First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors

Our plain-English summary of First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors, by M.J. Ratain, D. Geary, S.D. Undevia, et al (Investigational New Drugs, 2015).

The study

• Authors: M.J. Ratain, D. Geary, S.D. Undevia, C. Coronado, V. Alfaro, J.L. Iglesias, R.L. Schilsky, B. Miguel-Lillo
• Journal: Investigational New Drugs
• Published: 2015;33(4):901-10
• Cited by: 12 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

This first-in-human, phase I clinical trial was designed to determine the dose-limiting toxicities (DLTs) and the dose for phase II trials (P2D) of elisidepsin (PM02734) administered as a 30-min or as a 3-h intravenous infusion every 3 weeks (q3wk). Between March 2006 and April 2011, 53 patients with advanced malignant solid tumors were enrolled and treated with elisidepsin on the two different q3wk infusion schedules: 22 (30-min) and 31 (3-h), respectively. Doses evaluated ranged from 0.1 to 1.6 mg/m(2) (30-min q3wk) and from 2.0 to 11.0 mg flat dose (FD) (3-h q3wk). In the 30-min q3wk schedule, transient grade 3/4 increases in hepatic transaminases were the DLT, which appeared at the highest doses tested (from 1.1 to 1.6 mg/m(2)). No DLTs were observed on the 3-h schedule at doses up to 11.0 mg q3wk. Common adverse events were grade 1/2 pruritus, nausea, fatigue and hypersensitivity. Of note, myelotoxicity was not observed. Plasma maximum concentration and total drug exposure increased linearly with dose. Prolonged (≥3 months) disease stabilization was observed in pretreated patients with pleural mesothelioma (n = 1) in the 30-min q3wk arm, and with colorectal adenocarcinoma (n = 3), esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma (n = 1 each) in the 3-h q3wk arm. In conclusion, elisidepsin doses of 1.1 mg/m(2) (equivalent to a FD of 2.0 mg) and 11.0 mg FD are the dose levels achieved for further phase II trials testing the 30-min q3wk and 3-h q3wk schedules, respectively.

In plain English

This first-in-human phase I trial at The University of Chicago Medical Center tested elisidepsin (PM02734), an experimental cancer drug. From March 2006 to April 2011, 53 patients with advanced solid tumors received it every three weeks: 22 by 30-minute infusion (0.1 to 1.6 mg/m2), 31 by 3-hour infusion (2.0 to 11.0 mg flat dose). Three had pleural mesothelioma; asbestos was not studied. On the 30-minute schedule, temporary liver enzyme (transaminase) rises at 1.1 to 1.6 mg/m2 were dose-limiting. None were recorded on the 3-hour schedule up to 11.0 mg, under a definition changed to exclude liver enzyme rises lasting under 14 days; two patients' grade 4 ALT increases were reclassified as not dose-limiting. Most side effects were mild to moderate, mainly itching, nausea, fatigue and hypersensitivity. No tumor shrank enough to count as a response. Disease stayed stable at least 3 months in 8 pretreated patients, including one with pleural mesothelioma per schedule. The authors concluded that 1.1 mg/m2 (equivalent to 2.0 mg) and 11.0 mg were the phase II doses. The 3-hour arm closed early for low enrollment.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: First-in-human phase I dose-escalation clinical trial at a single site, testing two infusion schedules
• Who was studied: 53 adults with advanced solid tumors for whom standard treatment was not suitable or had been used up, treated at The University of Chicago Medical Center between March 2006 and April 2011. 22 were on the 30-minute schedule and 31 on the 3-hour schedule. Most had colorectal adenocarcinoma. Pleural mesothelioma: 2 patients on the 30-minute schedule and 1 on the 3-hour schedule.
• Exposure: The experimental drug elisidepsin (PM02734), given into a vein every 3 weeks. On the 30-minute schedule, 7 dose levels from 0.1 to 1.6 mg/m2 were given. On the 3-hour schedule, 8 dose levels from 2.0 to 11.0 mg flat dose were given. No asbestos exposure was studied.
• Main results:
  • 30-minute schedule, at 1.6 mg/m2: both of the first two patients had dose-limiting liver enzyme (ALT) increases, one grade 4 and one grade 3 lasting more than 7 days.
  • 30-minute schedule, at 1.1 mg/m2: this dose had already included 5 patients without dose-limiting toxicity. Of 2 additional patients, one had a grade 4 ALT/AST increase. 1.1 mg/m2 was chosen as the phase II dose.
  • 3-hour schedule (31 patients, 2.0 to 11.0 mg flat dose): no dose-limiting toxicities were observed. This was under a definition that, for the 3-hour schedule, had been amended to exclude transaminase elevations lasting less than 14 days.
  • 3-hour schedule: two patients had grade 4 ALT increases in cycle 1. These were first considered dose-limiting toxicities but were discarded after the protocol was amended.
  • 30-minute schedule: liver enzyme increases were temporary and caused no symptoms. They returned to grade 2 or lower at a median of 15 days for ALT and 8 days for AST.
  • Both schedules: most drug-related side effects were grade 1/2. The most common were pruritus (itching), nausea, fatigue and hypersensitivity.
  • No patient's tumor shrank enough to count as an objective response. Disease stayed stable for at least 3 months in one pleural mesothelioma patient on the 30-minute arm. On the 3-hour arm it did so in 3 colorectal adenocarcinoma patients and one patient each with esophagus adenocarcinoma, endometrium adenocarcinoma, pleural mesothelioma, and head and neck carcinoma.
  • Among the 48 patients evaluable for efficacy, median progression-free survival was 1.2 months (95% CI 1.2 to 1.5 months). The progression-free rate at 3 months was 17.2%.
• The authors' conclusion: The authors concluded that 1.1 mg/m2 (equivalent to a flat dose of 2.0 mg) for the 30-minute schedule and 11 mg flat dose for the 3-hour schedule are the dose levels reached for further phase II trials. They also concluded that both schedules were generally well tolerated, with manageable toxicity.
• Limitations the authors state:
  • Dose escalation on the 3-hour schedule was stopped because of low recruitment, before a maximum tolerated dose was identified.
  • The study was conducted at only one site, which the authors say contributed to low recruitment.
  • A large amount of drug-level (pharmacokinetic) data was missing at lower doses, mainly because the blood test was not sensitive enough.
  • The high variation between patients in how fast the drug was cleared from the body could not be explained.

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Pleural Mesothelioma, Adenocarcinoma, Carcinoma.

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