Oesophageal AdenocarcinomaPhase 1CHARIOTNCT03641547
M6620 Plus Standard Treatment in Oesophageal and Other Cancer
A Phase 1 study testing M6620, Cisplatin and Capecitabine in people with Oesophageal Adenocarcinoma and Squamous Cell Carcinoma, run by University of Oxford at 5 sites in United Kingdom.
Trial 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). Read more about this study
- Who is it for?
- Ages 16 years and older
- Conditions the study is for
- Oesophageal Adenocarcinoma, Squamous Cell Carcinoma, Solid Tumor
- What is being tested?
- M6620, Cisplatin and Capecitabine
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 36 participants
- Where
- 5 sitesUnited Kingdom
- Study dates
- 4 Dec 2018to 4 Apr 2022
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- For Stage A1:
- Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus)
- Tumor length 15cm or less
- Any stage of disease that is unsuitable for radical CRT or surgery but suitable for palliative RT
- Baseline investigations available: staging CT scan (within 42 days before first study dose) and endoscopy
- Previous chemotherapy treatment completed 28 days before first study dose
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- No oesophageal stent in-situ
- Any gender, aged ≥16 years.
- Life expectancy of at least 12 weeks
- ECOG performance score of 0-1
- Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Able to give written (signed and dated) informed consent according to GCP before registration
- Hematological and biochemical indices within the ranges below:
- Haemoglobin: ≥8.0g/dL
- Platelet count : ≥100x10^9/L
- Absolute neutrophil count: ≥1.5x10^9/L
- Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome
- AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases
- Estimated glomerular filtration rate: ≥40ml/min
- For Stage A2:
- Any histologically confirmed advanced solid tumor that is metastatic or unresectable where Investigator considers Cisplatin and Capecitabine based regimen as appropriate.
- Baseline investigations available: staging CT scan (within 35 days before first study dose)
- Previous chemotherapy treatment completed 28 days before first study dose
- Any gender, aged ≥16 years
- Life expectancy of at least 12 weeks
- ECOG performance score of 0-1
- Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Able to give written (signed and dated) informed consent according to GCP before registration
- Hematological and biochemical indices within the ranges below:
- Haemoglobin: ≥10.0g/dL
- Platelet count : ≥100x10^9/L
- Absolute neutrophil count: ≥1.5x10^9/L
- Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome
- AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases
- Ca, Mg, Phosphate: within normal limits
- Estimated glomerular filtration rate: ≥60ml/min
- For Stage B:
- Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus including Siewert type 1 or 2 tumors with ≤2cm gastric mucosal extension (not including cervical oesophagus)
- Tumor length 7cm or less
- Suitable for radical CRT and surgery not an option due to being medically unfit or unsuitable for surgery or patient choice
- No oesophageal stent in-situ
- Endoscopically or radiologically documented measurable disease
- Diagnostic PET CT scan*
- Staging CT scan*
- either CT or PET CT scan within 42 days of first study dose
- Adequate respiratory and cardiac function tests for safe delivery of CRT in the opinion of the Principle Investigator, specifically cardiac ejection fraction ≥60% and lung function FEV1>1 litre or 40% of predicted value or KCO (DLCO/VA) >40% predicted value.
- Any gender, aged ≥16 years
- ECOG performance score of 0-1
- Able to comply with protocol fully - absence of any physical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Able to give written (signed and dated) informed consent according to GCP before registration
- Haematological and biochemical indices within the ranges below:
- Haemoglobin: ≥10.0g/dL
- Platelet count : ≥100x10^9/L
- Absolute neutrophil count: ≥1.5x10^9/L
- Total bilirubin: ≤1.5 x upper limit of normal unless the subject has known or suspected Gilbert's syndrome
- AST/ALT: ≤2.5 times the upper limit of normal; ≤5 times if liver metastases
- Ca, Mg, Phosphate: within normal limits
- Estimated glomerular filtration rate: ≥60ml/min
Who cannot join
- Pregnant or breast-feeding women, or women of childbearing potential unless highly effective contraception is used
- Untreated and multiple brain metastases
- Clinically significant cardiovascular event within 6 months before study entry to include: a) congestive heart failure requiring therapy, b) unstable angina pectoris, c) myocardial infarction, d) class II/III/IV cardiac disease (New York Heart Association), e) presence of severe valvular heart disease, f) presence of ventricular arrhythmia requiring treatment
- History of arrhythmia that is symptomatic or requires treatment (CTCAE 3), symptomatic or uncontrolled atrial fibrillation, despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
- Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy)
- Second or third degree heart block with or without symptoms
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- QTc >450msec in adult male and >470 msec in adult females (by Fridericia's correction) not due to electrolyte abnormality and that does not resolve with correction of electrolytes.
- History of congenital long QT syndrome
- History of torsades de pointes (or any concurrent medication with a known risk of inducing torsades de pointes)
- Trachea-oesophageal fistula or invasion of the tracheo-bronchial tree
- Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to the start of treatment
- Strong CYP3A inhibitors and inducers or haemopoietic growth factors within 14 days before first dose of M6620 (Berzosertib)
- HER2 gastro-oesophageal positive cancer where anti-Her2 therapies may be more appropriate (however patients who have failed anti-HER2 therapy may be eligible for stage A1 and A2)
- Unable to have or unwilling to change to low molecular weight heparin instead of Warfarin
- Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
- Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions.
- Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
- Additional Exclusion Criteria for Stage A1 and B:
- 1) Previous radiotherapy to thorax or upper abdomen
- Additional exclusion criteria for Stage A2 and B:
- History of hand-foot syndrome
- History of hearing impairment
- Live vaccine received within 30 days prior to treatment start
- Complete or Partial DPD deficiency
- Additional Exclusion Criteria for Stage B:
- 1) Previous chemotherapy
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United Kingdom5 sites
Velindre Cancer Centre
Cardiff, CF14 2TL
Beatson Cancer Centre
Glasgow
St James's University Hospital
Leeds, LS9 7TF
The Christie
Manchester, M20 4BX
The Churchill Hospital, Oxford University Hospitals Trust
Oxford, OX3 7LE
About this study
Official title: 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
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).
Read the 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).
- Being tested
- M6620, Cisplatin, Capecitabine, Radiotherapy
- Keywords
- Oesophageal cancer
- Medical subject headings
- Adenocarcinoma Of Esophagus, Carcinoma, Squamous Cell, Esophageal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
M6620Drug
M6620 is an unlicensed small molecule ATR inhibitor which can be used in combination with DNA damaging agents. In pre-clinical models it has substantial activity when given with DNA damaging drugs or ionising radiation. The clinical agent (M6620) is currently studied in a phase I trial in Oxford and other centres in combination with gemcitabine, cisplatin, gemcitabine/cisplatin and cisplatin/etoposide.
CisplatinDrug
Cisplatin is a platinum based chemotherapy drug licensed to treat a number of different types of cancer. Cisplatin use is not considered standard practice in Stage A2 \& B, therefore Cisplatin is considered an investigational medicinal product for the purpose of this trial.
CapecitabineDrug
Capecitabine is a chemotherapy drug licensed to treat a number of different types of cancer, it is a noncytotoxic pre-cursor of the cytotoxic 5-fluourouracil. Capecitabine use is not considered standard practice in Stage A2 \& B, therefore Capecitabine is considered an investigational medicinal product for the purpose of this trial.
RadiotherapyRadiation
Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy.
| Study group | Role | What they receive |
|---|---|---|
| Stage A1, A2 & B | Experimental | 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 Receives: Drug: M6620; Drug: Cisplatin; Drug: Capecitabine; Radiation: Radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
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.
Measured: From start of M6620 (Berzosertib) treatment to 6-week follow up visit (9 weeks)
STAGE A2 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.
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.
Measured: From start of M6620 (Berzosertib) treatment to end of first week of cycle two of chemotherapy (4 weeks)
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.
Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate.
Measured: 24 weeks
Secondary outcomes (9)
STAGE A1 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
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).
Measured: 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
Treatment compliance of M6620 (Berzosertib) and palliative radiotherapy when taken concomitantly.
Measured: 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.
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).
Measured: 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
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).
Measured: 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.
Treatment compliance of M6620 (Berzosertib), capecitabine and cisplatin when taken concomitantly.
Measured: 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.
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).
Measured: 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.
Any toxicity grade ≥3 graded according to CTCAE v4.03 and length of time for toxicity to resolve.
Measured: 24 weeks
STAGE B - To Determine Tolerance and Ability to Deliver M6620 (Berzosertib) in Combination With Standard dCRT.
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.
Measured: 24 weeks
STAGE B - To Determine the Efficacy of the Long Term Safety of the Treatment Combination.
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
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Aug 2018
- Study start4 Dec 2018
- Primary completion4 Apr 2022
- Study completion4 Apr 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Oesophageal AdenocarcinomaStudies of the same condition, open and under way.
- More trials run by University of OxfordThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- CHARIOT will use a single arm, open-label, dose escalation, Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal treatment schedule.
- Masking
- None (open label)
- Enrolment
- 36 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Oxford
- Sponsor type
- University, hospital or other
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Responsible party
- Sponsor
- Investigators
- Maria A Hawkins, MD FRCR MRCP, Principal investigator, University College, London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03641547
- Sponsor's protocol ID
- OCTO_072
- Acronym
- CHARIOT
- Status last verified
- Apr 2022
- First submitted
- 10 Jul 2018
- Last updated
- 18 Jul 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Javed SR, Lord S, El Badri S, Harman R, Holmes J, Kamzi F, Maughan T, McIntosh D, Mukherjee S, Ooms A, Radhakrishna G, Shaw P, Hawkins MA. CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method. Br J Cancer. 2024 Feb;130(3):467-475. doi: 10.1038/s41416-023-02542-1. Epub 2023 Dec 21.
PubMed 38129525van Werkhoven E, Hinsley S, Frangou E, Holmes J, de Haan R, Hawkins M, Brown S, Love SB. Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples. BMC Med Res Methodol. 2020 Jun 22;20(1):162. doi: 10.1186/s12874-020-01012-z.
PubMed 32571298
Study at a glance
From the registry record, last updated by the sponsor on 18 Jul 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT03641547
- Acronym / sponsor ID
- CHARIOT / OCTO_072
- Keywords
- Oesophageal cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 36 participants (actual)
- Lead sponsor
- University of OxfordUniversity, hospital or other
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 4 Dec 2018 (actual)
- Primary completion
- 4 Apr 2022 (actual)
- Study completion
- 4 Apr 2022 (actual)
- First posted
- 22 Aug 2018 (actual)
- Results
- Posted 18 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- CHARIOT will use a single arm, open-label, dose escalation, Time-To-Event Continual Reassessment Method (TiTE-CRM) to find the optimal treatment schedule.
| Arm | Type | Receives |
|---|---|---|
| Stage A1, A2 & B | Experimental | Drug: M6620, Drug: Cisplatin, Drug: Capecitabine, Radiation: RadiotherapyThe 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 |
Who may qualify
- Ages
- 16 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (58 listed)
- Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus)
- Tumor length 15cm or less
- Any stage of disease that is unsuitable for radical CRT or surgery but suitable for palliative RT
- Baseline investigations available: staging CT scan (within 42 days before first study dose) and endoscopy
- Previous chemotherapy treatment completed 28 days before first study dose
Key exclusion criteria (26 listed)
- Pregnant or breast-feeding women, or women of childbearing potential unless highly effective contraception is used
- Untreated and multiple brain metastases
- Clinically significant cardiovascular event within 6 months before study entry to include: a) congestive heart failure requiring therapy, b) unstable angina pectoris, c) myocardial infarction, d) class II/III/IV cardiac disease (New York Heart Association), e) presence of severe valvular heart disease, f) presence of ventricular arrhythmia requiring treatment
- History of arrhythmia that is symptomatic or requires treatment (CTCAE 3), symptomatic or uncontrolled atrial fibrillation, despite treatment, or asymptomatic sustained ventricular tachycardia. Subjects with atrial fibrillation controlled by medication are permitted.
- Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| M6620M6620 is an unlicensed small molecule ATR inhibitor which can be used in combination with DNA damaging agents. In pre-clinical models it has substantial activity when given with DNA damaging drugs or ionising radiation. The clinical agent (M6620) is currently studied in a phase I trial in Oxford and other centres in combination with gemcitabine, cisplatin, gemcitabine/cisplatin and cisplatin/etoposide. | Drug | Stage A1, A2 & B |
| CisplatinCisplatin is a platinum based chemotherapy drug licensed to treat a number of different types of cancer. Cisplatin use is not considered standard practice in Stage A2 \& B, therefore Cisplatin is considered an investigational medicinal product for the purpose of this trial. | Drug | Stage A1, A2 & B |
| CapecitabineCapecitabine is a chemotherapy drug licensed to treat a number of different types of cancer, it is a noncytotoxic pre-cursor of the cytotoxic 5-fluourouracil. Capecitabine use is not considered standard practice in Stage A2 \& B, therefore Capecitabine is considered an investigational medicinal product for the purpose of this trial. | Drug | Stage A1, A2 & B |
| RadiotherapyStage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy. | Radiation | Stage A1, A2 & B |
Primary outcome
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.
9 secondary outcomes
STAGE A1 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
Time frame: 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
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 24 weeks
STAGE B - To Determine Tolerance and Ability to Deliver M6620 (Berzosertib) in Combination With Standard dCRT.
Time frame: 24 weeks
STAGE B - To Determine the Efficacy of the Long Term Safety of the Treatment Combination.
Time frame: 24 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Jul 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 38129525Javed SR, Lord S, El Badri S, Harman R, Holmes J, Kamzi F, Maughan T, McIntosh D, Mukherjee S, Ooms A, Radhakrishna G, Shaw P, Hawkins MA. CHARIOT: a phase I study of berzosertib with chemoradiotherapy in oesophageal and other solid cancers using time to event continual reassessment method. Br J Cancer. 2024 Feb;130(3):467-475. doi: 10.1038/s41416-023-02542-1. Epub 2023 Dec 21.
- Derived from this study: PubMed 32571298van Werkhoven E, Hinsley S, Frangou E, Holmes J, de Haan R, Hawkins M, Brown S, Love SB. Practicalities in running early-phase trials using the time-to-event continual reassessment method (TiTE-CRM) for interventions with long toxicity periods using two radiotherapy oncology trials as examples. BMC Med Res Methodol. 2020 Jun 22;20(1):162. doi: 10.1186/s12874-020-01012-z.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Maria A Hawkins, MD FRCR MRCP principal investigator
University College, London
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing M6620, Cisplatin and Capecitabine in people with Oesophageal Adenocarcinoma and Squamous Cell Carcinoma, run by University of Oxford at 5 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 58 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 18 Jul 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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)). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03641547, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jul 2024.