A multicentre randomised phase II study of aflibercept plus chemotherapy in patients with colorectal liver-only metastases deemed to be inoperable or unsuitable for upfront liver resectio

Phase 1

• Conditions: colorectal cancer with liver metastases; MedDRA version: 18.0Level: PTClassification code 10061451Term: Colorectal cancerSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2014-000845-64-GB
• Lead Sponsor: The Royal Marsden NHS Foundation Trust

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2015-07-23
• Last Update Posted: 10 April 2017

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 689

Inclusion Criteria

MAIN STUDY AND SAFETY RUN-IN PHASE OF THE STUDY:

A patient may be included if the answer to all of the following statements is yes”.
•Signed and dated informed consent, and willing and able to comply with protocol requirements,
•Histologically proven adenocarcinoma of the colon and/or rectum,
•Metastatic disease confirmed, with liver-only metastatic disease except in the safety run-in phase of the study, where extra-hepatic disease in the presence of liver metastases will be allowed. Presence of metachronous or synchronous liver metastases will be allowed. For patients enrolled in the safety run-in phase of the study, they will be required to have at least one liver metastasis but they will not have to meet the liver resectibility criteria set out for the main study.
•Liver metastases considered to be unresectable at randomisation based on at least one of the following:
i) No upfront R0/R1 resection of all hepatic lesions possible
Note: a patient with bilobar disease suitable for a two-stage resection would still fulfill the inclusion criteria for unresectability.
ii) Less than 30% estimated residual liver after resection
iii) Disease in contact with major vessels of the remnant liver (vessels remaining after potential hepatectomy).
These criteria should be discussed and agreed at an MDM in a local hepatopancreaticobiliary (HPB) centre.
•Presence of synchronous colorectal primary cancer will be allowed.
•General condition considered feasible for major abdominal surgery after first-line chemotherapy.
•No evidence of extrahepatic metastatic disease as determined by CT CAP or other investigations such as PET scan or biopsy (if required). However, for the SAFETY RUN-IN PHASE of FOLFOXIRI + aflibercept, all comers with metastatic colorectal cancer will be allowed, irrespective of their RAS mutation status. These patients must have hepatic metastatic disease with or without extra-hepatic metastatic disease. The patients included in the safety run-in phase of the study with extra-hepatic disease will not be included in the final analysis but will be followed up according to the trial follow up plan.
•Age =18 years
•WHO Performance status (PS) 0-2,
•Patients with adequate haematological, renal and liver functions as defined in the protocol.
•Proteinuria <2+ (dipstick urinalysis) or =1g/24hour.
•Regular follow-up feasible.
•For female patients of childbearing potential, negative serum pregnancy test within 1 week (7 days) prior of starting study treatment,
•Female patients must commit to using reliable and appropriate methods of contraception until at least six months after the end of study treatment (when applicable). Male patients with a partner of childbearing potential must agree to use contraception in addition to having their partner use another contraceptive method during the trial and for six months after the last study drug treatment.

Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 500
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 170

Exclusion Criteria

A patient will not be eligible to enter the study if the answer to any of the following statement is yes”.

•Pre-existing permanent neuropathy (NCI grade =2)
•Uncontrolled hypercalcemia,
•Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy,
•Concomitant protocol unplanned antitumor therapy (e.g. chemotherapy, molecular targeted therapy, immunotherapy),
•Treatment with any other investigational medicinal product within 28 days prior to study entry.
•Other serious and uncontrolled non-malignant disease,
•History or evidence upon physical examination of CNS metastasis
•Intolerance to atropine sulfate or loperamide
•Known dihydropyrimidine dehydrogenase deficiency
•Any of the following in 3 months prior to inclusion: grade 3-4 gastrointestinal bleeding (unless due to resected tumour), treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, or diverticulitis.
•Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >6months, Adjuvant or neo-adjuvant chemotherapy for prior tumour should be completed for more than 6 months of randomisation. In case of synchronous rectal cancer, radiotherapy with or without chemotherapy for primary rectal cancer will be allowed.
•Any other serious and uncontrolled non-malignant disease, major surgery or traumatic injury within the last 28 days
•Pregnant or breastfeeding women,
•Patients with known allergy to study drugs,
•History of myocardial infarction and/or stroke within 6 months prior to randomization. This includes, but is not limited to, the following examples: cerebrovascular accidents (= 6 months prior to registration), myocardial infarction (= 6 year prior to registration), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, clinically significant ECG findings (e.g. QTc = 460 or = 2º AV Block, etc.). Patients who suffer from serious cardiac arrhythmia requiring medication can enter the study only if they are considered to be in a stable condition regarding both the arrhythmia and their medication. Patients with pacemakers are allowed to enter the study only if they are considered as being in a stable condition. In case of doubt, the investigator should obtain a consultation with a local cardiologist.
•Bowel obstruction.
•Medical or psychiatric conditions that compromises the patient’s ability to give informed consent.
•Serious, non-healing wound, ulcer or bone fracture
•Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization
•Immunocompromised patients e.g. human immunodeficiency virus (HIV). Patients with hepatic disease e.g. patients with known serologically positive
Hepatitis B or Hepatitis C.
• Treatment with strong CYP3A4 inducers (e.g. Avasimibe,(5) carbamazepine, phenytoin, rifampin, St. John’s wort) unless discontinued > 7 days prior to randomization. For more detailed information on CYP3A4 inducers, please see:http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified