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Trial registered on ANZCTR


Registration number
ACTRN12618000233224
Ethics application status
Approved
Date submitted
5/12/2017
Date registered
14/02/2018
Date last updated
10/09/2019
Date data sharing statement initially provided
10/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
MONARCC: A randomised phase II study of Panitumumab monotherapy and panitumumab plus 5 fluorouracil as first line therapy for RAS and BRAF wild type metastatic colorectal cancer.
Scientific title
MONARCC: A randomised phase II study of Panitumumab monotherapy and panitumumab plus 5 fluorouracil as first line therapy for RAS and BRAF wild type metastatic colorectal cancer.
Secondary ID [1] 292818 0
AG0116CR / CTC 0151
Universal Trial Number (UTN)
Trial acronym
MONARCC
Linked study record

Health condition
Health condition(s) or problem(s) studied:
metastatic colorectal cancer 305736 0
Condition category
Condition code
Cancer 304953 304953 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intravenous panitumumab 6mg/Kg every 2 weeks until disease progression or unacceptable toxicity.
Intervention code [1] 299772 0
Treatment: Drugs
Comparator / control treatment
IV Panitumumab 6mg/Kg plus infusional 5-fluorouracil (5-FU) as per the modified De-Gramont schedule consisting of 5FU bolus 400mg/m2; leucovorin 200mg/m2; 5FU 46 hour infusion at 2400mg/m2 every 2 weeks until disease progression or unacceptable toxicity.
Control group
Active

Outcomes
Primary outcome [1] 304135 0
The primary endpoint is the rate of progression free survival at 6 months defined according to RECIST V1.1 criteria
Timepoint [1] 304135 0
Progression free survival (PFS) is defined as the interval from date of randomisation to
the date of first evidence of disease progression or death, whichever occurs first. The time point for PFS is 6 months after the last patient has been enrolled
Secondary outcome [1] 341064 0
Overall survival
Timepoint [1] 341064 0
Overall survival (OS) is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known follow-up alive. The time point for OS is at the end of patient follow up which is at least 18 months after the last patient has stopped treatment.
Secondary outcome [2] 341065 0
Time to treatment failure
Timepoint [2] 341065 0
This is defined as the time from randomisation until the permanent discontinuation of study
treatments for any reason, including disease progression, treatment toxicity and death. It will be estimated using the Kaplan- Meier method.
Secondary outcome [3] 341066 0
Objective tumour response rate
Timepoint [3] 341066 0
To determine objective tumour response rate (RR) (partial or complete response at 6 months as defined by RECIST criteria version 1.1
Secondary outcome [4] 341067 0
Safety (treatment toxicity)
Timepoint [4] 341067 0
The NCI Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events after each treatment cycle. This outcome may be assessed until 30 days +/- 7 days after the last dose of treatment.
Secondary outcome [5] 341069 0
Exploratory comparisons between the treatment arms including but not limited to depth of tumour response and early tumour shrinkage, overall survival, progression free survival.
Timepoint [5] 341069 0
Early tumour shrinkage is the percentage reduction in sum of the longest diameters of target lesions (shortest diameter for lymph node target lesions) at the 8 week CT scan. Depth of response is the maximum percentage reduction in sum of the longest diameters of target lesions (shortest diameter for lymph node target lesions) at any subsequent protocol scheduled CT scan, compared to baseline.
These parameters can be compared between the treatment arms, in addition to response rate as measured by RECIST 1.1
Secondary outcome [6] 341071 0
Overall treatment utility (a composite of clinical and radiological response, toxicity, adverse events and patient-response when asked if treatment has been worthwhile).
Timepoint [6] 341071 0
Overall treatment utility (OTU) is a composite endpoint of clinical and radiological response,
toxicity, adverse events and patients response when asked if treatment has been worthwhile and will be assessed at 8 weeks and 16 weeks after randomisation..
Secondary outcome [7] 341073 0
Feasibility and utility of a comprehensive geriatric assessment (Comprehensive Health and Limited Health Assessments questionnaires).
Timepoint [7] 341073 0
All participants (with some sections requiring health care professional input) will complete the Baseline Comprehensive Health Assessment (CHA), before starting chemotherapy.
At 16 weeks, participants (again, will require health care professionals to assist) will complete the Limited Health Assessment (LHA) and a Patient Symptom Questionnaire.
In addition, every 4 weeks until disease progression, participants will also complete the Patient Symptom Questionnaire,
Secondary outcome [8] 341075 0
Physical activity which will be measured by an activity tracking device and correlated with other health related parameters including the geriatric assessments, overall survival and toxicity.
Timepoint [8] 341075 0
Patients will be given an activity tracking device on cycle 1 day 1 and the device will stay on the patient for the first treatment cycle, or 2 weeks, whichever is shorter and again at for a further 2 weeks after 4 months. Distance travelled and step count over the 2 time periods will be compared.
Secondary outcome [9] 341076 0
Validation of a prognostic nomogram.
Timepoint [9] 341076 0
The utility of this nomogram to predict patient outcome in this distinct patient population utilising novel first line treatments will be evaluated by correlating nomogram scores with progression free and overall survival. This will be assessed at 18 months at the completion of patient follow up.
Secondary outcome [10] 341077 0
Exploratory outcome - study associations between clinical outcomes and potential predictive/prognostic biomarkers including, but not limited to, the percentage of RAS mutant cells in tumour inflammatory biomarkers; and resistance mechanisms, such as HER-2 overexpression. Since the identification of new biomarkers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of biomarkers remains to be determined. This will use serum assays, blood and tumour tissues.
Timepoint [10] 341077 0
This will be assessed at 18 months at the completion of patient follow up.

