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Trial registered on ANZCTR


Registration number
ACTRN12611001142921
Ethics application status
Not yet submitted
Date submitted
27/10/2011
Date registered
1/11/2011
Date last updated
11/07/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised phase II study evaluating Dual inhibition of epidermal growth factor receptor (EGFR) signalling using CetUXimab and Erlotinib or dose escalated Cetuximab in patients with chemotherapy refractory KRAS wild-type metastatic colorectal cancer
Scientific title
A randomised phase II study evaluating tumour response to Dual inhibition of EGFR signalling using CetUXimab and Erlotinib or dose escalated Cetuximab in patients with chemotherapy refractory KRAS wild-type metastatic colorectal cancer
Secondary ID [1] 273285 0
Nil
Universal Trial Number (UTN)
Trial acronym
DUX2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic colorectal cancer 279050 0
EGFR inhibitor induced skin toxicity 279051 0
Condition category
Condition code
Cancer 279240 279240 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Skin 279241 279241 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients randomised to treatment Arm B will receive dual EGFR inhibition, consisting of Cetuximab 400mg/m2 (initial dose), then 250mg/m2 via intravenous infusion each week, plus Erlotinib 100mg via oral tablet(s) daily continuously.

Patients randomised to treatment Arm C will receive high-dose Cetuximab, 500mg/m2 via intravenous infusion each week.

Treatment will continue until disease progression, unacceptable toxicity (as defined in the protocol), patient and/or clinician preference, or patient death.

Patients participating in the optional skin management study randomised to Group 1 will commence pre-emptive skin side effect treatments the day before starting study Cetuximab, and will continue until study treatment is ceased. Patients will be required to adhere to: daily use of moisturiser and topical 1% hydrocortisone (steroid) applied to face, hands, feet, neck, back each day; use of sunscreen before sun exposure; and taking doxycycline (antibiotic) 100mg via oral tablet(s) twice each day.
Intervention code [1] 283633 0
Treatment: Drugs
Intervention code [2] 283634 0
Prevention
Comparator / control treatment
Patients randomised to treatment Arm A will receive standard dose Cetuximab, consisting of an initial dose of 400mg/m2 via intravenous infusion on Day 1 week 1, then 250mg/m2 via intravenous infusion each week thereafter.

Patients participating in the optional skin management study randomised to Group 2 will receive reactive (investigator initiated) skin toxicity management, with the emergence of skin toxicity at any stage during treatment. The type and frequency of skin treatments used by the investigator are not restricted by the protocol, except where there is a known interaction with Cetuximab and/or Erlotinib. Patients are not prohibited from using skin moisturiser or sunscreen during the study.
Control group
Dose comparison

Outcomes
Primary outcome [1] 279867 0
Tumour response rate, as assessed by RECIST v.1.1 using chest, abdomen and pelvis CT.
Timepoint [1] 279867 0
Baseline, 6-weekly while on treatment then 3-monthly for 12 months of follow-up.

RECIST assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy or patient death.
Secondary outcome [1] 294631 0
Evaluate the effect of pre-emptive versus reactive skin toxicity management on papulopustular / acneiform skin rash, as assessed by investigators using CTCAE v.4 grading and patient completed Quality of Life Questionnaires (DLQI and FACT-EGFRI18).
Timepoint [1] 294631 0
Investigator assessments of adverse events (AEs) will be recorded at baseline, then 3-weekly during treatment, at the end of treatment, 30 days post end of treatment, and 3-monthly for 12 months of follow-up. Patients will complete Quality of Life Questionnaires (QoLs) at the same timepoints.

AE and QoL assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy or patient death.
Secondary outcome [2] 294632 0
Treatment-related toxicity, as assessed by investigators using CTCAE v.4 grading.
Timepoint [2] 294632 0
Investigator assessments of any present (CTCAE v.4 Grade 1 or higher) adverse events (AEs) will be recorded at baseline, then 3-weekly during treatment, at the end of treatment, 30 days post end of treatment, and 3-monthly for 12 months of follow-up.

AE assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy or patient death.
Secondary outcome [3] 294633 0
Overall survival, as assessed by investigators.
Timepoint [3] 294633 0
Investigators will record the date and cause of any patient death occuring between randomisation and completion of 12 months of follow-up.
Secondary outcome [4] 294634 0
Progression free survival, as assessed by RECIST v.1.1 using chest, abdomen and pelvis CT.
Timepoint [4] 294634 0
Baseline, 6-weekly while on treatment then 3-monthly for 12 months of follow-up.

RECIST assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy, or patient death.
Secondary outcome [5] 294635 0
Quality of Life, assessed by patient completed Quality of Life Questionnaires (DLQI and FACT-EGFRI18).
Timepoint [5] 294635 0
Patients will complete Quality of Life Questionnaires (QoLs) at baseline, then 3-weekly during treatment, at the end of treatment, 30 days post end of treatment, and 3-monthly for 12 months of follow-up.

QoL assessments cease for completion of follow-up, study withdrawal, progressive disease, new anti-cancer therapy, or patient death.
Secondary outcome [6] 294636 0
Exploratory studies of biological markers as predictors of outcome (correlation of relevant biomarkers with clinical outcomes), assessed through laboratory analysis of tumour tissue samples.
Timepoint [6] 294636 0
Tumour tissue sampled prior to study screening (whether by surgery or diagnostic procedures) will be collected after study randomisation. The analysis of samples will occur once the full study sample set is available.

Eligibility
Key inclusion criteria
1. Males or females with histologically confirmed colorectal cancer.
2. Age greater than or equal to 18 yrs.
3. Metastatic disease not amendable to resection, as confirmed by the investigator.
4. Metastatic disease which is assessable by CT scan using RECIST v1.1 criteria.
5. KRAS wild type tumour status, confirmed by means of mutation analysis performed on representative samples of diagnostic tumour tissue.
6. Received and failed fluoropyrimidine therapy, where failure is defined as radiological progression after therapy for metastatic disease, prior adjuvant therapy, or toxicity limiting further therapy.
7. Received and failed oxaliplatin therapy, where failure is defined as radiological progression after therapy for metastatic disease, prior adjuvant therapy, or toxicity limiting further therapy.
8. Received and failed irinotecan therapy, where failure is defined as radiological progression after therapy for metastatic disease or toxicity limiting further therapy.
9. ECOG performance status of 0 or 1.
10. Adequate bone marrow function with platelets >100 X 10^9/l and ANC > 1.5 X 10^9/l.
11. Adequate renal function (creatinine clearance >40 ml/min using the Cockcroft Gault formula.
12. Adequate hepatic function (serum bilirubin < 1.25 X ULN, and either ALT or AST <2.5 X ULN (or <5 X ULN if liver metastases present).
13. Life expectancy of at least 12 weeks.
14. Study treatment both planned and able to start within 14 days of randomisation.
15. Willing and able to comply with all study requirements, including treatment (e.g. able to swallow tablets), timing and/or nature of required assessments.
16. Signed, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Prior treatment with drugs targeting EGFR such as Cetuximab, Panitumumab or Erlotinib.
2. Participation in any investigational drug study within 4 weeks prior to planned study treatment start date.
3. Patients with uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris.
4. Untreated CNS metastases.
5. Other concurrent uncontrolled medical conditions.
6. Other malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer treated with curative intent >2 years previously without evidence of relapse.
7. Patients with a tetracycline allergy will be excluded from the second randomisation only.
8. Pregnancy, lactation, or inadequate contraception. Women must be post menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to the first randomisation. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomised using the minimisation method. Patients will be stratified according to study investigational site, gender, age and ECOG performance status. Patients participating in the optional skin management study will be stratified according to the assigned treatment arm (A, B or C)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Stopped early
Data analysis
Reason for early stopping/withdrawal
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,ACT,QLD,SA,WA,TAS
Recruitment outside Australia
Country [1] 3934 0
New Zealand
State/province [1] 3934 0

Funding & Sponsors
Funding source category [1] 284114 0
Commercial sector/Industry
Name [1] 284114 0
Merck Serono Australia Pty Ltd
Address [1] 284114 0
Units 3-4, 25 Frenchs Forest Road East,
Frenchs Forest, NSW 2086
Country [1] 284114 0
Australia
Funding source category [2] 284115 0
Commercial sector/Industry
Name [2] 284115 0
Roche Products Pty Limited
Address [2] 284115 0
4-10 Inman Road
Dee Why, NSW 2099
Country [2] 284115 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastrointestinal Trials Group (AGITG)
Address
Locked Bag 77
Camperdown, NSW 1450
Country
Australia
Secondary sponsor category [1] 269075 0
None
Name [1] 269075 0
Address [1] 269075 0
Country [1] 269075 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 272066 0
Cancer Institute NSW Clinical Research Ethics Committee
Ethics committee address [1] 272066 0
PO Box 41
Alexandria NSW 1435
Ethics committee country [1] 272066 0
Australia
Date submitted for ethics approval [1] 272066 0
26/11/2011
Approval date [1] 272066 0
Ethics approval number [1] 272066 0

Summary
Brief summary
This study aims to determine the safety and efficacy of three different anti-cancer treatments in patients with colorectal cancer which has not responded to chemotherapy. Who is it for? You may be eligible to join this study if you are aged 18 years or more and have colorectal cancer which is metastatic (i.e. has spread) and which has not responded to prior chemotherapy treatment. Patients with this health history routinely have a test performed on their cancer cells for a mutation in a gene called KRAS. Participants must have the non-mutated ('wild-type') variant of the KRAS gene to be eligible, among other health related criteria. Trial details Participants in this trial will be randomly (by chance) allocated to one of three arms (groups). Participants in Arm A will receive the standard dose of a drug called Cetuximab, which will be administered weekly by intravenous infusion (i.e. by a needle into the vein). Participants in Arm B will undergo the same treatment with Cetuximab, but will also take daily Erlotinib via an oral tablet (or tablets). Participants in Arm C will receive high dose Cetuximab on a weekly basis. Participants will also have the option to participate in an additional skin management study looking at 2 skin treatment options that might reduce some of the skin side effects commonly experienced by patients receiving these kinds of anti-cancer therapy. Patients participating in the skin management component will be randomly allocated to either of the 2 options. All participants will be assessed on a regular basis for the duration of their treatment, then for at least 12 months afterwards to determine response to treatment, safety and quality of life. It is not certain how long treatment will continue, as it is planned to be given until either the cancer progresses, or makes you feel too sick, or you indicate that you no longer want to participate, or you decide with your study doctor that there is no benefit to continuing treatment.
Trial website
http://www.gicancer.org.au/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 33322 0
Address 33322 0
Country 33322 0
Phone 33322 0
Fax 33322 0
Email 33322 0
Contact person for public queries
Name 16569 0
DUX2 Coordinator
Address 16569 0
NHMRC Clinical Trials Centre
The University of Sydney
Locked Bag 77
Camperdown
NSW 1450
Country 16569 0
Australia
Phone 16569 0
+61 2 9562 5000
Fax 16569 0
Email 16569 0
dux2@ctc.usyd.edu.au
Contact person for scientific queries
Name 7497 0
A/Prof Niall Tebbutt
Address 7497 0
Medical Oncology Unit, Lvl 6 Harold Stokes Building
Austin Hospital
145 Studley Road
Heidelberg, Victoria 3084
Country 7497 0
Australia
Phone 7497 0
+61 3 9496 5763
Fax 7497 0
Email 7497 0
Niall.Tebbutt@ludwig.edu.au

No data has been provided for results reporting
Summary results
Not applicable