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Abstract: With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets. [Copyright &y& Elsevier]

Abstract: Drug development in oncology is faced with the challenge of making active new compounds available for standard of care in the shortest possible time frame. While rules and regulations create an accepted factor in delaying trial execution, protocol issues and procedures are more often a delay factor than needed, particularly in industry-sponsored studies. This provides an option to decrease trial time, without affecting patient safety. Among the possible rooms for improvement are a balanced use of in- and exclusion criteria, justified by animal toxicology, and flexible dose escalation steps still defined a priori. It is also of crucial importance to make sure in the phase I programme that the pharmacology of the agent involved is appropriately understood. Including real-time pharmacokinetics, food-effect studies and, if possible, bioavailability studies in the phase I programme would decrease the risk of taking the wrong decisions for follow-on development. The concept of increasing the number of study sites to speed up accrual has a negative effect on trial execution and is actually a delay factor that in addition has the intrinsic risk of putting patient safety at stake. [Copyright &y& Elsevier]

Background Imatinib is approved worldwide for use in gastrointestinal stromal tumors (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. Methods 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. Findings At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). Interpretation If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival. [ABSTRACT FROM AUTHOR]

Abstract: Cancer for many patients is still a lethal disease, and we are at the edge of the time that it will be the leading cause of death in the western world. One of the hallmarks of cancer is its ability to spread to other organs, turning cancer in essence to a systemic disease. For this reason, systemic therapy plays an important role in our efforts to either obtain cure or to prolong life and palliate symptoms. The ultimate goal in the development of such new treatments is cure or prolongation of life, but the process to ascertain this may be lengthy. This presents a limitation to the rapid assessment of the potential benefit of new cancer treatments, which is why investigators and regulators have been interested in clinical trial measures that could provide early readouts of drug activity or efficacy, in other words for surrogate indicators for the ultimately desired outcome. [Copyright &y& Elsevier]

Introduction It is increasingly clear that definitions of dose-limiting toxicity (DLT) established for phase 1 trials of cytotoxic agents are not suitable for molecularly targeted agents because of specific toxicity profiles. An international survey collected expertise on the definition of DLT, as part of an initiative aimed at presenting new guidelines for phase 1 trials of targeted agents. Methods A 15-question survey was sent to corresponding authors of phase 1 reports. Questions involved: duration of the DLT assessment period, incorporation of specific grade 1 (G1) or G2 toxicity and their minimum duration to qualify as DLT, exclusion of specific G3 and inclusion of dose modification/delay. Results Among the 400 investigators contacted, 93 replied of whom 65 completed the questionnaires. A total of 87% opted for an extended DLT assessment period beyond cycle 1, with the proviso not to delay patient accrual. Reanalysis at the end of the study of all safety data was proposed in order to recommend the phase 2 dose. Most respondents (92%) suggested including dose modification in the definition of DLT when dose intensity was decreased to 70%. Whilst moderate toxicity was deemed relevant by 70%, the G1/2 toxicities selected to define DLT however varied. Conclusion The majority of experts favoured a longer DLT assessment period as well as incorporation of specific G2 toxicities into the DLT definition. However, no clear consensus existed on a re-definition of DLT. Therefore analyses of a large international data warehouse were also used to develop guidelines presented in a companion paper. [ABSTRACT FROM AUTHOR]

Abstract: Over the last decade, the focus of anticancer drug development has shifted from empirical cytotoxic chemotherapy to mechanism-defined molecularly targeted agents, for which appropriate patient selection at the earliest possible point in drug development is rational and critical to success. With the recently legislated “breakthrough product” definition in the U.S., it may be possible to plan a single trial for registration purposes to confirm a major clinical effect observed in phase I. However, most phase I trial designs remain excessively conservative and are driven by criteria developed for cytotoxic agents with the goal of identifying a “maximum tolerable dose” with acceptable risks to patients. This focus on empiric “most dose with acceptable risk” may be misguided for mechanism-targeting new agents, and this could lead to unnecessary delays, increased costs and even higher risk of missing important signals of activity and benefit. There is a compelling need to modify phase I trial designs to facilitate enrichment in molecularly selected patients who are the most likely to harbour disease driven by the targeted pathway and to avoid unjustified exclusions based on obsolete criteria so that the right subset of patients can participate. After discussion of the main inconsistencies of current phase I designs, we propose a new strategy to facilitate the inclusion of molecularly selected patients, in order to accelerate and mitigate risks in drug development as well as to increase the chance of benefit among trial participants. [Copyright &y& Elsevier]