Eligibility
Key inclusion criteria
1. Adults aged 70years and over.
2. Histologically or cytologically confirmed, previously untreated, metastatic colorectal cancer.
3. Suitable for panitumumab or panitumumab plus infusional 5FU, as deemed by the investigator.
4. Measurable metastatic disease (by RECIST 1.1)
5. RAS (KRAS exons 2,3 and 4; NRAS exons 2 and 3) wild type as assessed by the investigator’s choice of testing laboratory.
6. BRAF wild type as assessed by the investigator’s choice of testing laboratory. Patients with BRAF V600E mutations are not eligible. Patient with non-V600E BRAF mutations (if tested for) are eligible.
7. No prior chemotherapy except for adjuvant chemotherapy given in association with (i) complete resection of primary colon or rectal cancer provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment and/or (ii) complete resection of limited colorectal metastases to liver and/or lung provided there is no clinical, radiological or biochemical evidence of relapse for at least 6 months after completion of adjuvant treatment
8. Prior palliative radiotherapy is allowed, provided no concurrent chemotherapy was administered, at least 2 weeks after completion of therapy has elapsed before enrolment, and any toxicities have resolved to grade 1 or less.
a) Prior fluoropyrimidine chemotherapy, concurrent with radiation as neoadjuvant treatment for rectal cancer is allowed.
b) Prior radiotherapy, concurrent with radiation sensitizing fluoropyrimidines in the setting of metastatic disease is allowed.
9. Adequate haematological function: ANC > 1500/µl, Platelets >75,000/µl, Haemoglobin > 8g/dl. INR and APTT <1.5 x ULN. Note: patients previously on long term anticoagulation with warfarin or low molecular weight heparin are eligible.
10. Adequate liver function: Albumin > 25 g/l. Total bilirubin <3 x ULN. AST, ALT and/or alkaline phosphatase (ALP) <5 x ULN.
11. Adequate renal function, creatinine clearance, as measured by the Cockcroft and Gault formula) of >30mls/minute.
12. Serum potassium, magnesium and total calcium < grade 2 above or below the institution’s normal limits. Note: total calcium should be corrected for albumin level as per the institution’s usual calculation method.
13. ECOG performance status 0-2.
14. Patient is being treated with non-curative intent. This may be because the disease is anatomically not resectable or that resection is contra-indicated for any reason or the patient refuses resection.
15. Archival tissue for central review of RAF/BRAF mutation status.
16. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
17. Signed, written informed consent.
Minimum age
70 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications to investigational product.
2. Any prior treatment with cetuximab or panitumumab or bevacizumab.
3. Concurrent toxicity from any prior agent has not resolved to grade 1 or less.
4. Any major surgical procedure within two weeks of cycle 1 day 1.
5. Leptomeningeal disease as the only manifestation of their malignancy.
6. Known clinically significant dihydropyrimidine dehydrogenase deficiency.
7. History of interstitial lung disease or pulmonary fibrosis.
8. Untreated/active CNS metastases ie progressing, requiring ongoing corticosteroids or anticonvulsants for symptom control. Patients with CNS metastases are eligible if previously have been successfully treated with surgery and/or radiotherapy at least 8 weeks prior to cycle 1 day 1, are off all corticosteroids and/or anticonvulsants for at least 4 weeks and imaging within 4 weeks of cycle 1 day 1 excludes any progression.
9. Any other reason the investigator feels will prevent the patient from complying with the protocol specified treatments and assessments.
10. Invasive malignancy, other than CRC, diagnosed within 2 years of randomisation and that the investigator feels may have an impact on the patient’s outcome or disease assessments. Patients with prior or concurrent in-situ cervix carcinoma, skin SCC or basal cell carcinoma are eligible.
11. Other comorbidities or conditions that may compromise assessment of key outcomes
12. Life expectancy of less than 3 months.
13. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety.
14. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol

