A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma

Our plain-English summary of A phase 1b clinical trial of the CD40-activating antibody CP-870,893 in combination with cisplatin and pemetrexed in malignant pleural mesothelioma, by A.K. Nowak, A.M. Cook, A.M. McDonnell, et al (Annals of Oncology, 2015).

The study

• Authors: A.K. Nowak, A.M. Cook, A.M. McDonnell, M.J. Millward, J. Creaney, R.J. Francis, A. Hasani, A. Segal, A.W. Musk, B.A. Turlach, M.J. McCoy, B.W. Robinson, R.A. Lake
• Journal: Annals of Oncology
• Published: 2015;26(12):2483-90
• Cited by: 85 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background: Data from murine models suggest that CD40 activation may synergize with cytotoxic chemotherapy. We aimed to determine the maximum tolerated dose (MTD) and toxicity profile and to explore immunological biomarkers of the CD40-activating antibody CP-870,893 with cisplatin and pemetrexed in patients with malignant pleural mesothelioma (MPM).

Patients And Methods: Eligible patients had confirmed MPM, ECOG performance status 0-1, and measurable disease. Patients received cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 and CP-870,893 on day 8 of a 21-day cycle for maximum 6 cycles with up to 6 subsequent cycles single-agent CP-870,893. Immune cell subset changes were examined weekly by flow cytometry.

Results: Fifteen patients were treated at three dose levels. The MTD of CP-870,893 was 0.15 mg/kg, and was exceeded at 0.2 mg/kg with one grade 4 splenic infarction and one grade 3 confusion and hyponatraemia. Cytokine release syndrome (CRS) occurred in most patients (80%) following CP-870,893. Haematological toxicities were consistent with cisplatin and pemetrexed chemotherapy. Six partial responses (40%) and 9 stable disease (53%) as best response were observed. The median overall survival was 16.5 months; the median progression-free survival was 6.3 months. Three patients survived beyond 30 months. CD19+ B cells decreased over 6 cycles of chemoimmunotherapy (P < 0.001) with a concomitant increase in the proportion of CD27+ memory B cells (P < 0.001) and activated CD86+CD27+ memory B cells (P < 0.001), as an immunopharmacodynamic marker of CD40 activation.

Conclusions: CP-870,893 with cisplatin and pemetrexed is safe and tolerable at 0.15 mg/kg, although most patients experience CRS. While objective response rates are similar to chemotherapy alone, three patients achieved long-term survival.

Australia New Zealand Clinical Trials Registry Number: ACTRN12609000294257.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

In plain English

This was a small, single-centre, early-phase (phase Ib) drug trial in Perth, Australia, in people with malignant pleural mesothelioma who had not had previous treatment for it. Fifteen patients received standard chemotherapy (cisplatin and pemetrexed) plus an experimental antibody, CP-870,893, which activates an immune-system molecule called CD40. The main aim was to find the highest dose of the antibody that could be given safely. The authors reported this dose as 0.15 mg/kg. At 0.2 mg/kg, one patient developed hepatic vein thrombosis and splenic infarction, and another developed confusion with low blood sodium. Thirteen patients had cytokine release syndrome (rigors, fever, muscle aches, nausea, vomiting) at least once. Six patients (40%) had a partial tumour response and eight (53%) had stable disease. Median overall survival was 16.5 months (95% confidence interval 5.1 to 28.1 months), and three patients survived 44, 44 and 31 months from study start. The authors concluded that the combination at 0.15 mg/kg was tolerable and warranted a randomised trial. They noted that the study had no chemotherapy-only comparison group.

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: Prospective, single-centre, phase Ib dose-finding clinical trial (3 + 3 design with a 6-patient expansion cohort at the maximum tolerated dose); no control group
• Who was studied: Patients with confirmed malignant pleural mesothelioma, performance status 0-1, planned for first-line cisplatin/pemetrexed, at Sir Charles Gairdner Hospital, Perth, Australia. Sixteen were enrolled between March 2010 and October 2011; 15 were treated and analysed (14 male, 1 female; median age 63, range 43-70).
• Exposure: The study examined a drug treatment, not asbestos exposure. Patients received cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 of 21-day cycles, for up to 6 cycles. They received the CD40-activating antibody CP-870,893 on day 8 at 0.1, 0.2 or 0.15 mg/kg. Patients whose disease was stable or responding could continue CP-870,893 alone for up to 6 more cycles.
• Main results:
  • The maximum tolerated dose of CP-870,893 with cisplatin-pemetrexed was 0.15 mg/kg.
  • At 0.2 mg/kg, one patient developed hepatic vein thrombosis and splenic infarction after the fourth dose of study drug. A second patient had grade 3 hyponatremia (low blood sodium) with grade 3 confusion.
  • 13 of the 15 patients had cytokine release syndrome at least once. The maximum grade was 3 in 2 patients, 2 in 10 patients and 1 in 1 patient.
  • Best radiological response among the 15 patients: 6 (40%) partial response, 8 (53%) stable disease and 1 (7%) progressive disease.
  • Median overall survival was 16.5 months (95% CI 5.1 to 28.1 months). Median progression-free survival was 6.3 months (95% CI 2.3 to 10.3 months). At the time of reporting, 12 of 15 participants had died, all from mesothelioma.
  • Three patients were long-term survivors, at 44, 44 and 31 months from study start.
  • Over 6 cycles, the proportion of B cells (CD19+) among lymphocytes decreased (p less than 0.001). The proportion of memory B cells (CD27+) increased by almost 50% (p less than 0.001). The proportion of memory B cells expressing the activation marker CD86 also increased (p less than 0.001).
  • Change in serum mesothelin from baseline to its lowest level correlated with radiological response (rs = 0.587; p = 0.022). Baseline mesothelin was not associated with response or survival.
  • The authors saw no evidence that time to progression was longer than in historical data.
• The authors' conclusion: The authors concluded that cisplatin/pemetrexed with CP-870,893 at 0.15 mg/kg every 3 weeks is tolerable and shows efficacy at least that expected from chemotherapy alone. They said the combination warrants testing in a randomised clinical trial. They also suggested that 0.2 mg/kg may not have an acceptable safety profile with repeated dosing alongside chemotherapy.
• Limitations the authors state:
  • There was no chemotherapy-only control group, so the authors could not show that the immune changes are absent with standard treatment.
  • The study was not designed primarily to test efficacy.
  • The response criteria used pre-dated immune-related response criteria, which may have affected the time-to-progression results.
  • Patient numbers were small. The authors said more studies and patients are needed to characterise how often thromboembolic events occur.

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: Clinical Trial, Cisplatin, Pemetrexed (Alimta), Pleural Mesothelioma, Chemotherapy, Biomarker, ECOG Performance Status, Cytokine.

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