Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report

Our plain-English summary of Phase II study of dasatinib in patients with previously treated malignant mesothelioma (cancer and leukemia group B 30601): a brief report, by A.Z. Dudek, H. Pang, R.A. Kratzke, et al (Journal of Thoracic Oncology, 2012).

The study

• Authors: A.Z. Dudek, H. Pang, R.A. Kratzke, G.A. Otterson, L. Hodgson, E.E. Vokes, H.L. Kindler, Cancer and Leukemia Group B
• Journal: Journal of Thoracic Oncology
• Published: 2012;7(4):755-9
• Cited by: 46 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: We conducted a phase II trial of dasatinib in malignant mesothelioma (MM) patients to evaluate its toxicity and efficacy as a second-line treatment.

Methods: Patients with unresectable MM and no symptomatic effusions were given dasatinib 70 mg twice daily as part of a 28-day cycle. We also measured plasma vascular endothelial growth factor and platelet-derived growth factor b and colony stimulating factor 1 (CSF-1) and mesothelin-related protein at baseline and during therapy.

Results: Forty-six patients were enrolled in this study. Fifty percent of the first 12 patients enrolled experienced ≥grade 3 treatment-related adverse events, and therefore, the starting dose was reduced to 50 mg twice daily. Grade 3 and 4 toxicities included fatigue (11%) and pleural effusion (9%). The overall disease control rate was 32.6%, and progression-free survival at 24 weeks was 23% (95% confidence interval: 13.5-40.0%). Survival was markedly longer in patients with lower pretreatment CSF-1 levels and in patients whose CSF-1 levels decreased from baseline during therapy.

Discussion: Single-agent dasatinib has no activity in MM and is associated with pulmonary toxicities that prohibit its use in an unselected MM population.

In plain English

This phase II trial by the Cancer and Leukemia Group B tested dasatinib as second-line treatment for malignant mesothelioma not curable by surgery. The article does not discuss asbestos exposure. Forty-six patients whose disease had failed one pemetrexed-containing chemotherapy regimen enrolled from September 2007 to August 2009. Forty-three started treatment: 36 with mesothelioma of the pleura, 6 of the peritoneum and 1 elsewhere. The starting dose was 70 mg twice daily. After 23 patients had enrolled, it was lowered to 50 mg twice daily because of poor tolerance, including fatigue and pleural effusion. At 24 weeks, 23% of patients were alive without disease progression (95% confidence interval 13.5 to 40.0%), below the threshold the authors had set in advance for further study. Partial tumor shrinkage occurred in 4.7% of patients (95% CI 0.6 to 15.8%), and median overall survival was 26.1 weeks (95% CI 18.6 to 36.7). Higher levels of a blood protein, CSF-1, before treatment were associated with shorter survival. The authors concluded that dasatinib is inactive in unselected patients with previously treated mesothelioma and that its further development in this population should be precluded.

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 II single-arm clinical trial of a single drug (dasatinib), conducted by the Cancer and Leukemia Group B (study 30601)
• Who was studied: 46 patients with histologically confirmed malignant mesothelioma not amenable to curative surgery, enrolled September 15, 2007 to August 31, 2009 at multiple US institutions. All had failed one and only one pemetrexed-containing chemotherapy regimen. 3 withdrew before treatment, leaving 43 evaluable patients: 36 pleural (84.0%), 6 peritoneal (14.0%), 1 other (2.0%). Median age was 68 years (range 35 to 81).
• Exposure: The exposure studied was the drug dasatinib, an oral protein tyrosine kinase inhibitor, not asbestos. It was given in 28-day cycles at a starting dose of 70 mg twice daily. After 23 patients had enrolled, the starting dose was reduced to 50 mg twice daily. The article does not address asbestos or fiber exposure.
• Main results:
  • The 24-week progression-free survival rate (the primary endpoint) was 23% (95% CI: 13.5 to 40.0%) among the 43 treated patients.
  • No complete responses were seen. Partial responses occurred in 4.7% of patients (95% CI: 0.6 to 15.8%), stable disease in 28%, and progressive disease in 42%. The clinical benefit rate was 32.6% (95% CI: 19.1 to 48.5%).
  • Median progression-free survival was 9.1 weeks (95% CI: 7.4 to 16.9) and median overall survival was 26.1 weeks (95% CI: 18.6 to 36.7), with a 1-year survival rate of 25.6%.
  • The most common grade 3 and 4 non-blood side effects were fatigue (11%), pleural effusion (9%) and shortness of breath, called dyspnea (7.5%). Six of the first 12 patients had grade 3 adverse events.
  • Grade 3 toxicities were more frequent in patients receiving 70 mg (52%) than in those receiving 50 mg (39%). Overall survival and progression-free survival did not differ between patients treated with the initial and the reduced dose (p = 0.68 and p = 0.82).
  • A higher pretreatment level of CSF-1 (colony stimulating factor 1) was associated with shorter overall survival (HR = 1.63, 95% CI: 1.01 to 2.64; p = 0.046; n = 36). A decrease in CSF-1 from baseline to the end of cycle 2 was associated with longer progression-free survival (HR = 6.67, 95% CI: 1.13 to 39.4; p = 0.037; n = 11), with a median PFS of 25 weeks in these patients. No other biomarker associations were observed.
• The authors' conclusion: The authors concluded that dasatinib is inactive in unselected patients with previously treated unresectable mesothelioma. Because of its lack of activity and unfavorable toxicity, they said its further development should be precluded in an unselected mesothelioma population. They suggested that selecting tumors with markers of sensitivity might be a more successful strategy in future studies.

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, Unresectable, Platelet-Derived Growth Factor (PDGF), Mesothelin, Pleural Effusion, Progression-Free Survival, confidence interval.

Related studies

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• Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107) — T. Jahan, L. Gu, et al. (2012)
• A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group — S.A. Laurie, D. Hao, et al. (2017)
• Phase 2 study of sorafenib in malignant mesothelioma previously treated with platinum-containing chemotherapy — S. Papa, S. Popat, et al. (2013)
• Validation of Progression-Free Survival as a Surrogate Endpoint for Overall Survival in Malignant Mesothelioma: Analysis of Cancer and Leukemia Group B and North Central Cancer Treatment Group (Alliance) Trials — X. Wang, X. Wang, et al. (2017)
• A phase II study of sorafenib in malignant mesothelioma: results of Cancer and Leukemia Group B 30307 — S. Dubey, P.A. Jänne, et al. (2010)

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