Search

Dose-limiting toxicity (DLT) remains the preferred metric in dose-finding phase 1 trials. Nevertheless, this primary endpoint appears unsuitable for investigating non-cytotoxic drugs. We reviewed 201 recent dose-finding phase 1 trials and compared the DLT defined with cytotoxic (119 trials) and non-cytotoxic drugs (molecular-targeted therapies and immune-stimulant agents; 82 trials). DLT was less frequently identified with non-cytotoxic drugs (52 vs. 89%, p = 0.00005). Myelotoxicity remains the most frequent DLT in studies investigating cytotoxic agents (51%). Myelotoxicity was significantly less frequent in studies investigating non-cytotoxic drugs (14%, p = 0.00003). Skin toxicities (p = 0.038), coagulation perturbation (p = 0.025) and fever (p = 0.025) were the most frequent DLTs in studies investigating non-cytotoxic drugs. Moreover, DLTs identified with non-cytotoxic drugs were less frequently objectively measurable as they were based on biological anomalies (30 vs. 63%, p = 0.0026). Approximately 50% of dose-finding phase 1 trials investigating non-cytotoxic drugs led to DLT and then the maximum tolerated dose being found. However, the nature of these DLTs is different from those described with cytotoxic drugs and less objectively measurable in many cases.

Background The management of carcinoma of unknown primary site remains debatable. The literature data consists of about 29 phase-II studies investigating 38 regimens, providing a broad range of response rates (RR). Methods We performed a pooled published data analysis to identify the factors influencing RR in these 29 studies. Results In front-line treatment, the overall RR was 31% (430/1,380). At least nine factors significantly influenced the reported RR, excluding drugs under investigation, such as the impact factor of the journal, single-centre study, some eligibility criteria, central radiological review, sample size calculation based on statistical hypothesis and stratification. Two drugs seem to improve RR: cisplatin and doxorubicin. Two drugs seem to be associated with a worse RR: irinotecan and carboplatin. Conclusions This pooled data analysis illustrates that in a phase II trial setting, it is impossible to attribute the variation in RR solely to the modification of drugs under investigation.

Multidrug chemotherapy increases responses in advanced soft tissues sarcoma. Can a 20% increase of relative dose intensity of the MAID regimen, more improve responses? From 1994 to 1997, 162 patients were randomized in a phase III study to the conventional drug combination (6 cycles of MAID: 60, 7,500, 900 mg/m(2) for doxorubicin, ifosfamide and dacarbazine respectively), or at doses 20-33% higher per cycle (5 cycles of intensified MAID for similar cumulative doses) with systematic G-CSF. Primary endpoint was response rate; secondary were toxicity, event-free and overall survival. The objective response rate in assessable patients was 38% with intensified MAID and 35% with MAID (p = 0.72). Event-free and overall survivals were similar in both arms. Only grade 3-4 thrombocytopenia and anemia were significantly higher in intensified arm. Treatment with intensified MAID did not improve response rate neither survival and cannot be recommended for advanced or metastatic soft tissue sarcoma.

The number of patients treated at each dose-level in dose seeking phase I trials is arbitrarily established. The most frequently used design is the "classical 3 + 3 design (3 + 3D)". Recently, Simon et al. had introduced several "accelerated titration designs (ATD)". In the present analysis, we compared the performance of these two types of designs in 270 recently (1997-2008) published phase I trials. ATD had been used in only 10% of the recent studies. ATD had permitted to explore significantly more dose levels (seven versus five, p = 0.0001) and reduced the rate of patients treated at doses below phase-2 recommended dose (46% versus 56%, p = 0.0001). Nevertheless, ATD did not allow a reduction in the number of enrolled patients, shorten the accrual time nor increase the efficacy of phase I trials. These data support that ATD as an effective clinical trial design over a standard 3 + 3 dose escalation design.

Background: Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. Methods: The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon’s optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. Result: Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. Conclusions: Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step.

Selecting patients for phase I trials in order to investigate cytotoxic agents is challenging, since there is no clear and reliable guidance to estimate life expectancy among these patients. We retrospectively assessed prognostic factors in cancer patients screened for Phase1 trials between October 1997 and October 2002.148 consecutive patients, screened for inclusion in phase I trials investigating cytotoxic agents, were included in the present study. 70 out of them actually received phase I trial regimens. Univariate and multivariate analysis were undertaken to determine the prognostic factors for overall survival (OS) from the date of screening.The median OS of the 148 patients was 5.7 months. Ninety-two percent of them had PSor=1. The Cox model identified serum albumin38 g/l [HR 2.51 (1.51-4.18), p=0.0001] and lymphocyte count700/mm3 [HR 2.27 (1.13-4.62), p=0.024] as independent prognostic for overall survival. All patients presenting both prognostic factors died within 90 days.We propose a simple model, easily obtained at the bedside, which can discriminate patients who are likely to be alive at 3 months and thus could be included in a phase 1 anti-cancer trial. This model now needs to be validated on an independent cohort.

