M6620 Plus Standard Treatment in Oesophageal and Other Cancer (CHARIOT)

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).

Study Overview

• Status: Completed
• Conditions: Solid Tumor; Oesophageal Adenocarcinoma; Squamous Cell Carcinoma
• Intervention / Treatment: Drug: M6620; Drug: Cisplatin; Drug: Capecitabine; Radiation: Radiotherapy

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 Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • Cardiff, United Kingdom, CF14 2TL
    • Velindre Cancer Centre
  • Glasgow, United Kingdom
    • Beatson Cancer Centre
  • Leeds, United Kingdom, LS9 7TF
    • St James's University Hospital
  • Manchester, United Kingdom, M20 4BX
    • The Christie
  • Oxford, United Kingdom, OX3 7LE
    • The Churchill Hospital, Oxford University Hospitals Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

INCLUSION CRITERIA:

For Stage A1:

1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus (not including cervical oesophagus)
2. Tumor length 15cm or less
3. Any stage of disease that is unsuitable for radical CRT or surgery but suitable for palliative RT
4. Baseline investigations available: staging CT scan (within 42 days before first study dose) and endoscopy
5. Previous chemotherapy treatment completed 28 days before first study dose
6. No oesophageal stent in-situ
7. Any gender, aged ≥16 years.
8. Life expectancy of at least 12 weeks
9. ECOG performance score of 0-1
10. 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
11. Able to give written (signed and dated) informed consent according to GCP before registration

12. 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:

1. Any histologically confirmed advanced solid tumor that is metastatic or unresectable where Investigator considers Cisplatin and Capecitabine based regimen as appropriate.
2. Baseline investigations available: staging CT scan (within 35 days before first study dose)
3. Previous chemotherapy treatment completed 28 days before first study dose
4. Any gender, aged ≥16 years
5. Life expectancy of at least 12 weeks
6. ECOG performance score of 0-1
7. 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
8. Able to give written (signed and dated) informed consent according to GCP before registration

9. 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:

1. 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)
2. Tumor length 7cm or less
3. Suitable for radical CRT and surgery not an option due to being medically unfit or unsuitable for surgery or patient choice
4. No oesophageal stent in-situ
5. Endoscopically or radiologically documented measurable disease
6. Diagnostic PET CT scan*

7. Staging CT scan*

   *either CT or PET CT scan within 42 days of first study dose

8. 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.
9. Any gender, aged ≥16 years
10. ECOG performance score of 0-1
11. 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
12. Able to give written (signed and dated) informed consent according to GCP before registration

13. 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

EXCLUSION CRITERIA:

1. Pregnant or breast-feeding women, or women of childbearing potential unless highly effective contraception is used
2. Untreated and multiple brain metastases
3. 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
4. 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.
5. Uncontrolled hypertension (blood pressure ≥160/100 despite optimal therapy)
6. Second or third degree heart block with or without symptoms
7. 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.
8. History of congenital long QT syndrome
9. History of torsades de pointes (or any concurrent medication with a known risk of inducing torsades de pointes)
10. Trachea-oesophageal fistula or invasion of the tracheo-bronchial tree
11. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to the start of treatment
12. Strong CYP3A inhibitors and inducers or haemopoietic growth factors within 14 days before first dose of M6620 (Berzosertib)
13. 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)
14. Unable to have or unwilling to change to low molecular weight heparin instead of Warfarin
15. 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.
16. Any other active malignancy, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and non-melanoma skin lesions.
17. 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:

1. History of hand-foot syndrome
2. History of hearing impairment
3. Live vaccine received within 30 days prior to treatment start
4. Complete or Partial DPD deficiency

Additional Exclusion Criteria for Stage B:

