Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma

Our plain-English summary of Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma, by L.M. Krug, A.J. Wozniak, H.L. Kindler, et al (Lung Cancer, 2014).

The study

• Authors: L.M. Krug, A.J. Wozniak, H.L. Kindler, R. Feld, M. Koczywas, J.L. Morero, C.P. Rodriguez, H.J. Ross, J.E. Bauman, S.V. Orlov, J.C. Ruckdeschel, A.C. Mita, L. Fein, X. He, R. Hall, T. Kawabe, S. Sharma
• Journal: Lung Cancer
• Published: 2014;85(3):429-34
• Type of article: Randomized trial
• Cited by: 27 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin.

Methods: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months.

Results: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501.

Conclusions: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

In plain English

This randomized, open-label phase II trial enrolled people not previously treated with chemotherapy whose malignant pleural mesothelioma could not be surgically removed. It did not study asbestos exposure. At 14 international sites from October 2008 to October 2011, 65 patients were randomized two-to-one to standard chemotherapy (pemetrexed and cisplatin) plus an experimental drug, CBP501 (Arm A), or chemotherapy alone (Arm B); 63 were treated. On independent scan review, 25 of 40 patients (63%) in Arm A and 9 of 23 (39%) in Arm B lived at least 4 months without disease progression; Arm A met the trial's main goal. Median overall survival was 13.3 months (95% confidence interval 9.2 to 16.3) in Arm A and 12.8 months (6.5 to 16.1) in Arm B. Infusion reactions occurred in 70% of patients given CBP501; other side effects were generally comparable between arms. The authors concluded that adding CBP501 does not appear to improve outcomes over those expected with chemotherapy alone. They noted the trial was not powered to compare the arms directly and the control arm did worse than expected.

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: Randomized (2:1), open-label phase II clinical drug trial, preceded by a small dose-finding lead-in study
• Who was studied: Patients with unresectable, previously untreated malignant pleural mesothelioma of any subtype. Peritoneal mesothelioma was excluded. 65 patients were randomized and 63 treated (40 in Arm A, 23 in Arm B), accrued at 14 international sites from October 2008 to October 2011.
• Exposure: This is not an asbestos exposure study, and the article does not discuss asbestos. The intervention was CBP501 25 mg/m2 IV plus pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) every three weeks, compared with pemetrexed and cisplatin alone.
• Main results:
  • By independent radiology review of treated patients, 25/40 (63%) in Arm A (chemotherapy plus CBP501) and 9/23 (39%) in Arm B (chemotherapy alone) were progression-free at 4 months or longer.
  • By independent review, median progression-free survival was 5.1 months (95% CI 3.9, 6.5) in Arm A versus 3.4 months (2.5, 6.7) in Arm B.
  • By investigator assessment, 27/40 (68%) in Arm A and 13/23 (57%) in Arm B were progression-free at 4 months or longer.
  • Median overall survival was 13.3 months (95% CI 9.2, 16.3) in Arm A and 12.8 months (6.5, 16.1) in Arm B.
  • Among response-evaluable patients, on independent review, the objective response rate was 31% (17.0, 47.6) in Arm A and 10% (1.2, 31.7) in Arm B. The disease control rate was 69% (52.4, 83.0) in Arm A and 60% (36.1, 80.9) in Arm B.
  • Infusion-related reactions occurred in 70% of patients treated with CBP501 and in none of those given chemotherapy alone. No grade 3 or 4 infusion reactions occurred.
  • Toxicities of grade 3 or higher occurred with similar frequency in the two arms (53% in Arm A versus 57% in Arm B).
• The authors' conclusion: The authors concluded that, although the trial met its primary endpoint of progression-free survival at 4 months, adding CBP501 to standard chemotherapy does not appear to improve outcomes over those expected with chemotherapy alone in mesothelioma.
• Limitations the authors state:
  • The trial was underpowered to compare the CBP501 arm with the control arm.
  • The control arm did worse than expected. The authors call this a potential confounding factor whose cause is unknown.
  • Investigator assessment of progression and response could have been biased by the open-label design.
  • Serum mesothelin was assessed in only a minority of patients, because it was collected only from U.S. patients and because of technical issues.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pemetrexed (Alimta), Cisplatin, Pleural Mesothelioma, Clinical Trial, Ovarian Cancer, Mesothelioma, Chemotherapy, Unresectable.

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• Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma — A.S. Tsao, N. Harun, et al. (2014)
• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905) — A.S. Tsao, J. Moon, et al. (2017)

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