Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905)

Our plain-English summary of Phase I Trial of Cediranib in Combination with Cisplatin and Pemetrexed in Chemonaive Patients with Unresectable Malignant Pleural Mesothelioma (SWOG S0905), by A.S. Tsao, J. Moon, I.I. Wistuba, et al (Journal of Thoracic Oncology, 2017).

The study

• Authors: A.S. Tsao, J. Moon, I.I. Wistuba, N.J. Vogelzang, G.P. Kalemkerian, M.W. Redman, D.R. Gandara, K. Kelly
• Journal: Journal of Thoracic Oncology
• Published: 2017;12(8):1299-1308
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: In malignant pleural mesothelioma, targeting angiogenesis with cediranib, a vascular endothelial growth factor receptor and platelet-derived growth factor receptor inhibitor, may have therapeutic potential.

Methods: S0905 phase I combined cediranib (two dose cohorts [30 mg and 20 mg daily]) with cisplatin-pemetrexed for six cycles followed by maintenance cediranib in unresectable chemonaive patients with malignant pleural mesothelioma of any histologic subtype. The primary end point established the maximum tolerated dose in combination with cisplatin-pemetrexed in a dose deescalation scheme.

Results: A total of 20 patients were enrolled (seven to the 30-mg cohort and 13 to the 20-mag cohort). In the cediranib 30-mg cohort, two of the initial six patients reported dose-limiting toxicities and the dose was deemed too toxic to continue. In the next cohort, two patients experienced dose-limiting toxicities, and thus, the maximum tolerated dose of cediranib was established as 20 mg. During the six cycles of cisplatin-pemetrexed-cediranib, 20 mg, there were grade 3 toxicities (neutropenia and gastrointestinal) and grade 4 thrombocytopenia. No patients had any significant episodes of bleeding. According to the Response Evaluation Criteria in Solid Tumors (n = 17 evaluable patients), the median progression-free survival was 12.8 months (95% confidence interval [CI]: 6.9-17.2); according to the Modified Response Evaluation Criteria in Solid Tumors (n = 19 evaluable patients), the median progression-free survival was 8.6 months (95% CI: 6.1-10.9). For all patients, the disease control rate at 6 weeks was 90% and median overall survival time was 16.2 months (95% CI: 10.5-28.7).

Conclusions: Cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The phase II S0905 trial will evaluate the efficacy of the triplet regimen compared with the current standard of care, cisplatin-pemetrexed.

Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This phase I trial added a drug called cediranib to standard cisplatin-pemetrexed chemotherapy in 20 adults with malignant pleural mesothelioma. Their disease could not be surgically removed, and none had received chemotherapy before. They were enrolled from March 2010 to July 2011. The study did not look at asbestos exposure. Its main aim was to find the highest tolerable daily dose of cediranib. At 30 mg (7 patients), two of the first six evaluable patients had dose-limiting side effects: grade 3 fatigue, in one case together with grade 3 diarrhea. The investigators judged that dose too difficult to continue. At 20 mg (13 patients), two patients had dose-limiting side effects, so 20 mg became the maximum tolerated dose. In the 20 mg group, two patients had grade 4 low platelet counts, none had significant bleeding, and one death was attributed to treatment. Across all 20 patients, median overall survival was 16.2 months (95% confidence interval 10.5 to 28.7). The authors concluded that the combination had a reasonable toxicity profile and preliminary promising efficacy. They noted that the study was small and the patients highly selected.

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: Phase I, limited dose de-escalation clinical trial (the phase I portion of the SWOG S0905 phase I/II trial) testing two doses of cediranib with cisplatin-pemetrexed
• Who was studied: 20 adults with histologically confirmed, unresectable malignant pleural mesothelioma of any subtype and no prior systemic therapy, enrolled at SWOG member sites from March 15, 2010 to July 18, 2011: 7 in the 30 mg cohort and 13 in the 20 mg cohort
• Exposure: Asbestos exposure was not studied. The treatment was cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 intravenously every 3 weeks for 6 cycles, plus daily oral cediranib (30 mg or 20 mg), followed by maintenance cediranib.
• Main results:
  • 30 mg cohort: two of the initial 6 evaluable patients had dose-limiting toxicities, one from grade 3 fatigue and one from grade 3 fatigue and grade 3 diarrhea. Both were dose reduced.
  • 20 mg cohort: two patients had dose-limiting toxicities in cycle 1 (grade 3 dehydration and grade 3 hyponatremia), and 20 mg was set as the maximum tolerated dose.
  • 20 mg cohort, over the 6 cycles of combined therapy: two episodes of grade 4 thrombocytopenia were reported, and no patients had significant bleeding.
  • 20 mg cohort: one treatment-related death, in a patient suspected of having a septic event from pneumonia after 3 cycles of the triplet therapy.
  • 30 mg cohort, over all 6 cycles: five of 7 patients (71%) had grade 3 adverse events.
  • All patients, RECIST 1.1 (17 of 20 evaluable for response): response rate 24% (95% CI 3% to 44%); median progression-free survival 12.8 months (95% CI 6.9 to 17.2).
  • All patients, modified RECIST (19 measurable): response rate 63% (95% CI 41% to 85%); median progression-free survival 8.6 months (95% CI 6.1 to 10.9).
  • All 20 patients: disease control rate 90% (95% CI 77% to 100%); median overall survival 16.2 months (95% CI 10.5 to 28.7).
  • By cohort, median overall survival was 16.2 months (95% CI 7.5 to 28.7) in the 30 mg cohort and 13.6 months (95% CI 12.0 to 26.8) in the 20 mg cohort.
• The authors' conclusion: The authors concluded that cediranib combined with cisplatin-pemetrexed has a reasonable toxicity profile and preliminary promising efficacy. The randomized phase II portion of the trial will compare it with cisplatin-pemetrexed alone.
• Limitations the authors state:
  • The sample size was small and the patients were highly selected.

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: Cisplatin, Pemetrexed (Alimta), Unresectable, Pleural Mesothelioma, Angiogenesis, Platelet-Derived Growth Factor (PDGF), Histological Subtype, Neutropenia.

Related studies

• 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)
• 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)
• A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma — A.K. Nowak, A.M. Cook, et al. (2015)
• Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509 — L.L. Garland, K. Chansky, et al. (2011)
• A Phase II Trial of First-Line Combination Chemotherapy With Cisplatin, Pemetrexed, and Nivolumab for Unresectable Malignant Pleural Mesothelioma: A Study Protocol — N. Fujimoto, K. Aoe, et al. (2018)
• Tumour Treating Fields in combination with pemetrexed and cisplatin or carboplatin as first-line treatment for unresectable malignant pleural mesothelioma (STELLAR): a multicentre, single-arm phase 2 trial — G.L. Ceresoli, J.G. Aerts, et al. (2019)

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