1) Previous chemotherapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Drug: M6620; 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.; Drug: Cisplatin; 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.; Drug: Capecitabine; 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.; Radiation: Radiotherapy; Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
STAGE A1 - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose), administered concomitantly with radiotherapy only in the palliative treatment of oesophageal cancer	Highest treatment schedule resulting in less than 25% dose limiting toxicity rate	Week 9
STAGE A2 - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose) administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer	Highest treatment schedule resulting in less than 30% dose limiting toxicity rate	Week 4
STAGE B - Determine the best tolerated M6620 treatment schedule (or phase II recommended dose) 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 rate	Up to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
STAGE A1 - To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) and the length of time these toxicities take to resolve when M6620 is administered concomitantly with RT only in the palliative treatment of oesophageal cancer	To determine the safety and toxicity profile of M6620 administered concomitantly with RT only in the palliative treatment of oesophageal cancer	During radiotherapy weeks 1-3, week 4, 9 and 12
STAGE A1 - To determine if M6620 can be delivered in combination with palliative radiotherapy by the proportion of patients completing at least 75%, 90% and 100% of the planned radiotherapy dose	Proportion of patients completing at least 75%, 90% and 100% of the planned radiotherapy dose	End of radiotherapy, end of week 3
STAGE A1 - Efficacy of the combination (M6620 and radiotherapy), measured by objective tumour response	Objective tumor response as evaluated by CT scan as quantified by RECIST 1.1. PFS and OS from D1	12 weeks, 6 and 12 months
STAGE A2 -To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) and the time they take to resolve when M6620 is administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer	To determine the safety and toxicity profile of M6620 administered concomitantly with chemotherapy (Cisplatin and Capecitabine) only in the palliative treatment of solid cancer	During chemotherapy week 1-18, week 20, 26
STAGE A2 - To determine if M6620 can be delivered in combination with palliative chemotherapy by the proportion of patients completing at least 75%, 90% and 100% of the planned dose	Proportion of patients completing at least 75%, 90% and 100% of the planned dose	End of chemotherapy, week 18
STAGE A2 - Efficacy of the combination (M6620 and chemotherapy), measured by objective tumour response	Objective tumor response as evaluated by CT scan and quantified by RECIST 1.1; PFS and OS from D1; in field radiotherapy control	Week 6, 12, 18, 26 and 12 months
STAGE B -To determine the number of toxicities grade ≥3 (according to CTCAE v4.03) & the time they take to resolve when M6620 is administered concomitantly with dCRT (radiotherapy, cisplatin & capecitabine) in the radical treatment of oesophageal cancer	To determine safety and toxicity profile of M6620 administered concomitantly with dCRT in combination with cisplatin and capecitabine in the radical treatment of oesophageal cancer	Up to week 24
STAGE B - To measure the the proportion of patients completing at least 80% of the planned chemotherapy dose and at least 20 fractions of radiotherapy in order to determine tolerance and ability to deliver M6620 in combination with standard dCRT	To determine the tolerance and ability to deliver M6620 in combination with standard dCRT	End of induction chemotherapy and dCRT. End of week 11.
STAGE B - To measure objective tumor response as evaluated by CT scan and quantified by RECIST 1.1 and endoscopic biopsy findings	To determine the efficacy of the long term safety of the treatment combination	24 weeks, 12 and 24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
STAGE A2 - To measure M6620 area under the plasma concentration time curve using blood samples when delivered after Capecitabine and Cisplatin	To enable evaluation of pharmacokinetics of M6620 when administered in combination with Cisplatin and Capecitabine	1st dose of M6620 (C1D2) at the following timepoints: BOI, at 0.5 hours before EOI, at EOI and at 0.5, 1, 2,6, 23, 47 hours after EOI. For C1D9 and C1D16 doses at the following timepoints: BOI and EOI
STAGE A2 - To measure M6620 Cmax (observed peak plasma concentration) using blood samples when delivered after Capecitabine and Cisplatin administration	To enable evaluation of pharmacokinetics of M6620 when administered in combination with Cisplatin and Capecitabine	1st dose of M6620 (C1D2) at the following timepoints: BOI, at 0.5 hours before EOI, at EOI and at 0.5, 1, 2,6, 23, 47 hours after EOI. For C1D9 and C1D16 doses at the following timepoints: BOI and EOI
STAGE B - To explore target effects in tissue by measuring the change in level of ATR inhibition and apoptosis in M6620 treated tissue using IHC	To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue	Biopsies and blood samples at baseline, week 7 and 24
STAGE B - To explore target effects in tissue by assessing genotyping of tumours obtained from biopsies and blood samples	To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue	Biopsies and blood samples at baseline, week 7 and 24
STAGE B - To explore target effects in tissue by aiming to identify markers for oesophageal cancer in the blood	To explore change in level of ATR inhibition and apoptosis in M6620 treated tissue	Biopsies and blood samples at baseline, week 7 and 24

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Merck KGaA, Darmstadt, Germany
• Investigators: Principal Investigator: Maria A Hawkins, MD FRCR MRCP, University College, London

Publications and helpful links

General Publications

• van 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2018
• Primary Completion (Actual): April 4, 2022
• Study Completion (Actual): April 4, 2022

Study Registration Dates

• First Submitted: July 10, 2018
• First Submitted That Met QC Criteria: August 17, 2018
• First Posted (Actual): August 22, 2018

Study Record Updates

• Last Update Posted (Actual): April 28, 2022
• Last Update Submitted That Met QC Criteria: April 27, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Oesophageal cancer
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Cisplatin; Capecitabine
• Other Study ID Numbers: OCTO_072

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No