Traditional dose-limiting toxicity (DLT) definition, which uses grade (G) 3-4 toxicity data from cycle 1 (C1) only, may not be appropriate for molecularly targeted agents (MTAs) of prolonged administration, for which late or lower grade toxicities also deserve attention. Patients and methods In collaboration with pharmaceutical companies and academia, an European Organisation for Research and Treatment of Cancer (EORTC)-led initiative, Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies (DLT-TARGETT), collected data from completed phase 1 trials evaluating MTAs as monotherapy. All toxicities at least possibly related to the study drugs that occurred during C1-6, their type, grade (CTCAEv3.0), and duration as well as patients' relative dose-intensity (RDI), were recorded. Results The 54 eligible trials enrolled 2084 evaluable adult patients with solid tumours between 1999 and 2013, and evaluated small molecules (40), antibodies (seven), recombinant peptides (five) and antisense oligodeoxynucleotides (two). A maximum tolerated dose was set in 43 trials. Fifteen percent of the patients received <75% of the intended RDI in C1, but only 9.1% of them presented protocol-defined DLTs. After C1, 16-19% of patients received <75% of the intended RDI. A similar proportion of G < 3 toxicities was recorded in C1 and after C1 (936 and 1087 toxicities, respectively), with the first G < 3 toxicity occurring after C1 in 18.6% of patients. Conclusion Although protocol-defined DLT period is traditionally limited to C1, almost 20% of patients present significant reductions in RDI at any time in phase 1 trials of MTAs. Recommended phase 2 dose assessment should incorporate all available information from any cycle (notably lower grade toxicities leading to such RDI decrease), and be based on achieving >75% RDI. [ABSTRACT FROM AUTHOR]

Nowadays, treatment regimens for cancer often involve a combination of drugs. The determination of the doses of each of the combined drugs in phase I dose escalation studies poses methodological challenges. The most common phase I design, the classic '3+3' design, has been criticized for poorly estimating the maximum tolerated dose (MTD) and for treating too many subjects at doses below the MTD. In addition, the classic '3+3' is not able to address the challenges posed by combinations of drugs. Here, we assume that a control drug (commonly used and well-studied) is administered at a fixed dose in combination with a new agent (the experimental drug) of which the appropriate dose has to be determined. We propose a randomized design in which subjects are assigned to the control or to the combination of the control and experimental. The MTD is determined using a model-based Bayesian technique based on the difference of probability of dose limiting toxicities (DLT) between the control and the combination arm. We show, through a simulation study, that this approach provides better and more accurate estimates of the MTD. We argue that this approach may differentiate between an extreme high probability of DLT observed from the control and a high probability of DLT of the combination. We also report on a fictive (simulation) analysis based on published data of a phase I trial of ifosfamide combined with sunitinib.Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the safety and tolerability of LiPlaCis, a liposomal formulated platinum compound, in patients with solid tumours and to determine the maximum tolerated dose (MTD) of intravenous (i.v.) LiPlaCis. and to assess plasma and urine pharmacokinetics and plasma biomarkers. Patients and methods: Patients with solid tumours without standard therapeutic options were enrolled to receive LiPlaCis administered as a 1h infusion without additional hydration every 3weeks until RECIST progression or unacceptable toxicity. Cohorts of 3–6 patients were treated at each dose level until MTD was reached. Results: Eighteen patients were enrolled and 64 cycles were delivered. At the first dose level 3 patients experienced an infusion reaction. Despite prophylactic pre-medication and prolongation of the infusion to 2h in further patients, three other patients had mild acute infusion reactions. Toxicity at the fifth dose level of 120mg consisted of grade 2 renal toxicity reversible after hydration in 2 patients and grade 4 thrombocytopaenia in one of these patients. Peak plasma concentrations and AUC were dose proportional. The interpatient variability in the clearance of total LiPlaCis-derived platinum was 41%. Platinum was excreted via the urine mainly during the first 24h after administration. Investigated plasma biomarkers sPLA2 and SC5b-9 were related to, but not predictive for, acute infusion reactions. Conclusion: The observed safety profile suggests no benefit over standard cisplatin formulations and LiPlaCis will require reformulation to enable further development. [Copyright &y& Elsevier]

Designing combination drug phase I trials has become increasingly complex, due to the increasing diversity in classes of agents, mechanisms of action, safety profiles and drug-administration schedules. With approximately 850 agents currently in development for cancer treatment, it is evident that combination development must be prioritised, as based on a specific hypothesis, as well as a projected development path for the involved combination. In this manuscript the most relevant issues and pitfalls for combination drug phase I trial design are discussed. Several phase I study designs that incorporate controls to circumvent bias due to imbalances in observed background toxicity are discussed. [Copyright &y& Elsevier]

