Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials

Bachelot, Thomas; Ray‐Coquard, Isabelle; Catimel, G.; Ardiet, C; Guastalla, Jean‐Paul; Dumortier, A; Chauvin, Franck; Jp, Droz; Philip, Thierry; Clavel, M.

doi:10.1023/a:1008368319526

Cited by 108 publications

(120 citation statements)

References 20 publications

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“…Another study, which analysed 154 patients over an 8-year period, identified two independent risk factors, namely LDH 4600 IU and PS 41, which were correlated with a shorter 90-day OS for patients with both factors. The authors recommended that patients with these risk factors should not participate in a phase I trial (Bachelot et al, 2000). Interestingly, this study also revealed that patients X65 years had a significantly better OS than younger patients in keeping with our findings.…”

Section: Discussionsupporting

confidence: 90%

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

et al. 2008

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The main aim of phase I trials is to evaluate the tolerability and pharmacology of a new compound. However, investigating the potential for clinical benefit is also a key objective. Our phase I trial portfolio incorporates a range of new drugs, including molecular targeted agents, sometimes given together with cytotoxic agents. We performed this analysis of response rate, progression-free (PFS) and overall survival (OS) to assess the extent of clinical benefit rate (CBR: partial response (PR) þ stable disease (SD)) derived from current trials. We analysed 212 consecutive patients who were treated in 29 phase I studies, from January 2005 to June 2006. All patients had progression of disease prior to study entry. The median age was 58 years (range: 18 -86) with a male/female ratio of 2 : 1. A total of 148 patients (70%) were treated in 'first in human trials' involving biological agents (132 patients) or new cytotoxic compounds (16 patients) alone, and 64 patients (30%) received chemotherapy-based regimens with or without biological agents. After a median follow-up time of 34 weeks, the median PFS and OS were 11 and 43 weeks, respectively. The CBR was 53% (9% PR and 44% SD) after the first tumour evaluation after two cycles (between weeks 6 and 8) and has been maintained at 36 and 26% at 3 and 6 months, respectively. Treatment related deaths occurred in 0.47% of our patients and treatment had to be withdrawn in 11.8% of patients due to toxicity. A multivariate analysis (MVA) of 13 factors indicated that low albumin (o35 g l À1 ), lactate dehydrogenase4upper normal limit and 42 sites of metastasis were independent negative prognostic factors for OS. A risk score based on the MVA revealed that patients with a score of 2 -3 had a significantly shorter OS compared to patients with a score of 0 -1 (24.9 weeks, 95% CI 19.5 -30.2 vs 74.1 weeks, 95% CI 53.2 -96.2). This analysis shows that a significant number of patients who develop disease progression while receiving standard therapy derived benefit from participation in phase I trials. Risk scoring based on objective clinical parameters indicated that patients with a high score had a significantly shorter OS, and this may help in the process of patient selection for phase I trial entry.

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Section: Discussionsupporting

confidence: 90%

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

et al. 2008

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“…cyclophosphamide, methotrexate and infusional 5-FU; 5-FU, folinic acid and interferon). Subanalysis of response rates in the phase I studies of novel CT drugs, excluding these two trials, still showed a partial response rate of 10.3%, which is higher than many previous reports (Estey et al, 1986;Decoster et al, 1990;Bachelot et al, 2000;Sekine et al, 2002). Several of these drugs were new selective topoisomerase inhibitors and would be predicted to have antitumour activity.…”

Section: Discussionmentioning

confidence: 67%

“…Despite the emphasis on evaluation of side effects, and determination of a maximum tolerated dose (MTD), tumour responses remain an important secondary end point. Reported response rates for phase I trials are generally between 1 and 10% (Estey et al, 1986;Decoster et al, 1990;Bachelot et al, 2000) with most responses seen at 80 -120% of the recommended phase II dose (Von Hoff and Turner, 1991). Cytotoxic drugs that do not show antitumour activity in phase I trials rarely undergo further evaluation (Von Hoff and Turner, 1991;American Society of Clinical Oncology, 1997;Sekine et al, 2002).…”

