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Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose.

ABSTRACT: BACKGROUND:In the era of molecularly targeted agents (MTAs), it is recommended to account for toxicity over several cycles to identify the recommended phase II dose (RP2D). We investigated the relationship between the risk of toxicity at cycle 1 and the cumulative incidence of toxicity over subsequent cycles in trials of single MTAs. METHODS:On individual patient data from 26 phase I clinical trials of single MTAs provided by the National Cancer Institute, we estimated the probability of first-severe toxicity per treatment cycle as well as the cumulative incidence at, below, and above the maximum tolerated dose (MTD). Toxicity was further subclassified into nonhematologic and hematologic. A prediction table was developed to estimate the cumulative incidence up to six cycles based on the toxicity rate observed in the first cycle. RESULTS:Overall, 942 patients were included. For patients treated at the MTD, the probability of first-severe toxicity decreased from 24.8% (95% prediction interval [PI] = 20.3% to 32.9%) to 2.2% (95% PI = 0.1% to 7.7%) from cycle 1 to 6, whereas the cumulative incidence of toxicity reached 51.7% (95% PI = 40.5% to 66.3%) after six cycles. Toxicity rates ranging from 20.0% to 30.0% in the first cycle were associated with 46.8% (95% PI = 39.5% to 54.2%) and 65.8% (95% PI = 57.7% to 73.1%) cumulative incidence after six cycles. CONCLUSION:This study examined the risk of severe toxicity over time of single MTAs. The cumulative incidence of toxicity at the MTD was higher than the usually accepted toxicity targets, challenging the definition of the RP2D of MTAs. The prediction table may help calibrate the target rate at the RP2D.

SUBMITTER: Altzerinakou MA

PROVIDER: S-EPMC6855968 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN).DesignCross sectional study.Participants/settingGenome targeted cancer drugs recommended by NCCN guidelines in the advanced setting.Main outcome measuresMolecular target actionability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit of genome targeted oncology therapies was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT category level I associated with studies showing substantial clinical benefit by ESMO-MCBS (grades 4-5) were designated as high benefit, and those linked to studies achieving an ESMO-MCBS grade of 3 were categorized as being of promising but unproven benefit.Results411 recommendations related to 74 genome targeted drugs targeting 50 driver alterations were examined. Most recommendations (346/411; 84%) were associated with clinical trials of various phases, but 16% (65/411) relied on only case reports or pre-clinical studies. However, clinical trials mostly comprised phase I or phase II (271/346; 78%), single arm (262/346; 76%) studies. The primary endpoint assessed in most trials was overall response rate (271/346; 78%) rather than survival. ESCAT tier I targetability encompassed 60% (246/411) of target recommendations, 35% (142/411) were classified as tier II or III, and 6% (23/411) had their relevance yet to be determined (tiers IV to X). When ESMO-MCBS was applied to 267 scorable trials, only 12% (32/267) showed substantial clinical benefit (grades 4-5) and 45% (121/267) were grade 3. When both frameworks were combined, 12% (32/267) of trials supported a determination of high benefit and 33% (88/267) indicated promising but unproven benefit. Of the 118 interventions endorsed by NCCN authors as preferred, 62 (53%) applied to treatments with high or promising but unproven benefit.ConclusionAccording to the ESCAT and ESMO-MCBS frameworks, about one eighth of genome based treatments for solid cancer were rated as likely to offer a high benefit to patients, whereas around a third were identified as offering a promising but unproven substantial benefit. Ensuring that NCCN recommendations are aligned with expected clinical benefits is crucial for promoting informed, evidence based, genomic guided treatment decisions.

Project description:BACKGROUND:Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS:This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS:Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11?years (range 3-21?years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION:Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE:Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

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Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose.

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