A qualitative study evaluating causality attribution for serious adverse events during early phase oncology clinical trials

Mukherjee, Som D.; Coombes, Megan; Levine, Mark; Cosby, Jarold; Kowaleski, Brenda; Arnold, Andrew

doi:10.1007/s10637-010-9456-9

Cited by 18 publications

(22 citation statements)

References 28 publications

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“…Nevertheless, there was high predictive ability for phase I trials to identify clinically relevant toxicities. Attribution of toxicities to experimental agents is also not straightforward in phase I trials and errors are frequent in early trials (18). Interestingly, toxicities easily attributable to experimental drugs, such as hand-foot syndrome, neurotoxicity, peripheral neuropathy, neutropenia, and mucositis, were most concordant when comparing top 3 grade 3 and 4 toxicities between early and later trials.…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Jardim

Hess

LoRusso

et al. 2014

Clinical Cancer Research

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Phase I trials use a small number of patients to define a maximum tolerated dose (MTD) and the safety of new agents. We compared data from phase I and registration trials to determine whether early trials predicted later safety and final dose. We searched the U.S. Food and Drug Administration (FDA) website for drugs approved in nonpediatric cancers (January 1990-October 2012. The recommended phase II dose (R2PD) and toxicities from phase I were compared with doses and safety in later trials. In 62 of 85 (73%) matched trials, the dose from the later trial was within 20% of the RP2D. In a multivariable analysis, phase I trials of targeted agents were less predictive of the final approved dose (OR, 0.2 for adopting AE 20% of the RP2D for targeted vs. other classes; P ¼ 0.025). Of the 530 clinically relevant toxicities in later trials, 70% (n ¼ 374) were described in phase I. A significant relationship (P ¼ 0.0032) between increasing the number of patients in phase I (up to 60) and the ability to describe future clinically relevant toxicities was observed. Among 28,505 patients in later trials, the death rate that was related to drug was 1.41%. In conclusion, dosing based on phase I trials was associated with a low toxicity-related death rate in later trials. The ability to predict relevant toxicities correlates with the number of patients on the initial phase I trial. The final dose approved was within 20% of the RP2D in 73% of assessed trials.

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Section: Discussionmentioning

confidence: 99%

Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Jardim

Hess

LoRusso

et al. 2014

Clinical Cancer Research

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“…This finding suggests reluctance on the part of treating physicians to more definitely attribute a particular toxicity as drug related, even when the impact at the study level (ie, in what constitutes a DLT) would be the same. This finding may also reflect caution on the part of physicians; when physicians are uncertain about drug causality, they may call it ‘possibly’ related for safety reasons, knowing that ‘possibly’ related will ultimately be counted as related by standard clinical convention on Phase I studies [12]. By comparison, similar numbers of toxicities were attributed as ‘unrelated’ (27%) and ‘unlikely’ (27%) related, suggesting that physicians are not similarly hesitant to definitely attribute toxicities as unrelated to the study drug.…”

Section: Discussionmentioning

confidence: 99%

Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities

Eaton

Iasonos

Gounder

et al. 2016

Clinical Cancer Research

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Background Phase I studies rely on investigators to accurately attribute of adverse events as related or unrelated to study drug. This information is ultimately used to help establish a safe dose. Patterns of physician attribution in the Phase I setting have not been widely studied and assessing the accuracy of attribution is complicated by the lack of a gold standard. We examined dose-toxicity relationships as a function of attribution and toxicity category to evaluate for evidence of toxicity misattribution. Methods Individual patient records from 38 Phase I studies activated between 2000-2010 were used. Dose was defined as percent of maximum dose administered on each study. Relationships between dose and patient-level toxicity were explored graphically and with logistic regression. All p-values were two-sided. Results 11,909 toxicities from 1,156 patients were analyzed. Unrelated toxicity was not associated with dose (p=0.0920 for grade ≥3, p=0.4194 for grade ≥1) while related toxicity increased with dose (p<0.0001, both grade ≥3 and ≥1). Similar results were observed across toxicity categories. In the 5-tier system, toxicities attributed as ‘possibly’, ‘probably’, or ‘definitely’ related were associated with dose (all p<0.0001) while toxicities attributed as ‘unlikely’, or ‘unrelated’ were not (all p>0.1). Conclusions Reassuringly, we did not observe an association between unrelated toxicity rate and dose, an association which could only have been explained by physician misattribution. Our findings also confirmed our expectation that related toxicity rate increases with dose. Our analysis supports simplifying attribution to a 2-tier system by collapsing ‘possibly’, ‘probably’, and ‘definitely’ related.

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“…When a patient on a clinical trial experiences a DLT or a serious adverse event, the investigator must determine whether the event is attributable to the investigational drug or not. A recent qualitative study evaluating causality assessment during early-phase oncology trials found that it is a complex process, often without complete clinical and investigational data available to the investigator [26]. In early-phase oncology clinical trials (phase I), the toxicities of the study medication are frequently not well characterized, and often occur in the context of advanced cancer and multiple co-morbidities.…”

Section: Discussionmentioning

confidence: 99%

“…It is not always possible to assess the contributions of a new agent to toxicity. Investigators may follow a “precautionary principle” and err on the side of caution by attributing the toxicity to the study drug [26]. That a potentially active new agent is labeled toxic and not studied further, is a risk taken in order to assure patient safety.…”

Section: Discussionmentioning

confidence: 99%

Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors

Speranza

Gutierrez

Kummar

et al. 2011

Cancer Chemother Pharmacol

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Background The triterpenoid 2-Cyano-3, 12-Dioxoolean-1, 9-Dien-28-Oic Acid (CDDO, previously RTA-401) is a multifunctional molecule that controls cellular growth and differentiation. It is capable of activating the transcription factor peroxisome proliferator activator receptor-γ (PPARγ) and inducing apoptosis in malignant cells in vitro and in vivo. We conducted a phase I dose-escalation study to determine the toxicity, the maximum tolerated dose, and the pharmacokinetics and pharmacodynamics of CDDO, administered as a 5-day continuous infusion every 28 days in patients with advanced cancers. Methods An accelerated titration design was followed, with one patient per cohort entered, and doses ranging from 0.6 mg/m2/hr to 38.4 mg/m2/hr. Pharmacokinetics of CDDO was assessed and cleaved poly (ADP-ribose) polymerase (c-PARP), as a marker of apoptosis, was measured in peripheral blood mononuclear cells to assess drug effect. Results Seven patients, one patient per dose level up to dose level 7 (38.4 mg/m2/hr), were enrolled and received a total of 11 courses of treatment. Cmax increased proportionally with dose. Preclinically determined efficacious blood level (1 μM) of drug was attained at the highest dose level. One patient, at dose level 6, experienced grade 2 mucositis, nausea, vomiting, and anorexia. Four patients, on different dose levels, developed thromboembolic events subsequently considered as dose-limiting toxicity. No anti-tumor activity was noted. Conclusion A causal relationship of observed thromboembolic events to CDDO was considered possible but could not be established. Because of the adverse events and the development of an orally bioavailable derivative compound, CDDO methyl ester, this trial was terminated.

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A qualitative study evaluating causality attribution for serious adverse events during early phase oncology clinical trials

Cited by 18 publications

References 28 publications

Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Predictive Value of Phase I Trials for Safety in Later Trials and Final Approved Dose: Analysis of 61 Approved Cancer Drugs

Toxicity Attribution in Phase I Trials: Evaluating the Effect of Dose on the Frequency of Related and Unrelated Toxicities

Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors

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