Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001536459
Ethics application status
Approved
Date submitted
2/11/2016
Date registered
8/11/2016
Date last updated
8/01/2020
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Oxaliplatin Dose Modification for Colorectal Cancer Triggered by Patient Reported Toxicity: Acceptability and Effect on Chronic Chemotherapy Induced Peripheral Neuropathy
Scientific title
Oxaliplatin Dose Modification for Colorectal Cancer Triggered by Patient Reported Toxicity: Acceptability and Effect on Chronic Chemotherapy Induced Peripheral Neuropathy
Secondary ID [1] 290436 0
None
Universal Trial Number (UTN)
U1111-1189-3123
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
metastatic colorectal cancer 300788 0
chemotherapy induced peripheral neuropathy 300789 0
Condition category
Condition code
Cancer 300614 300614 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention involves a questionnaire that is given to patients prior to each cycle of chemotherapy which is given every 3 weeks as an outpatient at secondary hospital settings in the MidCentral Region. Patients will receive up to 8 cycles of chemotherapy.
This questionnaire is a modified version of the NCI PRO-CTCAE neurotoxicity questions. It has been modified for use in this study by also incorporating questions regarding symptom duration and persistence of symptoms. The answers to the questions are then used by the treating clinician who is either the specialist medical oncologist or the training registrar under the supervision of the medical oncologist, to modify the Oxaliplatin dose according to a pre-specified guideline which is outlined in a flow-diagram. This guideline suggests the following modifications:
* No numbness or tingling continue with same dose
* Reported mild numbness and tingling triggers a 20-25% dose reduction in Oxaliplatin for the subsequent cycle
* If a patient reports that mild numbness and tingling occurred on no more than or lasted for no longer than 3 days, the clinician has the option of continuing with the same dose of chemotherapy
* If a patient reports persistent mild numbness and tingling present at the time of clinic, this triggers a “hold” on Oxaliplatin and Capecitabine continues. If the numbness or tingling improves or remains mild at the subsequent pre-chemotherapy clinic, Oxaliplatin can be reintroduced with a 20-25% dose reduction
* Reported moderate numbness and tingling triggers a “hold” on Oxaliplatin for the subsequent cycle
* Capecitabine chemotherapy continues, without Oxaliplatin
* Assessment of numbness and tingling at the subsequent pre-chemotherapy clinic
* If numbness and tingling is present and has not improved, Oxaliplatin is discontinued
* If numbness and tingling has resolved or has improved and is reported as mild on the modified PRO-CTCAE questionnaire, Oxaliplatin can be reintroduced with a 20-25% dose reduction
* Reported severe or very severe numbness and tingling triggers discontinuation of Oxaliplatin
* Dose reductions for numbness and tingling can be made on two occasions. If there is ongoing numbness and tingling after 2 dose reductions, Oxaliplatin is discontinued
The questionnaire is given to the patient when they come for their pre-chemotherapy clinic and Oxaliplatin modifications made for their subsequent cycle. At each clinic, the clinician will fill out a form, reporting whether the intervention has been followed and if it hasn't, the reason for this.
Intervention code [1] 296282 0
Prevention
Intervention code [2] 296314 0
Treatment: Drugs
Comparator / control treatment
There is no control group for the primary outcome.
The secondary outcomes, specifically best tumour response and progression-free survival will be compared with historical controls at MidCentral Regional Cancer Treatment Services. These controls will come from a local audit performed on patients who were treated in 2014 with XELOX chemotherapy including Oxaliplatin given at a dose of 130 mg/m2 every 3 weeks. Currently, there is no clear, evidence-based guideline regarding dose modification for Oxaliplatin in response to neuropathy and practice varies between clinicians.
The secondary outcome of chronic chemotherapy induced peripheral neuropathy assessed as percentage reduction from baseline in the EORTC QLQ-CIPN20 questionnaire will be compared to findings in the N08CB/Alliance study (Clinical Trials Information: NCT00316914). This trial tested the ability of intravenous calcium and magnesium to reduce Oxaliplatin neuropathy. Patients were accrued for this study between June 2010 and June 2012 and in August 2015, Pachman et al. reported on the clinical course of Oxaliplatin induced neuropathy experienced by this patient population. Patients in this trial were treated with FOLFOX chemotherapy which included Oxaliplatin at a dose of 85 mg/m2 every 2 weeks. Oxaliplatin dose modification was not dictated in this trial but recommendations were included as guidelines for patient treatment. These recommendations included a dose reduction to 65 mg/m2 for patients with grade 2 sensory neuropathy (using NCI-CTCAE version 4.0) that did not resolve within 2 weeks and discontinuing Oxaliplatin in patients with persistent grade 3 neuropathy.
Although these comparisons will provide us with limited information, they will provide guidance on whether this intervention should be looked at in a prospective randomized study.
Control group
Historical

