Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium

Our plain-English summary of Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium, by N.P. Campbell, R. Kunnavakkam, N. Leighl, et al (Lung Cancer, 2012).

The study

• Authors: N.P. Campbell, R. Kunnavakkam, N. Leighl, M.D. Vincent, D.R. Gandara, M. Koczywas, B.J. Gitlitz, E. Agamah, S.P. Thomas, W.M. Stadler, E.E. Vokes, H.L. Kindler
• Journal: Lung Cancer
• Published: 2012;78(1):76-80
• Cited by: 50 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3.

Methods: We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily.

Results: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024).

Conclusion: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

In plain English

This phase II trial at 9 centers tested cediranib, an oral drug blocking signals from VEGF, a protein involved in tumor blood-vessel growth. It enrolled 51 patients with malignant mesothelioma not removable by surgery who had received at most one earlier chemotherapy regimen. Most tumors were pleural (94%). The study did not examine asbestos exposure. Patients started at 45 mg daily, but because of side effects the starting dose was lowered to 30 mg in June 2007. Of 50 patients evaluated, 5 (10%) had a partial response and 17 (34%) had stable disease. Disease control was 67% at the 45 mg starting dose and 34% at 30 mg (p = 0.04). Median overall survival was 4.4 months (95% confidence interval 0.9 to 41.7), and the one-year survival rate was 15%. At least one severe (grade 3 or higher) side effect occurred in 87% of the 45 mg group and 43% of the 30 mg group. The authors concluded that the trial did not meet its response goal and that the higher dose was poorly tolerated.

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: multi-center phase II drug trial (single-arm; Simon optimal two-stage design) with objective response rate as the primary endpoint
• Who was studied: 51 patients with malignant mesothelioma not suitable for curative surgery, with at most one prior chemotherapy regimen, enrolled at 9 centers in the United States and Canada between March 2006 and September 2010. 50 were evaluable. 47 had pleural and 3 had peritoneal mesothelioma. 84% were male, and the median age was 64.
• Exposure: Not an asbestos exposure study. The treatment studied was cediranib taken orally once daily in 28-day cycles. 15 patients started at 45 mg daily and 35 started at 30 mg daily after the starting dose was lowered because of toxicity.
• Main results:
  • 5 of 50 patients (10%) had a partial response, lasting a median of 6.5 months
  • Partial response was seen in 20% of patients starting at 45 mg and 6% of those starting at 30 mg. This difference was not statistically significant (p = 0.12).
  • 17 patients (34%) had stable disease as their best response
  • Disease control (partial response plus stable disease) was 44% overall: 67% in the 45 mg starting-dose group and 34% in the 30 mg group (p = 0.04)
  • Among all patients, median progression-free survival was 1.8 months (95% CI 0.1 to 14.2 months)
  • Among all patients, median overall survival was 4.4 months (95% CI 0.9 to 41.7 months), and the one-year survival rate was 15%
  • At least one grade 3 or greater side effect occurred in 87% of patients starting at 45 mg and 43% of those starting at 30 mg (p = 0.002). Fatigue and hypertension were the most common side effects.
  • Stopping cediranib because of side effects occurred in 47% of the 45 mg starting-dose group and 17% of the 30 mg group (p = 0.05)
  • Patients who developed grade 3 or 4 high blood pressure had a median overall survival of 8.5 months, compared with 4.1 months for other patients (p = 0.024)
• The authors' conclusion: The authors concluded that the trial did not meet its pre-specified response endpoint. The 45 mg starting dose gave better disease control but was poorly tolerated. The authors advocated looking beyond VEGF inhibition toward other molecular targets in future mesothelioma trials.

Topics

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

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Tyrosine Kinase Inhibitor, Unresectable, Chemotherapy, Progression-Free Survival, Median Overall Survival.

Related studies

• 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)
• Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509 — L.L. Garland, K. Chansky, et al. (2011)
• Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107) — T. Jahan, L. Gu, et al. (2012)
• Pharmacogenetically driven patient selection for a first-in-human phase I trial of batracylin in patients with advanced solid tumors and lymphomas — S. Kummar, M.E. Gutierrez, et al. (2013)
• Tremelimumab as second-line or third-line treatment in relapsed malignant mesothelioma (DETERMINE): a multicentre, international, randomised, double-blind, placebo-controlled phase 2b trial — M. Maio, A. Scherpereel, et al. (2017)
• 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)

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