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CHARIOT trial logo

Primary Publication

British Journal of Cancer 21 December 2023

CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method.

 

Lay Summary

Radiotherapy and chemotherapy are standard treatments for a number of tumour types, including cancer of the oesophagus (food pipe). When cancer cells are treated with radiotherapy and chemotherapy, the aim is to damage their DNA so that they can no longer survive and the tumour is destroyed. However, cancer cells have special mechanisms to try and repair this DNA damage, so resistance to these treatments is common. Therefore, there is a need to develop new approaches to improve outcomes for these patients.

One approach is to target the DNA repair process and prevent the cancer cells from recovering. Berzosertib is a type of targeted cancer drug that works by blocking signals that tell the damaged cancer cells to repair themselves.

This trial looked at whether it is safe to combine Berzosertib with radiotherapy or chemotherapy to treat people with oesophageal cancer or other solid tumours. The trial also aimed to find the best dose of Berzosertib to give patients in combination with these existing treatments and how often it should be given. Other goals were to find out how well Berzosertib works and more about the side effects.

There were planned to be three stages to the trial:  

  • Stage A1 – combining Berzosertib with radiotherapy delivered for oesophageal cancer with a palliative intent
  • Stage A2 – combining Berzosertib with chemotherapy (cisplatin and capecitabine) in patients with any cancer that have no other treatment options available
  • Stage B – combining Berzosertib with radiotherapy and chemotherapy in the curative setting for patients with oesophageal cancer that were not deemed suitable for surgery

However, Stage B of this trial did not go ahead due to a lack of funding available.

 

Stage A1

Sixteen patients were treated in this section of the trial. Each patient was given a standard dose of radiotherapy once a day, Monday to Friday, for 3 weeks.. They were then administered Berzosertib either once or twice a week.

The six dose levels of Berzosertib tested were:

  1. 90mg/m² once a week (3 doses)
  2. 90mg/m² twice a week (6 doses)
  3. 140mg/m² twice a week (6 doses)
  4. 240mg/m² once a week (3 doses)
  5. 240mg/m² twice a week (5 doses)
  6. 240mg/m² twice a week (6 doses)

The dose level for each patient was chosen with the help of a mathematical model. This used safety data collected on patients already in the trial to recommend whether to continue investigating the same dose level, or increase/decrease it for the next patient. 

All patients completed radiotherapy and there were no severe side effects seen due to the combined treatments.

In this stage, there were eight grade 3 adverse events (side effects) reported that were assessed to be related to the trial treatment, occurring in five patients. Grade 3 means the side effects were medically significant but not immediately life-threatening. Rash was the most common of these (reported in three patients).

The highest level of Berzosertib tested (240mg/m2) was identified as the best dose in combination with radiotherapy.

 

Stage A2

Eighteen patients were treated in this section of the trial. Each patient was given cisplatin treatment once every 3 weeks for up to 18 weeks (maximum 6 doses, each at 60mg/m2). They were also given capecitabine tablets to take twice a day throughout their cisplatin treatment (at a dose of 625mg/m2). Patients were administered Berzosertib either once or twice a week.

The four dose levels of Berzosertib tested were:

  1. 90mg/m² once a week (18 doses)
  2. 90mg/m² twice a week (36 doses)
  3. 140mg/m² once a week (18 doses)
  4. 140mg/m² twice a week (36 doses)

As for Stage A1, the dose level for each patient was chosen with the help of a mathematical model that used safety data collected on patients already in the trial to recommend whether to continue investigating the same dose level, or increase/decrease it for the next patient.

In this stage, the most common side effects assessed to be related to the trial treatment were neutropenia (low white cell count) and thrombocytopenia (low clotting factors). There were no treatment-related deaths.

Dose level three of Berzosertib (140mg/m2, once a week) was identified as the best dose in combination with chemotherapy.

This trial shows demonstrates that Berzosertib can be safely administered to patients with advanced cancer in combination with radiotherapy as well as chemotherapy (cisplatin and capecitabine). The best dose of Berzosertib to use with these existing treatments was identified and warrants further investigation to determine the efficacy of these combinations.

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