A phase II double-blind, randomised controlled trial of VEGF inhibitor axitinib monotherapy with early dynamic contrast-enhanced ultrasound monitoring in chemo-refractory third-line metastatic colorectal cancer

ISRCTN	ISRCTN70833965
DOI	https://doi.org/10.1186/ISRCTN70833965
EudraCT/CTIS number	2011-002598-49
ClinicalTrials.gov number	NCT04355156
Secondary identifying numbers	12424

Submission date: 25/10/2013
Registration date: 25/10/2013
Last edited: 24/07/2020

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

http://www.cancerresearchuk.org/cancer-help/trials/a-trial-looking-axitinib-advanced-bowel-cancer-axmus-c

Contact information

Miss Mohana Suppiah
Scientific

Hammersmith Hospital
Du Cane Road
London
W12 0HS
United Kingdom

Email	Mohana.Suppiah@imperial.nhs.uk

Study information

Study design	Randomised interventional treatment trial
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Scientific title	A phase II double-blind, randomised controlled trial of VEGF inhibitor axitinib monotherapy with early dynamic contrast-enhanced ultrasound monitoring in chemo-refractory third-line metastatic colorectal cancer
Study acronym	AXMUS-C
Study objectives	A Phase II, double-blind, two-arm pilot randomised placebo-controlled trial. 50 patients will be randomised 2:1 to Axitinib or placebo. Main inclusion criteria: chemo-refractory third-line metastatic CRC with US-assessable liver or other abdominal metastases that can have a baseline DCEUS baseline measurement. Arm A: Axitinib monotherapy started in all patients at 5 mg bd, and increased fortnightly by a dose level as tolerated to a maximum dose of 10 mg bd. Arm B: Placebo at 2:1 ratio to treatment Follow up: Optional visit at 48-72 hours post first dose for measurement of temperature, oxygen saturations, blood pressure and CEHPI. Outpatient monitoring at 2 weeks and 4 weeks post first dose and at 4-week intervals thereafter which will include medical history and examination, measurement of temperature, oxygen saturations and blood pressure, urinalysis and blood tests including GI profile and VEGF-PK samples. RECIST restaging at 8 weeks and at 8 weekly intervals thereafter. CEHPI will be performed at baseline, optionally at 48-72 hours, 2 weeks and 8 weeks for assessment of differential blood supply. At 8 weeks, after tumour CT RECIST assessments, conventional responders (CR/PR/SD) continue monotherapy. In non-responders (PD), monotherapy can be continued if the patient chooses to continue and if tolerated.
Ethics approval(s)	12/LO/0066; First MREC approval date 23/04/2012
Health condition(s) or problem(s) studied	Topic: National Cancer Research Network; Subtopic: Colorectal Cancer; Disease: Colon, Rectum
Intervention	Arm A: Axitinib monotherapy started in all patients at 5 mg bd, and increased fortnightly by a dose level as tolerated to a maximum dose of 10 mg bd. Arm B: Placebo at 2:1 ratio to treatment Axitinib/ Placebo +CEPHI, Axitinib, a substituted indazole derivative, is an oral, potent, and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3 After 4 hours of fasting, a DCE-US scan is performed on each subject in the supine position using an iU22 ultrasound scanner (Philips Healthcare, Andover, MA) with a C5-1 curvilinear transducer. The probe is held still in the right intercostal space in order to visualise the porta hepatis. This allows simultaneous visualization of the hepat. Study Entry : Single Randomisation only
Intervention type	Drug
Pharmaceutical study type(s)
Phase	Phase II
Drug / device / biological / vaccine name(s)	Axinitib
Primary outcome measure	To demonstrate a progression-free survival to Axitinib monotherapy in metastatic colorectal cancer
Secondary outcome measures	Not provided at time of registration
Overall study start date	05/09/2012
Completion date	31/03/2015

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	UK Sample Size: 51
Key inclusion criteria	Participants must meet all of the following inclusion criteria to eligible for enrollment into the trial: 1. Histologically or cytologically confirmed adenocarcinoma of the colon or rectum with liver metastas(es), at least one of which should not have had any focal therapy including radiofrequency ablation, chemoembolization, ethanol or cryoablation. 2. Failed at least two chemotherapy regimens in advanced disease. 3. Evidence of unidimensionally measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST). 4. Male and female, 18 years of age or older. 5. ECOG performance status of 0 or 1. 6. Resolution of all acute toxic effects of prior therapy e.g. radiotherapy or surgical procedure to NCI CTCv4 grade =1. 7. Adequate organ function as defined by the following criteria: 7.1. Serum aspartate aminotransferase (AST¿ serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine aminotransferase (ALT¿ serum glutamic pyruvic transaminase [SGPT]) ≤2.5 x upper limit of normal (ULN). For patients with liver metastases, <5 x ULN. 7.2. Total serum bilirubin <1.5 x ULN 7.3. Serum albumin ≥3.0 g/dL 7.4. Absolute neutrophil count ≥1500/μL 7.5. Platelets ≥100,000/μL 7.6. Haemoglobin ≥9.0 g/dL 7.7. Serum creatinine ≤1.5 x ULN 8. Signed and dated informed consent form 9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures 10. At least 2 weeks since the end of prior systemic treatment (4 weeks for Bevacizumab-containing regimens), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 3.0 grade ≤1 or back to baseline except for alopecia or hypothyroidism. 11. No evidence of pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be ≤140 mmHg, and the baseline diastolic blood pressure readings must be ≤90 mmHg. Patients whose hypertension is controlled by anti-hypertensive therapies are eligible. 12. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment. 13. Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrolment.
Key exclusion criteria	Participants must be excluded if they present with any of the following exclusion criteria: 1. Non-exposed to both oxaliplatin and irinotecan FP based cytotoxic chemotherapy (prior pelvic radiation therapy including adjuvant or neoadjuvant chemoradiation therapy for resected rectal cancer is allowed provided it is completed within 4 weeks prior to study entry) 2. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital, phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St Johns wort). Current use or anticipated need for treatment with drugs that are known CYP3A4 inhibitors (i.e., grapefruit juice, ketoconazole, nefazodone, itraconazole, miconazole, erythromycin, clarithromycin, telithromycin, verapamil, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir and delavirdine) 3. Any of the following within the 12 months prior to study drug administration: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack and 6 months for deep vein thrombosis or pulmonary embolism. 4. Non-English speaking 5. Pregnancy, breastfeeding, or unwillingness/inability to employ an effective method of birth control/contraception to prevent pregnancy during treatment and for up to 3 months after discontinuing study drug if of reproductive potential. 6. Hypertension uncontrolled by medication (>150/100 mmHg despite optimal medical therapy). 7. Diagnosis of any second malignancy within the last 3 years that is potentially liable to interfere with study outcomes (basal cell carcinoma, squamous cell skin cancer, or in situ carcinoma and hormone-controlled locally advanced prostate cancer that has been adequately treated with no evidence of recurrent disease for 12 months, are allowed) 8. Prior surgery or IMP within 4 weeks prior to study entry 9. Current treatment within another therapeutic clinical trial.
Date of first enrolment	05/09/2012
Date of final enrolment	31/03/2015

Locations

Countries of recruitment

England
United Kingdom

Study participating centre

Hammersmith Hospital

London
W12 0HS
United Kingdom

Sponsor information

Imperial College of Science, Technology and Medicine (UK)
University/education

School of Medicine, Hammersmith Hospital
Du Cane Road
London
W12 0HS
England
United Kingdom

"ROR"	https://ror.org/041kmwe10

Funders

Funder type

Industry

Pfizer Ltd

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
Publication and dissemination plan	Not provided at time of registration
IPD sharing plan

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
HRA research summary			28/06/2023	No	No

Editorial Notes

24/07/2020: ClinicalTrials.gov number added.
31/05/2019: Internal review.
16/02/2017: No publications found in PubMed, verifying study status with principal investigator.