Christopher Kaiser

Association between early and rapid weight gain and change in weight over one year of olanzapine therapy in patients with schizophrenia and related disorders.

Abstract: Weight gain is an important issue in the use of atypical antipsychotics, including olanzapine. A retrospective analysis of patterns of weight gain and possible covariates was performed for 1191 patients diagnosed with schizophrenia or schizoaffective disorder who were treated with olanzapine for up to 52 weeks. Patients were dichotomized into 2 main groups according to the percentage of body weight gained during the first 6 weeks of treatment with olanzapine: (1) patients who gained ≥7% of their body weight (Rapid Weight Gain Group [RWG]), and (2) patients who lost weight, gained no weight, or gained <7% of their body weight (Nonrapid Weight Gain Group [NRWG]). Results demonstrated that approximately 15% of the patient population showed rapid increases in weight (RWG group), whereas 85% of patients gained weight more slowly or not at all (NRWG group). Patients in the RWG group gained an average of 4% of their body weight (approximately 4-7 lb) within the first 2 weeks of treatment with olanzapine. Furthermore, patients in the RWG group were younger, had a lower baseline body mass index, were more likely to report an increase in appetite, and showed a more robust clinical response compared with patients in the NRWG group. Over the course of 52 weeks, patients in the RWG group gained significantly more weight and reached a higher plateau for mean weight increase at 38 weeks compared with the mean increase observed for patients in the NRWG group. By measuring the weight of patients during the first few weeks of olanzapine treatment and by assessing changes in appetite, clinicians may be able to identify those patients at risk for substantial weight gain.

The effect of correlation structure on treatment contrasts estimated from incomplete clinical trial data with likelihood-based repeated measures compared with last observation carried forward ANOVA

Valid analyses of longitudinal data can be problematic, particularly when subjects dropout prior to completing the trial for reasons related to the outcome. Regulatory agencies often favor the last observation carried forward (LOCF) approach for imputing missing values in the primary analysis of clinical trials. However, recent evidence suggests that likelihood-based analyses developed under the missing at random framework provide viable alternatives. The within-subject error correlation structure is often the means by which such methods account for the bias from missing data. The objective of this study was to extend previous work that used only one correlation structure by including several common correlation structures in order to assess the effect of the correlation structure in the data, and how it is modeled, on Type I error rates and power from a likelihood-based repeated measures analysis (MMRM), using LOCF for comparison. Data from four realistic clinical trial scenarios were simulated using autoregressive, compound symmetric and unstructured correlation structures. When the correct correlation structure was fit, MMRM provided better control of Type I error and power than LOCF. Although misfitting the correlation structure in MMRM inflated Type I error and altered power, misfitting the structure was typically less deleterious than using LOCF. In fact, simply specifying an unstructured matrix for use in MMRM, regardless of the true correlation structure, yielded superior control of Type I error than LOCF in every scenario. The present and previous investigations have shown that the bias in LOCF is influenced by several factors and interactions between them. Hence, it is difficult to precisely anticipate the direction and magnitude of bias from LOCF in practical situations. However, in scenarios where the overall tendency is for patient improvement, LOCF tends to: 1) overestimate a drugs advantage when dropout is higher in the comparator and underestimate the advantage when dropout is lower in the comparator; 2) overestimate a drugs advantage when the advantage is maximum at intermediate time points and underestimate the advantage when the advantage increases over time; and 3) have a greater likelihood of overestimating a drugs advantage when the advantage is small. In scenarios in which the overall tendency is for patient worsening, the above biases are reversed. In the simulation scenarios considered in this study, which were patterned after acute phase neuropsychiatric clinical trials, the likelihood-based repeated measures approach, implemented with standard software, was more robust to the bias from missing data than LOCF, and choice of correlation structure was not an impediment to its implementation.

A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer

PURPOSE We conducted a randomised phase II study to assess the safety and efficacy of standard versus high-dose pemetrexed in platinum-resistant epithelial ovarian cancer (PR-EOC). The expression of ten genes was also examined as potential biomarkers of pemetrexed/platinum activity. PATIENTS AND METHODS Patients received pemetrexed 500mg/m(2) (Pem500) or 900mg/m(2) (Pem900) on day 1 of each 21-d cycle. Responses were defined per RECIST for measurable disease or by Gynaecologic Cancer Intergroup (GCIG) CA-125 criteria for non-measurable disease. RESULTS Of 102 patients randomised, 98 were evaluable for toxicity (47 Pem500, 51 Pem900) and 91 were evaluable for efficacy (43 Pem500, 48 Pem900) of whom 68 had measurable disease and 23 had CA-125-defined disease. The overall RR was 9.3% (95% CI: 2.6-22.1%) on Pem500 and 10.4% (95% CI: 3.5-22.7%) on Pem900. The median progression-free survival (PFS) was 2.8 months on both arms, and the median survival was 11.9 and 10.3 months, respectively. Lower mRNA expression of excision repair cross-complementation group 1 (ERCC1) and reduced folate carrier 1 (RFC1) were associated with longer PFS and time to treatment failure, respectively. Grade 3/4 toxicities, including fatigue, nausea and vomiting, were numerically greater on Pem900. Pemetrexed-related SAEs occurred in 17% and 28% of Pem500 and Pem900 patients, respectively. CONCLUSIONS Pemetrexed has activity in PR-EOC equivalent to other agents in platinum-resistant disease; however, Pem500 has the preferable toxicity profile. ERCC1 and RFC1 may merit examination as predictive biomarkers in PR-EOC.