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confidence: 99%

“…Dosage level and age over 65 years are independently associated with grade 3 or 4 toxicity (Bachelot et al, 2000). Poor performance status (WHO grade 2 or 3) (Janisch et al, 1994;Bachelot et al, 2000), elevated lactate dehydrogenase (Bachelot et al, 2000), lower albumin, elevated platelet counts and previous cisplatin therapy (Janisch et al, 1994) have all been identified as independent adverse prognostic variables. Analyses have mostly been limited by small sample sizes and have not compared cytotoxic (CT) with non-cytotoxic (non-CT) drugs.…”

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confidence: 99%

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Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents

et al. 2003

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The aims of this study were to identify prognostic variables for toxicity and survival in patients with cancer participating in phase I clinical trials and compare characteristics of those treated with cytotoxic chemotherapy (CT) and non-cytotoxic drugs (non-CT). Data were collected from 420 (114 CT, 306 non-CT) patients enrolled in 16 phase I trials (five CT and 11 non-CT trials) in one cancer centre. Analyses of all patients were used to compare treatment groups, identify predictive variables for toxicity and to estimate prognostic factors in overall survival (OS). These were used to develop a prognostic index (PI). Multivariate analysis found those patients with better performance status, fewer sites of metastases, baseline Hb412 g dl À1 and WBC or LDH in the normal range had significantly better OS. Male gender, platelet count o450 Â 10 9 l À1 , high WBC or treatment with a non-CT phase I agent significantly reduced the chance of grade 3/4 toxicity. Overall survival was not significantly different between the CT and non-CT groups (260 vs 192 days, P ¼ 0.47) except for those with liver metastases (228 vs 137 days, P ¼ 0.02). Overall tumour response was 4.9% (95% CI: 2.7 -7.0%). The PI identified three distinct patient groups with median survival of 321, 257 and 117 days. In conclusion, entry into a phase I trial of a non-CT drug is a safe option for heavily pretreated patients with cancer. The PI generated from these data can estimate the survival probability for patients entering phase I studies.

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“…For these patient-subjects, there is generally little hope left for remission of disease. Phase I oncology research often involves measurement of pharmacokinetics as part of the assessment of the dosage effects, and in addition, trials of molecularly targeted agents may measure specific biochemical parameters relevant to the action of the drug, such as metabolite levels that indicate whether the specific drug effect has been achieved on a molecular level (29,30). Phase I research for new chemotherapeutic agents is often conducted with a dose-escalation design, whereby the first patient-subjects receive low doses of the new agent, and dosage is progressively increased as new patients are enrolled (31).…”

Section: Fertility and Sterilitymentioning

confidence: 99%

Safety issues in cell-based intervention trials

Dawson

Bateman-House

Agnew

et al. 2003

Fertility and Sterility

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We report on the deliberations of an interdisciplinary group of experts in science, law, and philosophy who convened to discuss novel ethical and policy challenges in stem cell research. In this report we discuss the ethical and policy implications of safety concerns in the transition from basic laboratory research to clinical applications of cell-based therapies derived from stem cells. Although many features of this transition from lab to clinic are common to other therapies, three aspects of stem cell biology pose unique challenges. First, tension regarding the use of human embryos may complicate the scientific development of safe and effective cell lines. Second, because human stem cells were not developed in the laboratory until 1998, few safety questions relating to human applications have been addressed in animal research. Third, preclinical and clinical testing of biologic agents, particularly those as inherently complex as mammalian cells, present formidable challenges, such as the need to develop suitable standardized assays and the difficulty of selecting appropriate patient populations for early phase trials. We recommend that scientists, policy makers, and the public discuss these issues responsibly, and further, that a national advisory committee to oversee human trials of cell therapies be established. (Fertil Steril 2003;80:1077-85.

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Multivariable analysis of prognostic factors for toxicity and survival for patients enrolled in phase I clinical trials

Abstract: Subgroups with different survival expectancy can be identified among patients who are eligible for phase I clinical trials. If confirmed, the proposed prognostic model may be useful for therapeutic decision making in palliative oncology.

Cited by 108 publications

References 20 publications

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

Clinical outcome and prognostic factors for patients treated within the context of a phase I study: the Royal Marsden Hospital experience

Comparison of prognostic factors in patients in phase I trials of cytotoxic drugs vs new noncytotoxic agents

Safety issues in cell-based intervention trials

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