in patients with recurrent or metastatic advanced solid tumors who had previously received a cumulative dose of cisplatin not higher than 475 mg/m(2). The recommended dose of brostallicin was expanded in order to have a better estimate of antitumor activity and to better define the safety profile of the combination. RESULTS: Twenty-one patients were treated. Two DLTs (grade 3 fatigue and febrile neutropenia) were observed at dose level 3 (brostallicin 9 mg/m(2)). Dose level 2 (brostallicin 7 mg/m(2) and cisplatin 75 mg/m(2)) was recommended for future phase II studies. Main toxicity was hematologic; in fact, only 1 patient out of 21 did not develop neutropenia and only 2 patients did not have thrombocytopenia. Grade 3-4 neutropenia was observed in 90.5% of patients, grade 3-4 thrombocytopenia in 38.1%, grade 3-4 anemia in 23.8%. The cycle 1 nadir (ANC < 500 x 10(9)/L) for neutrophils was Day 14 (median; range 11-17) with recovery to an ANC of >1,500 3.5 days after nadir (median; range 2-4) at dose level 3. The cycle 1 nadir (median of 51,000 x 10(9)/L) for platelets occurred on Day 13 (median; range 10-15) with recovery to a platelet count of >100,000 4 days after nadir (median; range 2-8). No objective responses were observed, but seven patients had a long lasting (>18 weeks) stable disease. CONCLUSIONS: Further studies of the combination of brostallicin and cisplatin are warranted.

"Within patient"-dependent outcomes in graft occlusion after coronary artery bypass. SINBA Group.

In clinical trials aimed at assessing the efficacy of drugs after coronary artery grafting, statistical analysis is usually carried out on a per-patient basis and on a per-graft basis. Owing to the independence of responses among patients, the former outcome is analyzed by assuming a binomial model. However, this model cannot be directly adopted in analyzing the latter outcome because multiple vein grafts in the same patient do not act independently. It has been suggested that patients be considered as clusters of distal anastomoses, subsequently comparing the frequencies of occlusion under different treatments after adjusting the variance of each frequency for the size of the cluster. Alternatively, one can measure the intraclass (intrapatient) correlation coefficient and adopt distribution functions that include this quantity as one of the parameters. This approach has been adopted by many authors although the studies differed in the statistical model used to represent this kind of data. Two probability functions, Altham's and beta-binomial, have found wide application in different biomedical fields. Both are able to model the extrabinomial variability since their tails tend to zero more slowly than those of the binomial distribution. An alternative to adopting a specific probabilistic model consists of specifying a mixed model or a Markov-like susceptibility model. These models follow the same rationale since they assume the existence of two processes, one that causes an individual to become susceptible to occlusion, the other that determines the subsequent probability of occlusion in the individual. After presenting these models in a unified framework, this paper compares the estimates obtained by fitting the models to data gathered at coronary angiography 1 year after surgery by the SINBA group on a total of 847 saphenous vein anastomoses in 349 patients. Finally, the issue concerning the contribution of each patient to the effective sample size is discussed.

A linear model suitable for assessing graft patency in controlled clinical trials. SINBA Group.

In clinical trials carried out to assess the efficacy of different drugs in reducing the frequency of occlusion after coronary artery bypass, the ratio of the number of patients with at least one occluded anastomosis to the number of patients catheterized up to a given day is a widely adopted statistic. In the early evaluation (at 1 or 2 months after surgery), this is affected by the distribution of timing of angiography and it tends to underestimate the cumulative probability of occlusion because patients whose anastomoses are all patent at angiography and occlude between angiography and the day at which the ratio is estimated do not contribute their events to the numerator of the ratio. One may sensibly assume that this underestimate does not affect the evaluation of the efficacy of treatments tested "within" the trial. In contrast, since the distributions of the timing of angiography vary substantially from trial to trial, it can make comparisons "between" trials unclear and possibly biased. The aim of this article is to suggest an alternative approach of statistical analysis in terms of logistic regression. By modeling the dichotomous response given by each patient in function of time at angiography, type of treatment, and other possible covariates, asymptotically unbiased estimates of the cumulative probability of occlusion are attained. Furthermore, the pertinent hazard function can be estimated. The main features of the model are discussed and the results obtained by fitting early data collected in the Studio Indobufen Nel Bypass Aortocoronarico (SINBA) are given.

The search for genetic homogeneity in affective disorders.

In the present study we tested the fit of the Single Major Locus (SML) hypothesis, using segregation analysis for single families of affective probands treated with lithium salts, with second degree relatives included. We tested the segregation pattern for every family with two different sets of parameters: one dominant for a group that did not relapse on lithium treatment and one recessive for a group that did. We calculated the likelihood ratios for each family. The results of this study partially confirm the importance of outcome on lithium treatment in susceptibility to affective disorders. However, application of segregation analysis suggested that there is genetic heterogeneity that cannot be completely detected when using only the simple pharmacological criterion of outcome on lithium.

Outcomes on lithium treatment as a tool for genetic studies in affective disorders.

From a genetic point of view, the application of mathematical models to affective disorders has not yet been useful, since they do not indicate a specific mode of transmission. To use these models correctly, we need to identify homogeneous genetic subgroups among those sharing the common phenotypic feature of affective illness. Our useful criterion for this is outcome on long-term lithium therapy, since experimental data suggest the existence of a close relationship between the genetic mechanisms that underly the affective disorders and those that underly outcome on lithium. We have studied 145 subjects with primary affective disorders, 92 of whom did not relapse during lithium treatment and 53 of whom did, together with 864 of their first-degree relatives. The data for both groups fit both single major locus and multifactorial polygenic models for genetic analysis, including a sex effect and therefore neither mode of transmission can be excluded.