Modelling semi-attributable toxicity in dual-agent phase I trials with non-concurrent drug administration

e13020 Background: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options. We compared prognostic factors and clinical outcomes of CC/GC pts treated on phase I trials with that of their first-, second-line and last Food and Drug Administration (FDA)-approved therapy given in setting of metastatic disease. Methods: We retrospectively reviewed electronic medical records of patients with GC and CC evaluated in the phase I program clinic from November 2004 to March 2011. Results: Of the 72 patients with CC or GC, 32 (44%) were not enrolled on a trial mainly due to clinical deterioration (n=25). Of 40 treated patients (GC=6; CC=34; median age 60 years; median prior systemic therapies = 3), 8 (20%) had stable disease (SD) > 6 months; 3 (8%) achieved a partial response (PR); SD > 6 months/PR was observed mainly on protocols with hepatic arterial infusion drug administration and/or angiogenic inhibitors, anti-her2/neu agents or a novel MAPK/ERK kinase (MEK) inhibitor. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0; p=0.95), 3.0 months (95% CI 2.3, 4.6; p=0.98), and 3.0 months (95% CI 2.4, 3.9; p=0.79) for their first-, second-, and last systemic therapy with FDA-approved agents given in the metastatic setting, respectively. In univariate analysis, factors associated with a shorter Phase I PFS were > 3 metastatic sites, elevated ALT (>56 IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL). Conclusions: In heavily pretreated patients, PFS in the clinical trials setting remained poor but did not differ significantly from that of their first-line, second-line, and last prior therapy with FDA-approved agents. Response rate (SD >6 months/PR) of 28% was seen in trials with locoregional treatment or inhibitors of angiogenesis, her2/neu or MEK.

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Predicting Successful Phase Advancement and Regulatory Approval in Multiple Myeloma From Phase I Overall Response Rates

JCO Clinical Cancer Informatics ◽

10.1200/cci.17.00055 ◽

2017 ◽

pp. 1-14 ◽

Cited By ~ 2

Author(s):

Ehsan Malek ◽

Caner Saygin ◽

Rebecca Ye ◽

Fahrettin Covut ◽

Byung-Gyu Kim ◽

...

Keyword(s):

Multiple Myeloma ◽

Drug Development ◽

Phase I ◽

Drug Administration ◽

Phase Ii ◽

Food And Drug Administration ◽

Regulatory Approval ◽

Phase I Trials ◽

Overall Response ◽

Investigational Agents

Purpose Drug development in oncology is resource intensive, time consuming, and frequently unsuccessful. Here, we hypothesized that therapeutic benefit of published phase I studies of antimyeloma investigational agents was associated with advancement to phase II and future regulatory approval. Patients and Methods Seventy four phase I trials that treated patients with multiple myeloma (n = 2,408) conducted from 2004 to 2015 were analyzed to assess drug safety, efficacy, phase advancement, and regulatory approval. Results The median overall response rate (ORR) for all single-agent trials evaluated was 13.2%. However, the ORR in trials that advanced to phase II was 19%, whereas it was only 4% in trials that failed to advance. The median ORR was 23% for trials testing agents that were ultimately approved by the US Food and Drug Administration compared with only 8% for trials testing agents that were not approved (hazard ratio, 2.21; 95% CI, 2.01 to 2.61; P = .012). Importantly, the absolute number of phase I trials in multiple myeloma, but not the success rate, significantly increased over the period studied. The proportion of industry-sponsored trials also steadily increased over that same period. The ratio of initial dose to maximum tolerated dose was 0.29, suggesting that many patients were undertreated. Conclusion Investigational agents with higher ORRs in phase I trials were more likely to advance to phase II trials and achieve US Food and Drug Administration approval. Our results suggest that designing phase I trials to maximize the antimyeloma efficacy of a given compound may lead to more successful and cost-effective drug development.

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