MONARCC: a randomised phase II study of panitumumab monotherapy and panitumumab plus 5-fluorouracil as first-line therapy for RAS and BRAF wildtype metastatic colorectal cancer: a study by the Australasian Gastrointestinal Trials Group (AGITG)

Background Doublet chemotherapy in combination with a biologic agent has been a standard of care in patients with metastatic colorectal cancer for over a decade. The evidence for a “lighter” treatment approach is limited to mono-chemotherapy plus bevacizumab in the RAS unselected population. Anti-EGFR antibodies have activity as monotherapy or in combination with chemotherapy in RAS wildtype metastatic colorectal cancer; however their role in first-line treatment in combination with 5-fluorouracil monotherapy or when given alone has not been well studied. MONARCC aims to investigate this approach in an elderly population. Methods/design MONARCC is a prospective, open-label, multicentre, non-comparative randomised phase II trial. Eligible patients aged ≥70 with unresectable metastatic, untreated, RAS/BRAF wildtype metastatic colorectal cancer will be randomised 1:1 to receive panitumumab alone or panitumumab plus infusional 5-fluorouracil. RAS and BRAF analyses will be performed in local laboratories. Comprehensive Health Assessment and Limited Health Assessments will be performed at baseline and at 16 weeks, respectively, to assess frailty. The Patient Symptom Questionnaire and Overall Treatment Utility are to be undertaken at different timepoints to assess the impact of treatment-related toxicities and quality of life. Treatment will be delivered every 2 weeks until disease progression, unacceptable toxicity (as determined by treating clinician or patient), delay of treatment of more than 6 weeks, or withdrawal of consent. The primary end point is 6-month progression-free survival in both arms. Secondary end points include overall survival, time to treatment failure, objective tumour response rate as defined by RECIST v1.1 and safety (adverse events). Tertiary and correlative endpoints include the feasibility and utility of a comprehensive geriatric assessment, quality of life and biological substudies. Discussion MONARCC investigates the activity and tolerability of first-line panitumumab-based treatments with a view to expand on current treatment options while maximising progression-free and overall survival and quality of life in molecularly selected elderly patients with metastatic colorectal cancer. Trial registration Australia New Zealand Clinical Trials Registry: ACTRN12618000233224, prospectively registered 14 February 2018. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08644-4.


1.
Completion by nurse at baseline.

Notes for Research Nurse/Data Manager:
This baseline health assessment is an indispensable part of the trial. It must be completed after obtaining the patient's consent, but before telephoning the CTC to register and randomise the patient. The CHA is in two parts, (a) a nurse-administered assessment of physical parameters, mental state and medical history, and (b) a patient-completed questionnaire dealing with various aspects of quality of life. Randomisation will not be performed until both parts of the CHA have been completed.

CHA Nurse-Administered Section:
For this section of the CHA, you need a quiet, private environment where the patient can answer questions without feeling pressurised or "on trial". Ensure the patient is comfortable and not hungry, thirsty or in need of the toilet or analgesia. Hearing aids, if used, should be working. The patient may have a carer present, but if so ask them not to answer questions on the patient's behalf. If an interpreter is required, use a professional interpreter in preference to a relative. You will need: a blank sheet of paper; scales and a measure for height and weight; a tape measure for arm circumference. This assessment includes a timed 20-metre walk. For this, a straight 20-metre distance should be marked out, for example in the clinic corridor, and you will need a watch or stopwatch. don't know weight loss. If so, how much? Approx …………..kg weight gain If so, how much? Approx …………..kg P.5) timed 20-metre walk. Use an unobstructed straight 20-metre distance (this should be marked off, for example, in the clinic corridor). Ask the patient to walk as fast as they can without running, starting at the start line and continuing for a few steps beyond the finish line. If they normally use a walking stick or frame, this should be used. Gentle support (e.g. holding elbow) may be given.

Introduce this section with something along the lines of: "Please don't be offended, but I'd like to ask you a few memory test questions now."
Then ask the patient the following questions (exact words in bold) clearly and score the patient's answers.
M.1) "What day of the week is it?" (must be exact to score as correct)  correct  incorrect M.2) "What is the date today?" (must be exact to score as correct) 3) "What is the month?" (must be exact to score as correct)  correct  incorrect M.4) "What is the season?" ("spring" acceptable for Mar -Jun; "summer" for Jun -Sep; "autumn" for Sep -Dec, and "winter" for Dec -Mar inclusive)   saying all three, please repeat them. Remember what they are because I am going to ask you to name them again in a few minutes: Apple…. Table…. Penny" (may repeat up to 5 times)  correct  incorrect M.29) "Please write a sentence of your choice on this piece of paper" (grammar and spelling not important; accept any sentence with a subject (real or implied) and verb. "Help" or "Go away" are acceptable)  correct  incorrect M.30) "Copy this drawing on a piece of paper" (show the patient the following drawing. To score correct, they must draw two intersection pentagons, and the intersection should be a diamond shape)  correct  incorrect Baseline Comprehensive Health Assessment: Completion by nurse at baseline.

