Comment:

The trend towards drug repurposing for cancer treatment has a basic underlying assumption that it is safe, even if not proven effective. This study shows that may not be the case with 4/10 patients showing hyperprogression. 

 

Summary:

Clinical Bottom Line

This early-phase study was stopped prematurely due to a complete lack of efficacy and concerning signals of potential harm. In this population of heavily pre-treated patients with advanced gastrointestinal cancer, individualized high-dose mebendazole monotherapy resulted in rapid and universal disease progression. The primary goal of achieving a target therapeutic serum concentration failed in most patients due to the drug’s poor bioavailability. Most alarmingly, half of the radiologically evaluable patients experienced hyperprogressive disease, suggesting the treatment may have accelerated tumor growth. While the drug itself was well-tolerated with no significant treatment-related adverse events, its clear lack of benefit and potential to hasten progression indicate it should not be used as a monotherapy in this clinical setting.

Results in Context

Primary Outcome The primary efficacy endpoints were tumor response rate and prolongation of Time to Tumour Progression (TTP) compared to the patient’s most recent prior therapy.

• Tumor Response: The treatment failed entirely on this endpoint. Of the 10 patients who began treatment, all 10 were withdrawn due to progressive disease. No objective tumor responses were observed.
• Time to Tumour Progression (TTP): Mebendazole was associated with a significantly shorter TTP. The median TTP on mebendazole was 59 days, which was substantially worse than the median TTP of 162 days these same patients had experienced on their previous line of therapy.

Key Secondary & Specialized Outcomes

• Hyperprogressive Disease (HP): This is a phenomenon where an anticancer treatment paradoxically accelerates tumor growth. It was defined in the study as a doubling or more in the speed of tumor growth compared to the pre-treatment rate. Four of the eight patients who had follow-up imaging met the criteria for hyperprogressive disease, a very concerning safety signal.
• Pharmacokinetics: A key goal was to achieve a target serum mebendazole concentration of approximately 300 ng/mL through individualized dose adjustments. This effort largely failed. Despite dose escalation up to 4 g/day, only five patients ever reached the target concentration, and only two patients achieved it on more than one occasion, highlighting the drug’s poor and erratic absorption.

Harms and Adverse Events Despite the negative efficacy outcomes, the drug was reported to be safe and well-tolerated.

• No dose-limiting toxicities were observed, even at the maximum daily dose of 4 grams.
• Nine serious adverse events (SAEs), including three deaths, occurred in five patients; however, none were considered by the investigators to be related to the study treatment.
• The vast majority (94%) of all adverse events were deemed unlikely to be related to mebendazole and were consistent with symptoms of advanced cancer, such as abdominal pain and decreased appetite.

Assertive Critical Appraisal

• Risk of Bias: As a single-arm, open-label study, the main risk is not in comparing groups but in the interpretation of results. The decision to terminate the study after enrolling just 11 of a planned 30 patients was appropriate and ethically necessary given the uniform findings of rapid progression and the signal for hyperprogression. This early termination prevents any optimistic interpretation of the data and provides a strong conclusion of futility. The objective radiological endpoints (RECIST 1.1) are standard, minimizing measurement bias.
• Applicability: The findings are highly applicable to patients with treatment-refractory, advanced gastrointestinal cancers. The results robustly demonstrate that this specific treatment approach lacks efficacy in this population. The study’s conclusion—that mebendazole should not be used outside of a carefully designed clinical trial—is well-supported and clinically relevant.

Research Objective

To conduct a phase 2a study investigating the safety and antitumor efficacy of individualized, dose-adjusted mebendazole in patients with advanced, treatment-refractory gastrointestinal cancer.

Study Design

This was a prospective, single-arm, open-label trial conducted at a single center. The study planned to enroll 30 patients but was stopped after 11 were included. Ten patients started the treatment phase, which involved weekly therapeutic drug monitoring to adjust the mebendazole dose with the goal of reaching a target serum concentration. Efficacy was assessed by CT scan at 8 and 16 weeks.

Setting and Participants

The study was conducted in Sweden. Participants were adults with advanced or metastatic gastrointestinal cancers who had progressed after standard chemotherapy and had a good performance status (WHO 0-1). The 11 enrolled patients were heavily pre-treated, having received a median of 3 prior lines of chemotherapy.

Bibliographic Data

• Title: A phase 2a clinical study on the safety and efficacy of individualized dosed mebendazole in patients with advanced gastrointestinal cancer
• Authors: S. Mansoori, M. Fryknäs, C. Alvfors, A. Loskog, R. Larsson & P. Nygren
• Journal: Scientific Reports
• Year: 2021
• DOI: 10.1038/s41598-021-88433-y

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