Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors

Our plain-English summary of Phase I study of gemcitabine, docetaxel and imatinib in refractory and relapsed solid tumors, by B. Saraiya, R. Chugh, V. Karantza, et al (Investigational New Drugs, 2012).

The study

• Authors: B. Saraiya, R. Chugh, V. Karantza, J. Mehnert, R.A. Moss, N. Savkina, M.N. Stein, L.H. Baker, T. Chenevert, E.A. Poplin
• Journal: Investigational New Drugs
• Published: 2012;30(1):258-65
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: In a phase I study, the combination of gemcitabine and imatinib was well tolerated with broad anticancer activity. This phase I trial evaluated the triplet of docetaxel, gemcitabine and imatinib.

Experimental Design: Imatinib was administered at 400 mg daily on days 1-5, 8-12 and 15-19. Gemcitabine was started at 600 mg/m(2) at a rate of 10 mg/min on days 3 and 10 and docetaxel at 30 mg/m(2) on day 10, on a 21-day cycle. Diffusion and dynamic contrast-enhanced perfusion MRI was performed in selected patients.

Results: Twenty patients with relapsed/refractory solid tumors were enrolled in this IRB-approved study. The mean age was 64, and mean ECOG PS was 1. Two patients were evaluated by diffusion/perfusion MRI. After two grade 3 hematological toxicities at dose level 1, the protocol was amended to reduce the dose of imatinib. MTDs were 600 mg/ m(2) on days 3 and 10 for gemcitabine, 30 mg/ m(2) on day 10 for docetaxel, and 400 mg daily on days 1-5 and 8-12 for imatinib. Dose limiting toxicities after one cycle were neutropenic fever, and pleural and pericardial effusions. The best response achieved was stable disease, for six cycles, in one patient each with mesothelioma and non small cell lung cancer (NSCLC) at the MTD. Two patients with NSCLC had stable disease for four cycles.

Discussion: An unexpectedly low MTD for this triplet was identified. Our results suggest drug-drug interactions that amplify toxicities with little evidence of improved tumor control.

In plain English

This phase I trial at the Cancer Institute of New Jersey and the University of Michigan tested three drugs together (gemcitabine, docetaxel and imatinib) to find the highest tolerable dose. Between February 2006 and January 2008, 20 adults with relapsed or treatment-resistant solid tumors were enrolled. Two of them had mesothelioma. The article does not discuss asbestos. The protocol was changed after unexpected suppression of blood counts. The authors reported a maximum tolerated dose of gemcitabine 600 mg/m2 on days 3 and 10 and imatinib 400 mg per day on days 1 to 5 and 8 to 12; for docetaxel, the Results give 30 mg/m2 but the Conclusion prints 40 mg/m2. The dose-limiting side effects were fever with low white-cell counts, and fluid around the lungs and heart. The best response was stable disease for six cycles, in one patient with mesothelioma and one with non-small cell lung cancer. Functional MRI was done in only two patients, too few for conclusions. The authors concluded that the combination was unexpectedly toxic without any apparent increase in efficacy in this limited patient population.

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 open-label dose-escalation trial at two centers
• Who was studied: 20 adults with refractory or relapsed solid tumors, enrolled February 2006 to January 2008 at the Cancer Institute of New Jersey and the University of Michigan. Median age was 64.5 (range 43 to 83); 12 were male and 8 female. Tumor types were 4 non-small cell lung cancer, 1 small cell lung cancer, 5 sarcoma, 3 pancreatic/biliary, 2 mesothelioma, 2 bladder and 4 other.
• Exposure: Chemotherapy combination on 21-day cycles. Imatinib 400 mg per day by mouth (initially days 1 to 5, 8 to 12 and 15 to 19). Gemcitabine started at 600 mg/m2 on days 3 and 10. Docetaxel started at 30 mg/m2 on day 10 (45 mg/m2 at dose levels 2 and 2A). Asbestos exposure was not studied.
• Main results:
  • Treatment at the second dose level caused unexpected suppression of blood counts. The authors attributed this to possible imatinib toxicity, and the protocol was amended.
  • In the Results, the maximum tolerated dose was gemcitabine 600 mg/m2, docetaxel 30 mg/m2, and imatinib 400 mg per day on days 1 to 5 and 8 to 12. The Conclusion section instead gives docetaxel 40 mg/m2 on day 10.
  • Dose-limiting toxicities included neutropenic fever (Table 3: 2 of 8 patients at level 1, 2 of 4 at level 2, 2 of 5 at level 2A with weakness, 1 of 2 at level 2B). One patient had a pericardial effusion and one had a pleural effusion during cycle 1, which the authors considered likely related to imatinib.
  • At least six patients had delays in starting the second cycle because of toxicities.
  • The best response was stable disease for six cycles, in one patient each with mesothelioma and non-small cell lung cancer, at the maximum tolerated dose. Two other patients with non-small cell lung cancer had stable disease for four cycles.
  • Across all patients, the median number of cycles was 2 and the median duration of therapy was 12 weeks (range 4 to 30 weeks).
  • Functional MRI was done in two patients and showed changes, but the authors stated that the clinical significance of these changes is unclear.
• The authors' conclusion: The authors concluded that the triplet was unexpectedly toxic without any apparent increase in efficacy in this limited patient population.
• Limitations the authors state:
  • No formal pharmacokinetic (drug-level) evaluations were performed.
  • Too few patients had functional MRI to draw any conclusions from that analysis.
  • Growth factors were not used, which the authors said likely contributed to higher rates of neutropenia.

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine, Pericardial Effusion, Mesothelioma, Small Cell Lung Cancer.

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