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)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation). Randomisation will be performed centrally using the method of minimisation.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Non-comparative phase II randomised open-label multicentre clinical trial. Treatment allocation will be balanced for the following strata: performance status (0 v >1,2); site of primary tumour (left v right) and number of metastatic sites (1 v >1) and treating institution. Patients will be allocated to either treatment group in a ratio of 1:1. Right sided tumours are defined as at, or distal to, the splenic flexure.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All randomised participants will be eligible for inclusion in the full analysis set. Analysis of efficacy endpoints will be undertaken on participants in the full analysis set unless participants are deemed non-evaluable by the Trial Management Committee. The safety population will comprise all randomised participants who received at least one administration of study medication. Participants will be analysed according to the regimen they actually received for the purposes of the safety analysis.

Recruitment
Recruitment status
Recruiting
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,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 9494 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [2] 9495 0
Border Medical Oncology - Albury
Recruitment hospital [3] 9496 0
Coffs Harbour Base Hospital - Coffs Harbour
Recruitment hospital [4] 9497 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [5] 9498 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [6] 9499 0
Royal Hobart Hospital - Hobart
Recruitment hospital [7] 9500 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [8] 9501 0
The Tweed Hospital - Tweed Heads
Recruitment hospital [9] 9502 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [10] 9503 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [11] 9504 0
Sunshine Coast University Hospital - Birtinya
Recruitment hospital [12] 9505 0
Gold Coast University Hospital - Southport
Recruitment hospital [13] 9506 0
The Prince Charles Hospital - Chermside
Recruitment hospital [14] 12074 0
Northern Cancer Institute - St Leonards
Recruitment hospital [15] 12075 0
Nepean Hospital - Kingswood
Recruitment hospital [16] 12076 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [17] 12077 0
Sunshine Hospital - St Albans
Recruitment hospital [18] 14756 0
Shoalhaven Hospital - Nowra
Recruitment postcode(s) [1] 18235 0
3084 - Heidelberg
Recruitment postcode(s) [2] 18236 0
3690 - Wodonga
Recruitment postcode(s) [3] 18237 0
2450 - Coffs Harbour
Recruitment postcode(s) [4] 18238 0
5042 - Bedford Park
Recruitment postcode(s) [5] 18239 0
5011 - Woodville
Recruitment postcode(s) [6] 18240 0
7000 - Hobart
Recruitment postcode(s) [7] 18241 0
3168 - Clayton
Recruitment postcode(s) [8] 18242 0
2485 - Tweed Heads
Recruitment postcode(s) [9] 18243 0
4029 - Herston
Recruitment postcode(s) [10] 18244 0
2010 - Darlinghurst
Recruitment postcode(s) [11] 18245 0
4575 - Birtinya
Recruitment postcode(s) [12] 18246 0
4215 - Southport
Recruitment postcode(s) [13] 18247 0
4032 - Chermside
Recruitment postcode(s) [14] 24235 0
2065 - St Leonards
Recruitment postcode(s) [15] 24236 0
2747 - Kingswood
Recruitment postcode(s) [16] 24237 0
4102 - Woolloongabba
Recruitment postcode(s) [17] 24238 0
3021 - St Albans
Recruitment postcode(s) [18] 27988 0
2541 - Nowra

Funding & Sponsors
Funding source category [1] 297447 0
Commercial sector/Industry
Name [1] 297447 0
Amgen
Address [1] 297447 0
Mezzanine Level 115 Cotham Road
Kew, VIC 3101
Country [1] 297447 0
Australia
Primary sponsor type
Other Collaborative groups
Name
AGITG
Address
Level 6, 119–143 Missenden Road, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 296444 0
None
Name [1] 296444 0
Address [1] 296444 0
Country [1] 296444 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298556 0
Sydney Local Health District Human Research
Ethics committee address [1] 298556 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 298556 0
Australia
Date submitted for ethics approval [1] 298556 0
10/07/2017
Approval date [1] 298556 0
06/09/2017
Ethics approval number [1] 298556 0
X17-0248

Summary
Brief summary
This trial (MONARCC) seeks to determine what the best initial treatment is for a patient population with metastatic colorectal cancer that cannot withstand the expected side effects of the commonly used combination chemotherapy regimens.

Who is it for?
You may be eligible to join this study if you are aged 70 years or above and have a confirmed diagnosis of untreated metastatic colorectal cancer.

Study details
Participants in this study will be randomly (by chance) allocated to one of two groups. Participants in one group will receive low intensity targeted therapy, panitumumab, which is generally well tolerated as a single treatment without chemotherapy. Participants in the other group will receive panitumumab combined with chemotherapy (5FU), a standard treatment. All treatments are administered via the intravenous route (i.e. directly into the vein) and will be administered every 2 weeks until disease progression or unacceptable toxicity.

All participants will be followed up to 18 months in order to assess treatment efficacy and safety. The hypothesis is that panitumumab will be a safe, acceptable, effective and convenient regimen to elderly patients with newly diagnosed advanced colorectal cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77454 0
Dr Matthew Burge
Address 77454 0
Royal Brisbane and Women's Hospital, Bowen Bridge Rd & Butterfield St, Herston QLD 4029
Country 77454 0
Australia
Phone 77454 0
+61 2 9562 5000.
Fax 77454 0
Email 77454 0
monarcc@ctc.usyd.edu.au
Contact person for public queries
Name 77455 0
Ms MONARCC Trial Coordinator
Address 77455 0
NHMRC Clinical Trials Centre, University of Sydney
119–143 Missenden Road, Camperdown NSW 2050
Country 77455 0
Australia
Phone 77455 0
+61 2 9562 5000.
Fax 77455 0
Email 77455 0
monarcc@ctc.usyd.edu.au
Contact person for scientific queries
Name 77456 0
Ms MONARCC Trial Coordinator
Address 77456 0
NHMRC Clinical Trials Centre, University of Sydney
119–143 Missenden Road, Camperdown NSW 2050
Country 77456 0
Australia
Phone 77456 0
+61 2 9562 5000.
Fax 77456 0
Email 77456 0
monarrc@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD sharing according to local SOPs, policies and agreements
What supporting documents are/will be available?
No other documents available
Summary results
No Results