M6620 plus standard treatment in oesophageal and other cancer
Research type
Research Study
Full title
A phase I dose escalation safety study combining the ATR inhibitor M6620 with chemoradiotherapy in oesophageal cancer & other sold cancers using time to event continual reassessment method
IRAS ID
190687
Contact name
Maria-Andreia Hawkins
Contact email
Sponsor organisation
University of Oxford
Eudract number
2015-003965-27
Duration of Study in the UK
4 years, 11 months, 31 days
Research summary
Summary of Research
What is the best dose of novel drug, M6620, when combined with chemotherapy and radiotherapy treatment for adults with oesophageal cancer?
Treatment for oesophageal cancer has shown limited improvement in the last decade and survival rates remain low when compared with other cancers. The study aims to evaluate a new treatment for adults with oesophageal cancer combining a novel drug with the standard chemoradiotherapy treatment. The novel drug, M6620 should enhance the effect of chemotherapy and radiotherapy.
With any new treatment it is important to determine the optimal dose. The study will commence with a low dose of M6620 and as each dose is found to be safe the dose will be increased. If the dose isn’t tolerated it will be decreased for the next participant. Participants will be recruited until the highest tolerable dose is found.
The study has two stages and the first stage (A) has two arms: one arm will recruit patients receiving palliative radiotherapy and the other palliative chemotherapy. Participants will receive M6620 at least once weekly whilst receiving either 3 weeks of radiotherapy treatment or 6 cycles of cisplatin/capecitabine treatment. A maximum tolerated dose of M6620 will be identified in both arms. In Stage B, participants will receive standard radical chemoradiotherapy treatment (6 weeks chemotherapy followed by 5 weeks of chemoradiotherapy) and 13 weeks of follow up. Participants will receive M6620 twice during chemotherapy and at least once weekly during chemoradiotherapy. Some participants will have blood samples taken to examine how the body metabolises M6620 (Stage A) and blood and tissue samples to examine the way M6620 acts on tumour tissue (Stage B).
Patients who have previously had radiotherapy to the chest or upper abdomen and chemotherapy (Stage B) cannot take part for reasons of safety. The trial will take place at hospitals where participants are receiving their standard treatment, currently Oxford, Leeds, Cardiff, Manchester and Glasgow.
: 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 surgeryHowever, 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.
REC name
South Central - Oxford A Research Ethics Committee
REC reference
16/SC/0395
Date of REC Opinion
19 Aug 2016
REC opinion
Favourable Opinion