Ranpirnase and its potential for the treatment of unresectable malignant mesothelioma

Our plain-English summary of Ranpirnase and its potential for the treatment of unresectable malignant mesothelioma, by C. Porta, C. Paglino, L. Mutti (Biologics, 2008).

The study

• Authors: C. Porta, C. Paglino, L. Mutti
• Journal: Biologics
• Published: 2008;2(4):601-9
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Ribonucleases are a superfamily of enzymes which operate at the crossroads of transcription and translation, catalyzing the degradation of RNA; they can be cytotoxic because the cleavage of RNA renders indecipherable its information. Ranpirnase is a novel ribonuclease which preferentially degrades tRNA, thus leading to inhibition of protein synthesis and, ultimately, to cytostasis and cytotoxicity. Ranpirnase has demonstrated antitumor activity both in vitro and in vivo in several tumor models. The maximum tolerated dose emerging from phase I studies was 960 g/m(2), with renal toxicity as the main dose-limiting toxicity. A large phase II trial showed that ranpirnase has disease-modifying activity against malignant mesothelioma. Ranpirnase proved to be superior to doxorubicin in a phase III trial, while preliminary results of another large, phase III trial, suggest that the combination of ranpirnase and doxorubicin could be more effective than doxorubicin alone. In all the above studies, ranpirnase seems to act mainly as a cytostatic rather than a cytotoxic drug, stabilizing progressive disease and potentially prolonging patients' survival. Ranpirnase may thus find its niche in combination with doxorubicin for mesothelioma as a second-line therapy, where no standard of care presently exists.

In plain English

This article reviewed ranpirnase, an enzyme found in frog eggs and embryos that breaks down RNA, as a possible treatment for malignant mesothelioma that cannot be removed by surgery. It did not study asbestos exposure. The authors summarized laboratory, animal and human studies by other researchers. In a phase II trial of 105 mesothelioma patients given ranpirnase alone, overall median survival was 6 months (95% CI 4.7–10.0). The review does not make clear which patient group this figure covers. In a phase III trial of ranpirnase versus the drug doxorubicin, final results on 144 patients showed no significant difference between the arms. The ranpirnase arm had more poor-prognosis patients (37% versus 17%). A post-hoc analysis excluded these patients and five whose mesothelioma was not confirmed on central pathology review. It gave a survival risk ratio of 1.60 favoring ranpirnase (95% CI 1.03–2.50; p = 0.04). Unpublished interim data from a second phase III trial showed median survival of 12 months with ranpirnase plus doxorubicin versus 10 months with doxorubicin alone. The authors concluded that ranpirnase may find its niche, combined with doxorubicin, as second-line therapy, where no standard of care exists.

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: Narrative review of preclinical (cell and animal) studies and phase I, II and III clinical trials of ranpirnase
• Who was studied: The studies reviewed included a phase II trial of 105 malignant mesothelioma patients, a phase III trial that enrolled 154 mesothelioma patients, and an ongoing phase III trial in patients with pleural or peritoneal mesothelioma
• Exposure: No asbestos exposure was studied. The treatment reviewed was ranpirnase (Onconase), a ribonuclease from the Northern Leopard frog, given intravenously alone or with doxorubicin
• Main results:
  • Phase II trial (Mikulski et al 2002): overall median survival 6 months (95% CI 4.7–10.0 months). The same sentence also gives 8.3 months 'for the ITT populations', so the group each median belongs to is unclear
  • Phase II trial, intent-to-treat population: 1- and 2-year survival rates were 34.3% and 21.6%
  • Phase II trial: among 81 patients assessable for tumor response, 4 had partial responses, 2 had minor responses and 35 had disease stabilization
  • First phase III trial (Vogelzang et al 2000), ranpirnase versus doxorubicin: final results on 144 patients (75 ranpirnase, 69 doxorubicin) showed no significant differences between the arms. The intent-to-treat survival risk ratio was 1.34 favoring ranpirnase (95% CI 0.93–1.94; p = 0.12)
  • First phase III trial: the ranpirnase arm had more poor-prognosis patients (CALGB groups 5 and 6) than the doxorubicin arm, 37% versus 17%
  • First phase III trial, post-hoc analysis excluding poor-prognosis patients and 5 further patients with mesothelioma unconfirmed by central pathology review: survival risk ratio 1.60 favoring ranpirnase (95% CI 1.03–2.50; p = 0.04); median survival 11.6 versus 9.6 months
  • First phase III trial: the most common grade 3 or 4 toxicity was asthenia (10.8%)
  • Second phase III trial, interim analysis at 105 deaths (personal communication): median survival 12 months with ranpirnase plus doxorubicin versus 10 months with doxorubicin alone; 1-year survival 47% versus 36%
• The authors' conclusion: The authors concluded that ranpirnase proved superior to doxorubicin in one phase III trial and may find its niche, combined with doxorubicin, as second-line therapy for malignant mesothelioma, where no standard of care exists
• Limitations the authors state:
  • Final results of the second phase III trial were not yet available; the interim data were provided as a personal communication
  • The favorable result in the first phase III trial came from a post-hoc analysis. That analysis was performed after an imbalance in poor-prognosis patients was found, and it also excluded patients without centrally confirmed mesothelioma
  • The authors noted that standard radiological response criteria may not be the best way to evaluate a mainly cytostatic drug such as ranpirnase

Topics

Medical terms in this study, explained in our Lexicon: Unresectable, Mesothelioma, Doxorubicin, Second-Line Therapy.

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