A Phase 1 Dose Escalation Safety Study Combining the ATR Inhibitor M6620 With Chemoradiotherapy in Oesophageal Cancer & Other Solid Cancers Using Time to Event Continual Reassessment Method
Overview
- Phase
- Phase 1
- Intervention
- M6620
- Conditions
- Oesophageal Adenocarcinoma
- Sponsor
- University of Oxford
- Enrollment
- 36
- Locations
- 5
- Primary Endpoint
- STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This Phase I study will test the combination of a novel ATR inhibitor (M6620) with chemoradiotherapy in oesophageal cancer; utilizing three experimental cohorts (Stage A1, A2 and B).
Detailed Description
There is strong scientific rationale for combining ATR inhibitors with DNA damaging agents such as radiation and cisplatin. In particular, ATR inhibition has been shown to be cytotoxic to tumor cells with an impaired DNA damage response, such as those with deficiency in the ATM- or p53 pathway. The high incidence of p53 mutations and the fact that cisplatin and radiation are key therapeutics, makes oesophageal cancer an attractive tumor type to test the activity of an ATR inhibitor. Given the reported synthetic lethal relationship between ATM and ATR, it is likely that ATR inhibition in an ATM- or p53- deficient background will offer a specific and effective way of targeting OAC and SCC of the oesophagus, and enhance the current standard of care. The trial will be divided into three stages. Stage A1 will explore the combination of M6620 plus radiotherapy in the palliative setting and Stage A2 will explore the combination of M6620 plus chemotherapy in the palliative setting. Stage B, will explore the combination of all 3 (M6620 plus chemoradiotherapy in the radical setting). In Stage A1 of the study M6620 will be combined with radiotherapy for the first time and the starting dose will be 140mg/m2 M6620, which has been well-tolerated. M6620 will be administered with daily palliative radiotherapy during this stage in order to study the specific interaction of M6620 with radiotherapy (acting as the DNA damaging agent during this trial stage). In Stage A2 of the study, M6620 will be combined with Cisplatin and Capecitabine combination chemotherapy for the first time; with a starting dose of 90mg/m2 M6620. M6620 will be administered 24 hours post cisplatin infusion, aiming to achieve maximum treatment benefit. Stage A1 and A2 together will help give an indication of a toxicity profile before administration with chemoradiotherapy (Stage B).
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Stage A1, A2 & B
The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria. Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy
Intervention: M6620
Stage A1, A2 & B
The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria. Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy
Intervention: Cisplatin
Stage A1, A2 & B
The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria. Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy
Intervention: Capecitabine
Stage A1, A2 & B
The trial is a single arm study. Different populations are recruited to each stage and the stages run independently of each other. Stage A1 \& A2 will commence before Stage B so that safety data can be obtained in the palliative setting prior to Stage B commencing. Stage A1 may be ongoing when Stage B begins. Each Stage has a separate eligibility criteria. Stage A1: M6620 \& palliative radiotherapy Stage A2: M6620 \& palliative chemotherapy (Cisplatin \& Capecitabine) Stage B: M6620 \& definitive chemoradiotherapy
Intervention: Radiotherapy
Outcomes
Primary Outcomes
STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
Time Frame: From start of M6620 (Berzosertib) treatment to 6-week follow up visit (9 weeks)
To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with radiotherapy (RT) only in the palliative treatment of oesophageal cancer.
STAGE A2 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.
Time Frame: From start of M6620 (Berzosertib) treatment to end of first week of cycle two of chemotherapy (4 weeks)
To determine the best tolerated M6620 (Berzosertib) treatment schedule (or phase II recommended dose, RPTD) administered concomitantly with chemotherapy (cisplatin and capecitabine) only in the palliative treatment of solid cancer.
STAGE B - To Determine the Best Tolerated M6620 (Berzosertib) Treatment Schedule (or RPTD) Administered Concomitantly With Radiotherapy (dCRT) in Combination With Cisplatin and Capecitabine in the Radical Treatment of Oesophageal Cancer.
Time Frame: 24 weeks
Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate.
Secondary Outcomes
- STAGE A1 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.(From start of M6620 (Berzosertib) treatment to 9-week follow up visit (12 weeks))
- STAGE A1 - Number of Patients Completing at Least 75%, 90% and 100% of the Planned Treatment Dose of M6620 (Berzosertib) in Combination With Palliative Radiotherapy(From start of M6620 (Berzosertib) treatment to last dose (3 weeks))
- STAGE A1 - Objective Tumour Response to M6620 (Berzosertib) Plus Radiotherapy, as Evaluated by CT Scan and Quantified by RECIST 1.1.(At 12 weeks following start of M6620 (Berzosertib) treatment)
- STAGE A2 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer(From start of M6620 (Berzosertib) treatment to 8-week post-end of treatment follow up visit (26 weeks))
- STAGE A2 - Number of Patients Completing at Least 75%, 90% and 100% of the Planned Treatment Dose of M6620 (Berzosertib) in Combination With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.(From start of M6620 (Berzosertib) treatment to last dose (18 weeks))
- STAGE A2 - Objective Tumour Response to M6620 (Berzosertib) Plus Chemotherapy, as Evaluated by CT Scan and Quantified by RECIST 1.1.(At 12 weeks following start of M6620 (Berzosertib) treatment)
- STAGE B - To Determine the Safety and Toxicity Profile of M6620 (Berzosertib) Administered Concomitantly With dCRT in Combination With Cisplatin and Capecitabine in the Radical Treatment of Oesophageal Cancer.(24 weeks)
- STAGE B - To Determine Tolerance and Ability to Deliver M6620 (Berzosertib) in Combination With Standard dCRT.(24 weeks)
- STAGE B - To Determine the Efficacy of the Long Term Safety of the Treatment Combination.(24 weeks)