Outcomes
Primary outcome [1] 300028 0
Acceptability of the intervention defined by clinician compliance with the intervention - this will be measured as a percentage of individuals in which the intervention is implemented. This will be assessed using forms which are filled out by the clinician at clinic. The forms will ask what has the patient has recorded on their questionnaire, what modifications have been made to chemotherapy and if the intervention has not been followed, why this is. Acceptability requires that the intervention is implemented in at least 80% of individuals.
Timepoint [1] 300028 0
This is assessed at the completion of oxaliplatin chemotherapy, this being when the patient has stopped all oxaliplatin. Compliance is where the intervention has been followed throughout the chemotherapy course for an individual patient.
The reason for completion of chemotherapy, ie. toxicity, progression, completed all intended cycles, will be captured on forms filled out by the clinician at clinic.
Secondary outcome [1] 328837 0
the severity of chronic chemotherapy induced peripheral neuropathy determined by the percent reduction from baseline in the EORTC QLQ-CIPN20 score
Timepoint [1] 328837 0
assessed at 6, 12 and 18 months following commencement of chemotherapy
Secondary outcome [2] 328838 0
the proportion of patients receiving low (<421 mg/m2), moderate (421-842 mg/m2) and high ( >/= 842 mg/m2) cumulative doses of oxaliplatin. This is a composite outcome and will be assessed using clinical records of oxaliplatin doses given.
Timepoint [2] 328838 0
This is assessed at the completion of oxaliplatin chemotherapy, this being when the patient has stopped all oxaliplatin. The reason for completion of chemotherapy, ie. toxicity, progression, completed all intended cycles, will be captured on forms filled out by the clinician at clinic.
Secondary outcome [3] 328839 0
best tumour response achieved with chemotherapy categorized as response, stable disease or progressive disease
Timepoint [3] 328839 0
assessed with CT using RECIST v1.1, performed following completion of chemotherapy.
Secondary outcome [4] 328840 0
progression free survival
Timepoint [4] 328840 0
at 6, 12 and 18 months following commencement of chemotherapy

Eligibility
Key inclusion criteria
1. Male or female patients with histologically proven colorectal adenocarcinoma
* Histological confirmation of metastatic disease or of the primary lesion where an alternative cause for metastatic disease is considered unlikely
2. Unresectable metastatic disease with radiological measurable disease according to RECIST v1.1 on computed tomography (CT)
3. Assessed as suitable for palliative XELOX chemotherapy
4. No contraindications to capecitabine or oxaliplatin chemotherapy
5. Able to complete questionnaires and comply with intervention, assessments and follow-up
6. Written, informed consent
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Age < 18 years
2. Patients with a pre-existing neurological condition including established diabetic peripheral neuropathy
3. Patients who have previously been treated with neurotoxic chemotherapy agents including platinums, taxanes and vinka-alkaloids
4. Patients with contra-indications to capecitabine or oxaliplatin

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The study aims to recruit 30 patients over 12 months. This has been chosen as MidCentral District Health Board Treats approximately 40 patients with metastatic colorectal cancer annually using Xelox chemotherapy. This will provide sufficient information to inform whether the intervention will be taken forward to a prospective, multi-centre, randomized controlled study and will be considered if the intervention reaches acceptability criteria. Acceptability of the intervention requires clinician compliance with the intervention in at least 80% of individuals.
Analysis will include patients who have received at least 1 cycle of XELOX chemotherapy and who have been assessed for cycle 2.
* Patients lost to follow up prior to planned study completion will be included in the analysis
Primary outcome:
* Success requires an intervention compliance rate of 80%. This will be analysed as clinician compliance with the intervention in 80% of individuals
Secondary outcomes will be compared to historical controls, which has limitations. These outcomes serve as a guide to further inform whether this intervention will be taken forward to a multi-centre, prospective, randomized, controlled study
* An exploratory analysis looking at neurotoxicity by compliance will be performed
Variables will be presented as means, medians, ranges, frequencies and percentages as appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
16/01/2017
Actual
6/03/2017
Date of last participant enrolment
Anticipated
11/09/2020
Actual
Date of last data collection
Anticipated
11/03/2022
Actual
Sample size
Target
30
Accrual to date
23
Final
Recruitment outside Australia
Country [1] 8363 0
New Zealand
State/province [1] 8363 0
Mid Central