Section C (Charlson Comorbidity Index)
This section is completed from the medical notes, although it is helpful to do so whilst the patient is still present so that you can clarify any missing data (using lay terms Completion by patient at baseline.

CHA Patient Questionnaire Section:
This section of the CHA is a patient-completed questionnaire. Please ensure the patient has a relaxed, private environment such as a clinic room, not a public waiting area. Ensure they are comfortable and not hungry, thirsty or in need of the toilet or analgesia. The patient may have a carer present, but if so ask them not to answer questions on the patient's behalf. If an interpreter is required, use a professional interpreter rather than a relative, if possible.
Some patients will require help reading or interpreting the questions, or ticking the response boxes. The research nurse or data manager should offer to sit with the patient and help if they wish, but if so should not change the patient's initial "gut reaction" responses. When the patient has finished, the research nurse or data manager should look through the questionnaire before the patient leaves, check that there are no missing or unclear answers and check that the patient ID and date are complete.

Dear Patient,
As part of our research into finding the best chemotherapy for your condition, we'd like to ask you some questions about your activities, symptoms and feelings. Would you please go through this questionnaire and, for each question, tick the answer that fits most closely, even if it is not exact. If there are questions you cannot answer, please ask the nurse for help (or, if you would prefer, the nurse can sit with you and read out all the questions Very poor Excellent

During the past week …
Baseline Comprehensive Health Assessment: Completion by patient at baseline.

Finally, please answer these questions about your feelings. For each statement please mark the box which best describes how you have been feeling over the past week:
H.1) "I feel tense or 'wound up'…"

Limited Health Assessment (LHA)
Completion once by nurse and patient ONCE after 16 weeks.
The Limited Health Assessment must be completed prior to the patient seeing the treating clinician on that visit day.

Notes for Research Nurse/Data Manager:
This health assessment, along with the baseline CHA, is an indispensable part of the trial. It is completed once after the first 16 weeks of chemotherapy. These forms will provide important data for the trial. Like the CHA, the LHA is in two sections, (a) a nurse-administered assessment of physical parameters, and (b) a patient-completed questionnaire dealing with various aspects of quality of life.

LHA Nurse-Administered Section:
You will need: scales and a measure for height and weight; a tape measure for arm circumference. This assessment includes a timed 20-metre walk. For this, a straight 20metre distance should be marked out, for example in the clinic corridor, and you will need a watch or stopwatch. Ask the patient if they are aware of having lost or gained weight:  don't know  weight loss. If so, how much? Approx …………..kg  weight gain If so, how much? Approx …………..kg P.5) timed 20-metre walk. Use an unobstructed straight 20-metre distance (this should be marked off, for example, in the clinic corridor). Ask the patient to walk as fast as they can without running, starting at the start line and continuing for a few steps beyond the finish line. If they normally use a walking stick or frame, this should be used. Gentle support (e.g. holding elbow) may be given.

LHA Patient Questionnaire Section:
This section of the LHA is a patient-completed questionnaire. Please ensure the patient has a relaxed, private environment such as a clinic room, not a public waiting area. Ensure they are comfortable and not hungry, thirsty or in need of the toilet or analgesia. The patient may have a carer present, but if so ask them not to answer questions on the patient's behalf. If an interpreter is required, use a professional interpreter rather than a relative, if possible.
Some patients will require help reading or interpreting the questions, or ticking the response boxes. The research nurse or data manager should offer to sit with the patient and help if they wish, but if so should not change the patient's initial "gut reaction" responses. When the patient has finished, the research nurse or data manager should look through the questionnaire before the patient leaves, check that there are no missing or unclear answers and check that the patient ID and date are complete.

Dear Patient,
As part of our research into finding the best chemotherapy for your condition, we would like to ask you the same questions that we did at the start of your treatment, about your activities, symptoms and feelings. Very poor Excellent Finally, please answer these questions about your feelings. For each statement please mark the box which best describes how you have been feeling over the past week: