M6620 Plus Standard Treatment in Oesophageal and Other Cancer

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Oesophageal Adenocarcinoma, Squamous Cell Carcinoma, Solid Tumor

Intervention / Treatment
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* Drug: M6620
* Drug: Cisplatin
* Drug: Capecitabine
* Radiation: Radiotherapy


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: 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 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 EXCLUSION CRITERIA: 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 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

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage A1, A2 & B<br>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<br>* 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.<br>Drug: Cisplatin<br>* 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.<br>Drug: Capecitabine<br>* 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.<br>Radiation: Radiotherapy<br>* Stage A1 uses palliative radiotherapy. Stage B uses definitive radiotherapy.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oesophageal cancer