M6620 Plus Standard Treatment in Oesophageal and Other Cancer

Phase 1

Completed

• Conditions: Oesophageal Adenocarcinoma; Squamous Cell Carcinoma; Solid Tumor
• Interventions: Drug: M6620; Drug: Cisplatin; Drug: Capecitabine; Radiation: Radiotherapy

• Registration Number: NCT03641547
• Lead Sponsor: University of Oxford

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).

Study Timeline

• Study First Submitted: 2018-07-10
• Study First Submitted QC: 2018-08-17
• Study First Posted: 2018-08-22
• Study Start: 2018-12-04
• Status Verified: 2022-04
• Primary Completion: 2022-04-04
• Study Completion: 2022-04-04
• Results First Submitted: 2023-04-13
• Results First Submitted QC: 2024-02-02
• Last Update Submitted: 2024-02-02
• Results First Posted: 2024-07-18
• Last Update Posted: 2024-07-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

Inclusion Criteria

Not provided

Read More

Exclusion Criteria

Not provided

Read More

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Stage A1, A2 & B	M6620	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
Stage A1, A2 & B	Radiotherapy	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
Stage A1, A2 & B	Cisplatin	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
Stage A1, A2 & B	Capecitabine	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

Primary Outcome Measures

Name	Time	Method
STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.	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.	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.	24 weeks	Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate.

Secondary Outcome Measures

Name	Time	Method
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)	Toxicity profile when M6620 is administered concomitantly with RT in the palliative treatment of oesophageal cancer. Worst grade adverse event for each patient by dose schedule (according to the Common Terminology Criteria for Adverse Events, Version 4.03). Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant, but not immediately life-threatening); Grade 4 (life-threatening); Grade 5 (death).
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)	Treatment compliance of M6620 (Berzosertib) and palliative radiotherapy when taken concomitantly.
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	Efficacy of the combination (M6620 and radiotherapy), measured by objective tumour response via RECIST 1.1 (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026). From Progressive Disease (PD) to Complete Response (CR).
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)	Toxicity profile when M6620 is administered concomitantly with chemotherapy in the treatment of oesophageal cancer. Worst grade adverse event for each patient by dose schedule (according to the Common Terminology Criteria for Adverse Events, Version 4.03). Grade 1 (mild); Grade 2 (moderate); Grade 3 (severe or medically significant, but not immediately life-threatening); Grade 4 (life-threatening); Grade 5 (death).
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)	Treatment compliance of M6620 (Berzosertib), capecitabine and cisplatin when taken concomitantly.
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	Efficacy of the combination (M6620 and chemotherapy), measured by objective tumour response via RECIST 1.1 (Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026). From Progressive Disease (PD) to Complete Response (CR).
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	Any toxicity grade ≥3 graded according to CTCAE v4.03 and length of time for toxicity to resolve.
STAGE B - To Determine Tolerance and Ability to Deliver M6620 (Berzosertib) in Combination With Standard dCRT.	24 weeks	Treatment tolerance and deliverability measured by proportion of patients completing at least 80% of the planned chemotherapy dose and at least 20 fractions of RT.
STAGE B - To Determine the Efficacy of the Long Term Safety of the Treatment Combination.	24 weeks	To measure objective tumour response as evaluated by CT scan and quantified by RECIST 1.1 and endoscopic biopsy findings \& PFS and OS from D1

Trial Locations

Locations (5)

St James's University Hospital; 🇬🇧 Leeds, United Kingdom

The Christie; 🇬🇧 Manchester, United Kingdom

Velindre Cancer Centre; 🇬🇧 Cardiff, United Kingdom

The Churchill Hospital, Oxford University Hospitals Trust; 🇬🇧 Oxford, United Kingdom

Beatson Cancer Centre; 🇬🇧 Glasgow, United Kingdom