| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Stage A1 and B: Oesophageal carcinoma
Stage A2: Any advanced solid tumours (carcinomas) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the oesophagous (all stages) and other cancers which cannot be operated on and have spread to other parts of the body (stage A2 only). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10030137 |
| E.1.2 | Term | Oesophageal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Stage A1: to find the best tolerated dose of the drug M6620 in combination with palliative radiotherapy in patients with oesophageal cancer.
Stage A2: to find the best tolerated dose of the drug M6620 in combination with palliative cisplatin/capecitabine chemotherapy in patients with advanced solid tumours.
Stage B: to find the best tolerated M6620 treatment schedule in combination with curative chemoradiotherapy in patients with oesophageal cancer. |
|
| E.2.2 | Secondary objectives of the trial |
Stage A1: to determine the safety and toxicity profile of the drug M6620 when given with radiotherapy for palliative treatment of oesophageal cancer (treatment of symptoms and to slow the growth of the cancer)
Stage A1: to determine if M6620 can be given in combination with radiotherapy without compromising the ability to give appropriate radiotherapy treatment.
Stage A1: to determine the effectiveness of the combination of M6620 and radiotherapy treatment.
Stage A2: To determine the safety and toxicity profile of the drug M6620 when given with chemotherapy (cisplatin and capecitabine) for palliative treatment of advanced solid tumours.
Stage A2: to determine if M6620 can be given in combination with chemotherapy without compromising the ability to give appropriate chemotherapy treatment.
Stage A2: to determine the effectiveness of the combination of M6620 and chemotherapy treatment.
Stage B: to determine the safety and toxicity profile of the drug M6620 when given with chemoradioth |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Any gender, age 16 years or over
2. Life expectancy of at least 12 weeks (N/A Stage B)
3. ECOG performance score of 0-1
4. 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
5. Able to give written (signed and dated) informed consent according to GCP before registration
6. Haematological and biochemical indices: Platelet count ≥ 100 x 10^9/L; Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; Total bilirubin ≤ 1.5 x upper limit of normal unless the subject has known or suspected Gilbert’s syndrome; AST (SGOT)/ALT (SGPT) ≤ 2.5 x upper limit of normal; ≤5 X ULN if liver metastases
Additional for Stage A1
1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus(not including cervical oesophagous)
2. Tumour length 10 cm 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 (up to 42 days before first study dose) and endoscopy
5. No oesophageal stent in situ
6. Haemoglobin (Hb) ≥ 8.0 g/dL
7. Estimated glomerular filtration rate ≥40mL/min
8. Previous chemotherapy treatment completed 28 days before first study dose
Additional for Stage A2
1. Any histologically confirmed advanced solid tumour that is metastatic or unresectable where investigator considers Cisplatin and Capecitabine based regimen as appropriate
2. Baseline investigations available: staging CT scan (up to 35 days before first study dose)
3. Haemoglobin (Hb) ≥ 10.0 g/dL
4. Estimated glomerular filtration rate ≥60mL/min
5. Previous chemotherapy treatment completed 28 days before first study dose
6. Calcium, magnesium and phosphate within normal limits
Additional for Stage B
1. Histologically confirmed adenocarcinoma or squamous cell carcinoma of the oesophagus including Siewert type 1 or 2 tumours with ≤2cm gastric mucosal extension (not including cervical oesophagous).
2. Tumour 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 measureable disease.
6. Diagnostic PET CT scan*
7. Staging CT scan*
*either CT or PET CT within 42 days of first study dose
8. Adequate respiratory and cardiac function tests for safe delivery of CRT in the opinion of the Principal 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. Haemoglobin (Hb) 10.0 g/dL
10. Estimated glomerular filtration rate ≥60mL/min
11. Calcium, magnesium and phosphate within normal limits |
|
| E.4 | Principal exclusion criteria |
A patient will not be eligible for the trial if any of the following apply:
1. Pregnant or breast-feeding women, or women of childbearing potential unless effective methods of contraception are used
2. 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 a 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 >450 msec in adult male and >470 msec in adult females (by either Fridericia’s or Bazett’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 enrolment
12. Strong CYP3A inhibitors and inducers or Haemopoetic growth factors within 14 days before first dose M6620
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 Stage A1 and B
1. Previous radiotherapy to thorax or upper abdomen
Additional exclusion criteria 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
Additional exclusion criteria Stage B
1. Previous chemotherapy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage A1: Highest treatment schedule resulting in less than 25% dose limiting toxicity (DLT) rate.
Stage A2: Highest treatment schedule resulting in less than 30% dose limiting toxicity (DLT) rate.
Stage B: Highest treatment schedule resulting in less than 45% dose limiting toxicity (DLT) rate. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage A1: 9 weeks from start of treatment
Stage A2: 4 weeks from start of treatment
Stage B: 24 weeks from start of treatment |
|
| E.5.2 | Secondary end point(s) |
Endpoints 1 to 3:
All Stages:
1. Any toxicity grade ≥3 graded according to CTCAE v4.03 and length of time for toxicity to resolve
2. Objective tumour response (OR) as evaluated by CT scan and quantified by Response Criteria Evaluation (RECIST 1.1) and in Stage B endoscopic and biopsy findings
3. PFS and OS rates from D1
Endpoint 4:
Stage A1
4. Proportion of patients completing at least 75%, 90% and 100% of the planned RT dose
Stage A2
4. Proportion of patients completing at least 75%, 90% and 100% of the planned dose
Stage B:
4. 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
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Endpoint number from above:
1. Stage A1, A2 and B: 12 weeks; 26 weeks & 24 weeks respectively
2. Stage A1, A2 and B: 12 weeks; 26 weeks & 24 weeks respectively
3. Stage A1/2 and B: 6 and 12 months; 12 and 24 months respectively
4. Stage A1, A2 and B: 3 weeks; 18 weeks & 11 weeks respectively |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First use in combination with radiotherapy and cisplatin/capecitabine chemotherapy |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| For the purpose of the Research Ethics Committee approval the trial end date will be the Last Patient start of treatment for Stage B plus 24 months. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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