Purpose Most current dose-seeking phase 1 trials include an expanded cohort at phase-2-recommended dose (P2RD) to better characterize the drug safety or to obtain a better estimate of secondary endpoints. Nevertheless, the sample size of this expanded cohort has generally not been justified. Materials and methods We reviewed 330 phase 1 trials (1998–2008). We estimated the rate of patients experiencing dose-limiting toxicity (DLT) at P2RD. Next, we estimated the probability of observing 1, 2 or 3 DLT in different fictive cohorts (from 8 to 22 patients). Results In the literature, the rate of patients experiencing DLT at P2RD was 367/2433, or 15.0%. We drew a table estimating the probability of observing 1, 2 or 3 DLTs in the different fictive cohorts. For example, in a cohort of 16 patients, the probabilities of observing 1, 2 or 3 DLTs are about 92.6%, 91.3 and 91.1% respectively. Conclusion This simple tool could provide a justification for the sample size of an expanded cohort when DLT remains the metric for dose-seeking.

Background Several cancer therapies can prolong cardiac repolarization. This study assessed the potential of eribulin to affect cardiac repolarization in patients with advanced solid tumors. Methods In this Phase I, open-label, single-arm study, patients received eribulin mesylate (1.4 mg/m2; Days 1 and 8 of a 21-day cycle). The primary objective was to assess the effect of eribulin on the QTcF pre- and post-infusion; QTcF and QTcNi were compared for ability to remove heart-rate dependence of the QT interval. Relationship between concentration of eribulin and ΔQTc was explored using linear mixed-effects analysis. Secondary objectives explored pharmacokinetics, safety, and tolerability. Results Twenty-six patients were enrolled. QTcNi was more effective than QTcF in correcting for heart-rate dependency of the QT interval. On Day 1, mean ΔQTcNi were ~0 at all timepoints. An apparent time-dependent increase in ΔQTc was observed: on Day 8, changes from baseline were larger and more variable, without clear relation to plasma levels of eribulin. Day 8 predose ΔQTcNi was 5 ms, post-infusion mean values ranged from 2 to 9 ms (largest mean ΔQTcNi at 6 h). No new or unexpected toxicities were reported. Conclusion Eribulin demonstrated an acceptable safety profile and a minor prolongation of QTc not expected to be of clinical concern in oncology patients.

Introduction For decades, determination of the recommended Phase 2 dose (RP2D) was based on the toxicity (especially the maximum tolerated dose or MTD) experienced by patients enrolled in dose-escalating Phase 1 trials investigating anti-cancer agents. Recent studies suggest that this toxicity-based strategy is not suitable for modern anti-cancer agents. We conducted a retrospective study to identify the risk factor(s) for failing to determine the RP2D according to the MTD. Material and methods We analyzed 320 recently published (1997–2008) Phase 1 trials using the maximum tolerated dose (MTD) to define the P2RD. We analyzed the current definitions of RP2D and then identified the risk factors for not establishing the RP2D using the odds ratio and 95% confidence intervals. Interactions between these risk factors were explored using the logistic regression model and CHAID algorithm. Results 18% of contemporary dose-seeking Phase 1 trials did not identify a RP2D. The logistic regression analysis showed that the risk factors for not identifying the RP2D were: investigation of molecular targeted therapies (RR = 3.0, p = 0.0017), lack of justification of the starting dose (RR = 5.9, p = 0.0121) and lack of definition of the MTD (RR = 8.4, p = 0.0006). The CHAID algorithm confirmed the importance of the methodological parameters. Discussion This study confirms the difficulty of determining the RP2D of molecular targeted therapy using conventional methods. However, it underlines the major importance of two methodological points: definition of the MTD and justification of the starting dose.

Several previous reports suggest that thrombospondin (TSP-1) may be a mediator of the antiangiogenic effects of low-dose metronomic cyclophosphamide-based chemotherapy (MC). We conducted a randomized phase II trial evaluating megestrol acetate (n = 44) versus MC (n = 44) in patients having exhausted all standard treatments. We measured the TSP-1 levels at baseline and D15. We did not observe significant differences in TSP-1 at baseline in the two arms (p = 0.07). TSP-1 levels decreased in patients receiving metronomic cyclophosphamide (from 16.6 ± 7.2 µg/ml to 12.8 ± 7.4 µg/ml; p = 0.057). The TSP-1 level was stable in patients receiving megestrol acetate. Nevertheless, the TSP-1 level driven by MC did not correlate to clinical benefit.