Abstract: Background: After the initial RECIST 1.0 were published in 2000, the criteria were widely implemented in the scientific oncology community. Since then, the RECIST working group has identified several issues to examine further. Two key issues that required careful, data-based assessment were the maximum number of lesions that should be assessed at each evaluation and the added value of requiring confirmation of response. Methods: To address these questions, data were obtained from 16 clinical trials in metastatic cancer, with patients enrolled between 1993 and 2005. A total of 6512 patients were included in the primary analysis dataset, accounting for over 18,000 potential target lesions. Nine percent of the included patients (n =585) had six or more reported target lesions. The response and progression outcomes in the database were calculated using an adjusted RECIST methodology with a maximum of 5 (or 3) target lesions with/without confirmation and this was compared to the original RECIST version 1.0 which required up to 10 target lesions plus confirmation of response. Results: Assessment of 5 lesions per patient led to a difference in best overall response assignment for an estimated 209 (3.2%) patients as compared to RECIST version 1.0. However, these changes did not affect the overall response rate. Progression-free survival was only minimally affected by measuring fewer lesions. In contrast, removing the requirement for response confirmation led to a significant increase in the numbers of patients classified as responders, resulting in a relative increase of approximately 19% in response rate. An algorithm using a maximum of three target lesions shows high concordance with the 10 lesions requirement in terms of response and TTP assignment. Concern that appropriate assessment of disease within an organ requires two lesions to be followed per organ suggests the approach of following two target lesions per organ, up to a maximum of five target lesions overall. Both strategies seem reasonable based on the data warehouse. The requirement of response confirmation in trials where this is a primary end-point is recommended to be maintained as its removal would substantially increase reported response rates. [Copyright &y& Elsevier]

Abstract: Rationale: The 62005 EORTC phase III trial, comparing two doses of imatinib in patients with advanced GIST, reported a median progression-free survival of 25 months with a trend towards dose dependency for progression-free survival. The current analysis of that study aimed to assess whether histological/immunohistochemical parameters correlate with clinical response to imatinib. Patients and methods: Pre-treatment samples of GISTs from 546 patients enroled in phase III study were analysed for immunohistochemical characteristics, correlations with clinicopathological data, with survival and with tumours’ genotype. Results: There was no correlation between immunomorphological or clinical characteristics and response to treatment, PFS or OS. No correlations between immunophenotype of the tumour and PFS or OS in the two dose arms were observed. Conclusions: The results confirm the heterogeneity of GIST in terms of immunophenotypic expression, but indicate that these parameters have no impact on the outcome of the patients under imatinib treatment. [Copyright &y& Elsevier]

The anticancer drug docetaxel is extensively metabolized by cytochrome P450 (CYP) 3A isozymes. Furthermore, docetaxel is also a substrate for the transmembrane ATP-binding cassette efflux transporter protein ABCB1. CYP3A-inhibition significantly reduces docetaxel total systemic clearance, on average by 50%. However, data on the effect of CYP3A-inhibition on the fecal and urinary excretion of docetaxel are lacking. To further elucidate the role of CYP3A- and ABCB1-mediated elimination pathways for docetaxel we investigated the effect of the potent CYP3A-inhibitor, and also ABCB1-inhibitor, ketoconazole on the fecal and urinary disposition of docetaxel in cancer patients. Fifteen patients were treated with docetaxel (100 mg/m2), followed 3 weeks later by a reduced dose in combination with orally administered ketoconazole, or vice versa. Six patients were also administered [3H]-radiolabeled docetaxel. Fecal and urinary specimens, collected up to 72-h post-infusion, were analyzed for cumulative parent drug and radioactivity excretion. Ketoconazole coadministration increased fecal parent drug excretion twofold from 2.6 ± 2.8 to 5.2 ± 5.4% (mean ± SD, P = 0.03) but did not affect urinary parent drug excretion ( P = 0.69). The sum of fecal and urinary parent drug excretion was 5.3 ± 3.0% for docetaxel alone and 7.8 ± 5.6% in the presence of ketoconazole, respectively ( P = 0.04). Total recovered radioactivity values were 45.8 ± 19.1 and 32.4 ± 19.7%, respectively ( P = 0.23). CYP3A-inhibition by ketoconazole increases fecal parent drug excretion twofold in cancer patients. A more pronounced increase was not achieved, most likely due to concomitant intestinal ABCB1-inhibition. [ABSTRACT FROM AUTHOR]

Imatinib pharmacokinetics (PK) may be affected by a number of factors that are related to the disease being treated and to the response of that disease to imatinib. Patients in the phase I and phase II trials conducted by the EORTC in patients with gastrointestinal stromal tumours (GISTs) and other sarcomas had detailed blood sampling for imatinib PK on day 1 and on day 29. Patients with GISTs also had repeat sampling, using a limited sampling strategy, after approximately 12 months on therapy. This population PK study was carried out to examine what covariates affected imatinib PK in GIST patients and what PK changes occurred over time. In the model producing the best fit, low clearance (CL) correlated with low body weight and high granulocyte count, whereas low haemoglobin correlated with low volume of distribution. For a patient with 77% of the median body weight or with 1.87 times the median granulocyte count, the apparent CL is 6.53 l/h, about 70% of the typical apparent CL of 9.33 l/h; for a patient of 84% of the typical haemoglobin level, the volume of distribution is about 70%. Total white blood cell count correlated closely with granulocyte count and there was a moderate correlation between haemoglobin and albumin (r = 0.454). There was a trend towards increased imatinib clearance after chronic exposure over 12 months. The typical apparent CL increased 33% from day 1. Nevertheless, the approximate 95% confidence interval of the increase of the typical apparent CL was 33 +/- 34.6%, which contains zero. It is not yet clear whether this is a significant factor in the amelioration of imatinib toxicity that occurs with time or is related to disease control, and further work is required to confirm this observation. [ABSTRACT FROM AUTHOR]

The prescribed dose of anticancer agents is most commonly calculated using body surface area as the only independent variable, and it has been shown that this approach still results in large interpatient variability in drug exposure. Here, we retrospectively assessed the pharmacokinetics of 33 investigational agents tested in phase I trials from 1991 through 2001, as a function of body surface area in 1650 adult cancer patients. Twelve of the drugs were administered orally, 19 were administered intravenously, and two were administered by both routes. Body surface area-based dosing was statistically significantly associated with a reduction in interpatient variability in drug clearance for only five of the 33 agents: docosahexaenoic acid (DHA)-paclitaxel, 5-fluorouracil/eniluracil, paclitaxel, temozolomide, and troxacitabine. These results do not support the use of body surface area in dose calculations and suggest that alternate dosing strategies should be evaluated. We conclude that body surface area should not be used to determine starting doses of investigational agents in future phase I studies. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and side effects of ondansetron with those of high-dose metoclopramide in treating acute and delayed cisplatin-induced nausea and vomiting.Design: Randomized, double-blind, crossover trial.Setting: Conducted at two university hospitals, a cancer institute, and six community hospitals.Patients: Of 125 patients, 95 were evaluable for the acute phase and 79 for the delayed phase. Major reasons for not being evaluable were no second course (14 patients), protocol violation (5 patients), and change in cisplatin dose (3 patients) for the acute phase, and rescue medication on day 1 (7 patients), protocol violation (3 patients), and inadequate data (4 patients) for the delayed phase.Interventions: All patients received cisplatin, 50 to 100 mg/m2 body surface area (median, 75 mg/m2); none had previously received chemotherapy. Thirty minutes before the cisplatin administration, ondansetron was given intravenously over 15 minutes, at a loading dose of 8 mg followed by a continuous infusion of 1 mg/h for 24 hours. Metoclopramide was given at a loading dose of 3 mg/kg body weight, followed by a continuous infusion for 8 hours (4 mg/kg). For the delayed phase (days 2 through 6), the first oral dose was given as soon as the infusion was completed; the oral dose consisted of either metoclopramide, 20 mg three times daily, or ondansetron, 8 mg three times daily for another 5 days.Measurements and Main Results: In the acute phase, a major or complete response was seen in 72% of the ondansetron-treated and 41% of the metoclopramide-treated patients (P less than 0.001). Nausea was significantly better controlled among the ondansetron-treated patients (P = 0.04). In the delayed phase, no statistically significant difference was seen between ondansetron- and metoclopramide-treated patients. Nausea was significantly better controlled with metoclopramide (P = 0.016).Conclusions: Ondansetron is significantly more effective than metoclopramide in preventing acute nausea and vomiting. In the delayed phase, the results of both drugs were disappointing, although metoclopramide's effect on delayed nausea was superior. Patients preferred ondansetron. [ABSTRACT FROM AUTHOR]