Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors

Our plain-English summary of Phase I trial of bortezomib daily dose: safety, pharmacokinetic profile, biological effects and early clinical evaluation in patients with advanced solid tumors, by R. Bahleda, M.C. Le Deley, A. Bernard, et al (Investigational New Drugs, 2018).

The study

• Authors: R. Bahleda, M.C. Le Deley, A. Bernard, S. Chaturvedi, M. Hanley, A. Poterie, A. Gazzah, A. Varga, M. Touat, E. Deutsch, C. Massard, H. Van De Velde, A. Hollebecque, M. Sallansonnet-Froment, D. Ricard, H. Taillia, E. Angevin, V. Ribrag, J.C. Soria
• Journal: Investigational New Drugs
• Published: 2018;36(4):619-628
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose This phase I study investigated bortezomib in solid tumors used as a daily subcutaneous regimen. Previous regimens showed only modest activity in solid tumors which was potentially related to sub-optimal tumor penetration. We aimed at exploring if daily low dose administration of bortezomib may allow a greater and tolerable pharmacokinetic exposure which might be required for antitumor activity in solid tumors. Patients and methods This 3 + 3 design, dose escalation, monocentric study aimed at defining the maximum tolerated dose of daily low dose schedule of bortezomib. Tolerability, pharmacokinetics, pharmacodynamics, antitumor activity, biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies were also evaluated. Results A total of eighteen patients were dosed in 3 bortezomib cohorts (0.5, 0.6 and 0.7 mg/m2), with 3, 11 and 4 patients respectively. Three patients experienced dose-limiting toxicities: Grade (G) 3 Sweet's syndrome (at 0.6 mg/m2), G3 asthenia and anorexia or ataxia (2 patients at 0.7 mg/m2). The most common study drug-related adverse events (all grades) were thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). Dose 0.6 mg/m2 of bortezomib was considered as the recommended phase II dose. A significant tumor shrinkage (-36% according to WHO criteria) was observed in one patient with heavily pre-treated GIST, and 2 minor responses (-20%) were recorded in two patients with melanoma and mesothelioma. Conclusion This daily subcutaneous regimen of bortezomib showed a dose dependent plasma exposure, evidence of target inhibition and preliminary signs of clinical activity. However, cumulative neurological toxicity of this dose-dense daily regimen might preclude its further clinical development.

In plain English

This phase I trial at one cancer centre in Villejuif, France, tested the drug bortezomib, injected under the skin every weekday for three weeks followed by one week off, in 18 adults with advanced solid tumors. Two of them had pleural epithelioid mesothelioma. The study did not examine asbestos. Patients received 0.5, 0.6 or 0.7 mg/m2. Three patients had dose-limiting side effects: severe Sweet's syndrome (a skin condition) at 0.6 mg/m2, and, in two patients at 0.7 mg/m2, severe weakness with loss of appetite or loss of coordination. The 0.6 mg/m2 dose was chosen for further study. Common treatment-related side effects included neutropenia (89%), thrombocytopenia (72%), fatigue (56%) and neuropathy (50%). Of 15 patients assessed after two cycles, 11 had progressing disease, 4 had stable disease and none had partial or complete responses. One patient with GIST had tumor shrinkage, and patients with melanoma and mesothelioma had minor responses. The authors concluded that insufficient anti-tumor activity and cumulative nerve toxicity might preclude further development of this schedule in solid tumors.

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, single-centre, dose-escalation drug trial using a 3 + 3 design, with an expansion cohort
• Who was studied: 19 patients aged 18 or older with advanced solid tumors were enrolled and 18 were treated, at Gustave Roussy, Villejuif, France. Median age was 57.5 years and the median number of previous treatment lines was 5. Tumor types included breast cancer (4), GIST (4) and pleural epithelioid mesothelioma (2). Study dates are not stated.
• Exposure: No asbestos exposure was studied. The exposure was the drug bortezomib, given subcutaneously at 0.5, 0.6 or 0.7 mg/m2, daily 5 days on and 2 days off for 3 weeks, followed by 1 week of recovery, in 4-week cycles.
• Main results:
  • Three dose-limiting toxicities: grade 3 Sweet's syndrome at 0.6 mg/m2, and two at 0.7 mg/m2 (grade 3 asthenia and ataxia; grade 3 asthenia and anorexia). The 0.7 mg/m2 dose was judged not tolerable.
  • 0.6 mg/m2 was selected as the recommended phase II dose. Among 8 evaluable patients at that dose, the estimated probability of a dose-limiting toxicity was 0.13 (95% confidence interval less than 0.01 to 0.53).
  • The most common drug-related adverse events (all grades, 18 patients) were neutropenia (89%), thrombocytopenia (72%), fatigue (56%), neuropathy (50%), anorexia (44%) and rash (39%). There was no grade 3 peripheral neuropathy and there were no treatment-related deaths.
  • Of 11 patients with repeated neurological evaluations, 3 developed grade 2 sensory neuropathy during treatment.
  • Of 15 patients evaluated after 2 cycles, 11 had disease progression and 4 had disease stabilization. There were no partial or complete responses.
  • One heavily pre-treated patient with duodenal GIST had tumor shrinkage of the primary tumor (-36%). Two minor responses were seen, in patients with melanoma and mesothelioma.
  • Median progression-free survival was 4.7 weeks (95% confidence interval 3.6 to 8.9). Over a median follow-up of 25.4 months, disease progression was reported in 17 patients, leading to death in 13.
  • In 6 patients with both measurements, bortezomib concentrations ranged from 0.674 to 2.75 ng/mL in plasma and from 10.3 to 370 ng/g in tumor.
  • Of 4 patients whose tumor proteasome inhibition could be measured, 3 showed inhibition by day 5, ranging from 34.08 to 85.72%.
• The authors' conclusion: The authors concluded that, despite evidence that the drug reached the tumor and acted on its target, anti-tumor activity was largely insufficient. In their view, insufficient activity and cumulative neurological toxicity might preclude further clinical development of this daily schedule in solid tumors.
• Limitations the authors state:
  • The small sample size does not allow a definitive conclusion about the drug's penetration into tumors.
  • Drug levels in the blood varied widely between patients.
  • Tumor proteasome inhibition could not be measured in half of the biopsy samples, because of low protein content or low proteasome activity.
  • Treatment duration was short.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma.

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