Introduction New drug development is a time- and resource-consuming process. Phase 1 trials constitute a major key-step of this development. Shortening the accrual time is of major importance. Methods 292 published phase-1-trials were retrospectively reviewed to establish the determinants of accrual time using Log-rank test and then Cox Model. Results Out of 292 trials (1997–2008), only 107 reports (36%) described the accrual time (median: 20 months, 5–72). Phase-2-recommended dose was established in 87 studies (81%). Most studies investigated regimens including cytotoxic drugs (77%) or molecular targeted therapies (29%). Under univariate analysis, two parameters shortened the accrual time: studies conducted in USA vs. other places (19 vs. 21 months p = 0.03) and regimen with more than 2 dose-escalated drugs (13 vs. 21 months, p = 0.003). One parameter was significantly associated with longer accrual time: starting dose justified by animal toxicology data vs. previous clinical trials (22 vs. 19 months, p = 0.03). Most of parameters did not significantly affect the accrual time: nature of investigated drugs, duration of treatment cycle, phase 1 dedicated to specific tumoral subtypes, number of centers, method of drug escalation (classical 3+3 vs. accelerated titration design), type of increment (modified Fibonacci method vs. others) and presence of expansion of cohort at the phase-II-recommended dose. Cox model analysis retained one determinant: starting dose justified by animal toxicology data: HR = 2.00 [1.45–5.20], p = 0.047. Conclusion Few parameters influence the accrual time of dose-escalation phase-1 trials. Real first-in-man phase 1 studies based on starting dose estimated from animal toxicological data require longer accrual time.

Introduction In Western countries, the number of frail elderly people with metastatic melanoma (MM) keeps increasing. Conventional chemotherapy frequently induces imbalance in frail physiological cases. We propose to treat these patients with oral metronomic cyclophosphamide. Patients and methods This retrospective study analyses the data of patients with unresectable MM who received 50 to 100 mg of cyclophosphamide a day, 3 weeks out of 4. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and overall survival. Results Thirteen patients were included (median age: 80, 5 AJCC stage III and 8 AJCC stage IV). Clinical and biological safety were good, leading to long home staying and rare treatment discontinuations. Main toxicity observed was lymphopenia; no opportunist infection occurred. The control rate was 46%: one partial response and five stable diseases (median: 10 months). Survival after beginning of treatment ranged from 4 to 37 months (median: 8 months). Discussion Literature about MM in frail elderly is limited. Still, specific treatment is necessary. Cyclophosphamide in metronomic schema was well tolerated. The response rate was difficult to assess (small population) but several patients presented with long lasting stabilisation. The mechanisms of action of this treatment are original, associating antiangiogenic action and immunomodulation. Conclusion Cyclophosphamide in metronomic schema showed good safety results for this frail population. Oral treatment enabled patients to stay at home longer and limited hospitalisation time. A larger controlled study will be necessary to confirm these encouraging results in elderly with MM, a classical chemoresistant tumor.

The aim of this study was to determine which parameter may affect impact factor (IF) of journals publishing reports of phase II trial (P2T) investigating molecular targeted therapies (MTT). We reviewed 74 reports of P2Ts investigating MTT (imatinib, n = 55; sorafenib, n = 11; sunitinib, n = 5; dasatinib, n = 3) issued between 1/2002 and 6/2008. As a result, we found that the final result of the trial itself was the most important parameter that was related to IF, as the median-IF was significantly lower for negative trials than for positive trials (2.71 vs 6.14, p = 0.004).

Malignant solitary fibrous tumors are rare soft-tissue sarcomas. They are considered as low-grade malignancies, but may display metastatic potential in 20% of the cases. In case of metastatic or locally advanced, unresectable disease, standard treatments, like anthracycline-based regimens, are poorly effective. Previous studies suggested that antiangiogenic drugs, such as sorafenib, could be efficient to treat vascular sarcomas and solitary fibrous tumors. Five patients with progressive SFT were included in this phase 2 study, and treated with sorafenib at a dose of 800 mg daily. Two patients out of the five achieved a 9 months disease control with sorafenib, while their disease had progressed within the month preceding their inclusion. Consequently, our data suggest a potential efficacy of sorafenib in SFT, Further investigation is needed to confirm these data.