Funding & Sponsors
Funding source category [1] 294844 0
Hospital
Name [1] 294844 0
MidCentral Regional Cancer Treatment Services
Country [1] 294844 0
New Zealand
Primary sponsor type
Hospital
Name
MidCentral Regional Cancer Treatment Services
Address
MidCentral Regional Cancer Treatment Services
Palmerston North Hospital
50 Ruahine Street
Palmerton North
NewZealand
5510
Country
New Zealand
Secondary sponsor category [1] 293681 0
None
Name [1] 293681 0
Address [1] 293681 0
Country [1] 293681 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296227 0
Health and Disability Ethics Committees
Ethics committee address [1] 296227 0
Ministry of Health
Ethics Department
133 Molesworth Street
Thorndon
Wellington
6011
Ethics committee country [1] 296227 0
New Zealand
Date submitted for ethics approval [1] 296227 0
18/11/2016
Approval date [1] 296227 0
09/12/2016
Ethics approval number [1] 296227 0
16/STH/197

Summary
Brief summary
Combination chemotherapy with fluoropyrimidine and oxaliplatin is a commonly used first line chemotherapy regimen, in patients with unresectable metastatic colorectal cancer. Potential oxaliplatin toxicities include chemotherapy induced peripheral neuropathy (CIPN), which can be both acute and chronic and can substantially affect quality of life (QoL). Although acute CIPN is almost always reversible, chronic CIPN can persist following completion of chemotherapy and is frequently irreversible. Chronic CIPN can be reduced, however, by reducing the cumulative dose of oxaliplatin, however currently there is no evidence to guide dose reductions and achieve improved outcome. This study aims to define an acceptable guideline for oxaliplatin dose modification, using patient reported CIPN.
Aims and Objectives:
The aim of this study is to assess the acceptability of patient reported CIPN in addition to standard care, as a trigger for oxaliplatin dose modification. This could later be compared to standard care alone, in a prospective randomised trial.
Primary objective:
To determine the acceptability of patient reported CIPN as a trigger for oxaliplatin dose modification, defined as the compliance rate of clinicians with the intervention.
Secondary objectives:
To determine the interventions effect on:
1. The severity of chronic CIPN
2. Cumulative dose of oxaliplatin
3. Tumour response rate
4. Progression free survival
Hypothesis:
The addition of patient reported CIPN as a trigger for oxaliplatin dose modification is acceptable and results in reduced severity of chronic CIPN.
Study Design and Target Population:
A single arm phase 2 acceptability trial, in patients with unresectable metastatic colorectal cancer undergoing palliative XELOX chemotherapy.
Intervention:
Patients will complete a modified PRO-CTCAE questionnaire prior to each cycle of chemotherapy and this will trigger pre-specified oxaliplatin dose modifications.
Outcomes and Measures:
Primary outcome: acceptability of the intervention defined by a clinician compliance rate of at least 80%.
Secondary outcomes:
* Severity of chronic CIPN defined by the percent reduction from baseline EORTC QLQ-CIPN score
* Cumulative dose of oxaliplatin at the completion of chemotherapy
* Tumour response rate defined by the best response achieved on CT
* Progression free survival at 6, 12 and 18 months
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 1339 1339 0 0
/AnzctrAttachments/371756-HDEC Letter - 16STH197 - Approved Application.pdf (Ethics approval)

Contacts
Principal investigator
Name 70082 0
Dr Liyana Satterthwaite
Address 70082 0
c/o MidCentral Regional Cancer Treatment Services
Palmerston North Hospital
50 Ruahine Street
Palmerston North
5510
Country 70082 0
New Zealand
Phone 70082 0
+64273053410
Fax 70082 0
Email 70082 0
liyana.satterthwaite@gmail.com
Contact person for public queries
Name 70083 0
Dr Liyana Satterthwaite
Address 70083 0
c/o MidCentral Regional Cancer Treatment Services
Palmerston North Hospital
50 Ruahine Street
Palmerston North
5510
Country 70083 0
New Zealand
Phone 70083 0
+64273053410
Fax 70083 0
Email 70083 0
liyana.satterthwaite@gmail.com
Contact person for scientific queries
Name 70084 0
Dr Liyana Satterthwaite
Address 70084 0
c/o MidCentral Regional Cancer Treatment Services
Palmerston North Hospital
50 Ruahine Street
Palmerston North
5510
Country 70084 0
New Zealand
Phone 70084 0
+64273053410
Fax 70084 0
Email 70084 0
liyana.satterthwaite@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.