A current review of olanzapine's safety in the geriatric patient: from pre-clinical pharmacology to clinical data

Olanzapine (OLZ) is unique among currently available antipsychotic medications in its antagonism of a range of receptor systems including dopamine, norepinephrine, serotonin, acetylcholine, and histamine. Olanzapines mechanistic complexity provides a broad efficacy profile in patients with schizophrenia and acute, pure or mixed mania. Patients experience symptomatic relief of mania, anxiety, hallucinations, delusions, and agitation/aggression and reduced depressive, negative, and some cognitive symptoms. This paper will review the safety profile of OLZ, focusing on the elderly, where data are available.

Molecular determinants of efficacy for 5‐FU‐based treatments in advanced colorectal cancer: mRNA expression for 18 chemotherapy‐related genes

5‐Fluorouracil (5‐FU)‐based regimens remain a cornerstone in the treatment of colorectal cancer (CRC). However, the attendant toxicity prevents these regimens from reaching maximum therapeutic potential. In this retrospective analysis, we examined the pretreatment expression of 18 genes in archival tumor bank samples from patients with advanced CRC to determine if one or more of the selected genes showed promise as either a prognostic or predictive marker of 5‐FU‐based treatment outcomes. One hundred and forty‐four CRC patient samples (collected from 1983 to 2004) were analyzed via real‐time PCR for gene expression. Univariate analyses were used to correlate gene expression with efficacy and time‐to‐event variables. Low thymidine phosphorylase (TP), dihydrofolate reductase, dihydropyrimidine dehydrogenase (DPD), excision repair cross‐complementing 1 (ERCC1) and thymidylate synthase gene expression were associated with better time‐to‐progression in the entire population. Low TP, DPD and ERCC1 expression were independently associated with improved overall survival. Low TP gene expression was also predictive of response. This study suggests that TP gene expression in particular is a predictive as well as a prognostic biomarker for advanced CRC patients. Gene panels assessing pretreatment TP, DPD, ERCC1, dihydrofolate reductase and thymidylate synthase gene expression may help improve the therapeutic potential of 5‐FU‐ or other novel antifolate‐based regimens. Further analysis of the prognostic or predictive value of these genes in prospective trials in CRC patients seems warranted.

A randomized, double-blind, phase II study of two doses of pemetrexed as first-line chemotherapy for advanced breast cancer

Purpose: Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity. Experimental Design: Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m2 (P600 arm) or 900 mg/m2 (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B12 supplementation. Results: The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with ∼50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. γ-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low γ-glutamyl hydrolase (P = 0.024). Conclusion: The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.

Evaluating and utilizing probability of study success in clinical development

Background Drug development has become increasingly costly, lengthy, and risky. The call for better decision making in research and development has never been stronger. Analytic tools that utilize available data can inform decision makers of the risks and benefits of various decisions, which could lead to better and more informed decisions. Purpose Through some real oncology examples, we will demonstrate how using available data to analytically evaluate probability of study success (PrSS) can lead to better decisions in clinical development. Methods The predictive power, or average conditional power, is used to quantify the PrSS. To calculate the probability, we follow a general two-step process: (1) use Bayesian modeling and appropriate assumptions to synthesize relevant data to derive the distribution of treatment effect and (2) evaluate the PrSS analytically or via trial simulation. Results We applied the procedure to several compounds in our oncology pipeline. The analysis informed decision making where PrSS was an important factor to consider. Limitations When modeling the treatment effect, we made certain assumptions, including how two drugs work together and exchangeable treatment effects across studies. Those assumptions are reasonable for our specific situations but may not generalize well. Conclusions From our experience, PrSS based on available data can help decision making in drug development, particularly the Go/No-Go decision after the proof of concept trial is completed. When applicable, we recommend this evaluation be regularly done in addition to the routine data analysis for clinical trials.

The Effects of Antipsychotic Drug Treatment on Prolactin Concentrations in Elderly Patients

OBJECTIVE To describe the change in serum prolactin concentrations in elderly agitated nursing home patients with dementia who were newly initiated on olanzapine or switched to olanzapine treatment from either conventional antipsychotics or risperidone. METHODS During an 8-week open-label olanzapine efficacy trial in elderly nursing home patients demonstrating clinically significant behavioral and psychological symptoms of dementia, serum prolactin concentrations were drawn on four occasions: at time of consent, following a washout period from previous therapy, midway through the study, and at endpoint. To assess post-hoc the effects of prolactin concentrations upon switching to olanzapine treatment, patients were divided into three different groups, based upon status at time of consent: those not taking antipsychotic medication, those taking any conventional antipsychotic, and those taking risperidone. Prolactin concentrations were assessed using a mixed-effect repeated-measures model. Symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS), the Cohen-Mansfield Agitation Inventory (CMAI), the Clinical Global Impression (CGI)-Severity scale, and the Mini-Mental State Examination (MMSE), and the same repeated measures analysis was performed on these scales. RESULTS Patients not on antipsychotic medication at study entry (29 females, 7 males) experienced a significant increase in prolactin concentration baseline to endpoint (P < 0.05) but remained below upper limit of normal for prolactin for both males and females. There was a nonsignificant increase in prolactin concentrations when patients were switched from conventional antipsychotic medications (mean dose 152.41 +/- 192.48 mg/day chlorpromazine equivalents) to olanzapine (2.5 to 10 mg/day) (22 females, 9 males). Patients who entered the study on risperidone (mean dose 1.31 +/- 0.91 mg/day) (13 females, 4 males) experienced a significant decrease in prolactin concentration (P < 0.001). While 62.5% of risperidone-treated patients had above-normal prolactin concentrations at baseline, only 21.4% had above-normal concentrations at endpoint (P = 0.033). Clear correlations between prolactin concentrations and clinical outcomes could not be determined. CONCLUSION Consistent with previous findings in younger patients, olanzapine appeared to be a prolactin-sparing antipsychotic medication in the elderly with only modest prolactin increases observed. In addition, patients who were receiving risperidone and then switched to olanzapine experienced a significant reduction in prolactin concentrations that was sustained over the 8-week treatment course with olanzapine. One possible explanation for olanzapines relatively modest increase in prolactin is that, unlike conventionals or risperidone, olanzapine binds less tightly with the dopamine D(2) receptor.

A Randomized Phase II Trial of Pemetrexed plus Irinotecan (ALIRI) versus Leucovorin-Modulated 5-FU plus Irinotecan (FOLFIRI) in First-Line Treatment of Locally Advanced or Metastatic Colorectal Cancer

Background: This multicenter, randomized trial compared overall response rate between pemetrexed plus irinotecan (ALIRI) and leucovorin-modulated 5-fluorouracil plus irinotecan (FOLFIRI) in patients with advanced colorectal cancer. Secondary objectives included overall and progression-free survival, duration of response, toxicities, and biomarkers. Patients and Methods: ALIRI patients received pemetrexed 500 mg/m2 and irinotecan 350 mg/m2 with vitamin supplementation on day 1 of each 21-day cycle. FOLFIRI patients received irinotecan 180 mg/m2 on days 1, 15, 29; on days 1, 2, 15, 16, 29, 30, patients received leucovorin 200 mg/m2, bolus 5-fluorouracil 400 mg/m2, and 5-fluorouracil 600 mg/m2 as 22-hour infusion. Results: Of 132 patients randomly assigned, 130 patients (64 = ALIRI, 66 = FOLFIRI) received ≧1 dose of treatment. Response rates (ALIRI = 20.0%, FOLFIRI = 33.3%) were not significantly different between arms (p = 0.095). Progression-free survival was 5.7 months for ALIRI and 7.7 months for FOLFIRI (p < 0.001). Neutropenia, fatigue, diarrhea, nausea, and vomiting were the major toxicities. There were 5 drug-related deaths (ALIRI = 4, FOLFIRI = 1). Biomarker analysis failed to reveal that any of the 18 preselected genes were clearly associated with tumor response. Conclusions: Neither efficacy nor safety improved on the ALIRI arm compared to the FOLFIRI arm. Progression-free survival on FOLFIRI was significantly longer compared to ALIRI. Potential biomarkers capable of predicting response to either regimen in advanced or metastatic colorectal carcinoma need further characterization.

Phase 2 study of tabalumab, a human anti‐B‐cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma

In this double‐blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2 on a 21‐day cycle. No significant intergroup differences were observed among primary (median progression‐free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80–1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72–1·45], P = 0·884). The most commonly‐reported treatment‐emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut‐off point (mPFS [95% CI] = 8·3 [7·0–9·3] months vs. 5·8 [3·7–6·6] months; HR [95% CI] = 1·59 [1·11–2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.