Clinical trial NCT03641547: M6620 Plus Standard Treatment in Oesophageal and Other Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Oesophageal Adenocarcinoma
Squamous Cell Carcinoma
Solid Tumor
Keywords: Oesophageal cancer
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Merck KGaA, Darmstadt, Germany
First posted: 2018-08-22
Enrollment: 36
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention 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.
Primary purpose: TREATMENT

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).

Eligibility criteria: 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

Primary outcomes:
measure: STAGE A1 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
timeFrame: From start of M6620 (Berzosertib) treatment to 6-week follow up visit (9 weeks)
measure: STAGE A2 - Number of Dose Limiting Toxicities for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer.
timeFrame: From start of M6620 (Berzosertib) treatment to end of first week of cycle two of chemotherapy (4 weeks)
measure: 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.
timeFrame: 24 weeks
Secondary outcomes:
measure: STAGE A1 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Radiotherapy (RT) in the Palliative Treatment of Oesophageal Cancer.
timeFrame: From start of M6620 (Berzosertib) treatment to 9-week follow up visit (12 weeks)
measure: 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
timeFrame: From start of M6620 (Berzosertib) treatment to last dose (3 weeks)
measure: STAGE A1 - Objective Tumour Response to M6620 (Berzosertib) Plus Radiotherapy, as Evaluated by CT Scan and Quantified by RECIST 1.1.
timeFrame: At 12 weeks following start of M6620 (Berzosertib) treatment
measure: STAGE A2 - Severity of Worst Adverse Events for M6620 (Berzosertib) Administered Concomitantly With Chemotherapy (Cisplatin and Capecitabine) in the Palliative Treatment of Solid Cancer
timeFrame: From start of M6620 (Berzosertib) treatment to 8-week post-end of treatment follow up visit (26 weeks)
measure: 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.
timeFrame: From start of M6620 (Berzosertib) treatment to last dose (18 weeks)
measure: STAGE A2 - Objective Tumour Response to M6620 (Berzosertib) Plus Chemotherapy, as Evaluated by CT Scan and Quantified by RECIST 1.1.
timeFrame: At 12 weeks following start of M6620 (Berzosertib) treatment
measure: 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.
timeFrame: 24 weeks
measure: STAGE B - To Determine Tolerance and Ability to Deliver M6620 (Berzosertib) in Combination With Standard dCRT.
timeFrame: 24 weeks
measure: STAGE B - To Determine the Efficacy of the Long Term Safety of the Treatment Combination.
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre
city: Glasgow
country: United Kingdom
facility: Beatson Cancer Centre
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: Manchester
country: United Kingdom
facility: The Christie
city: Oxford
country: United Kingdom
facility: The Churchill Hospital, Oxford University Hospitals Trust
Study officials:
affiliation: University College, London
name: Maria A Hawkins, MD FRCR MRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.