Clinical Trial of a Novel Dose Adjustment Algorithm for Preventing Cytopenia-Related Delays During FOLFOX Chemotherapy

Study Overview
=================
Brief Summary
-----------------
The study is testing an intervention of an investigator-developed chemotherapy dose adjustment algorithm. The primary objective of this study is to evaluate the effectiveness of the chemotherapy dose adjustment algorithm for reducing unplanned delays in patients receiving FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin)-type chemotherapy, while maintaining acceptable chemotherapy dose-intensity.

Detailed Description
-----------------
The study intervention will involve implementation of a clinical algorithm to guide chemotherapy dose reductions and treatment delays in patients with neutropenia and/or thrombocytopenia during treatment with FOLFOX-type regimens. The clinical algorithm was developed by the principal investigator, and the algorithm has been iteratively revised over time based on experiences from use in routine care. Features of the dose adjustment algorithm that differ from criteria used in clinical trial protocols and routine care include: At presentation for cycle 2 and 3 - the algorithm employs proactive chemotherapy dose reductions, without treatment delay, in patients with mild cytopenias (absolute neutrophil count [ANC] 1000-1499/mm3 and/or platelet count 75,000-99,000/mm3). In usual care, mild cytopenias during early treatment cycles do not trigger a chemotherapy dose reduction, but these early cytopenia events often lead to more severe cytopenias and subsequent delays in later treatment cycles. At any cycle - the algorithm employs chemotherapy dose reductions without treatment delay in patients with moderate cytopenias (ANC 750-999/mm3 and/or platelet count 50,000-74,000/mm3). In usual care, moderate cytopenias trigger both a chemotherapy treatment delay AND a subsequent dose reduction, whereas the study algorithm will introduce a dose reduction without a treatment delay. Decisions about dose modifications and delays for reasons other than neutropenia and/or thrombocytopenia will be made at the discretion of the treating clinician, as per standard-of-care treatment.

Official Title
-----------------
A Pragmatic, Single-Arm Clinical Trial of a Novel Dose Adjustment Algorithm for Preventing Cytopenia-Related Delays During FOLFOX Chemotherapy

Conditions
-----------------
Colorectal Cancer, Gastric Cancer, Esophageal Cancer, Ampullary Cancer, Small Bowel Cancer, Appendix Cancer

Intervention / Treatment
-----------------
* Other: Algorithm for cytopenia-related delay and dose-reduction of mFOLFOX chemotherapy


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age greater than 18 Diagnosis of adenocarcinoma of the gastrointestinal tract (to include cancers of the colorectum, stomach, esophagus, appendix, and small bowel) The treating oncologist's recommendation must be for six or more cycles of standard-dose mFOLFOX chemotherapy (with or without concurrent bevacizumab, cetuximab, panitumumab, or trastuzumab). Intent of treatment may be either curative or palliative in nature. Completion of day 1 of cycle 1 of standard-of-care FOLFOX chemotherapy Exclusion Criteria: Prior receipt of systemic chemotherapy in the 12 months prior to day 1 of cycle 1 of mFOLFOX (other than radiation-sensitizing chemotherapy) History of baseline neutropenia; defined as neutrophil count <1500 in the 30 days preceding planned day 1 of cycle 1 of mFOLFOX History of baseline thrombocytopenia; defined as platelet count <100,000) in the 30 days preceding planned day 1 of cycle 1 of mFOLFOX Patients with a history of an uncorrected bleeding condition that would preclude safe use of the dose adjustment algorithm, in the judgement of the enrolling investigator Patients who have started a new prescription anticoagulant (e.g. warfarin, heparin derivatives, or direct oral anticoagulants) in the 14 days preceding day 1 of cycle 1 of mFOLFOX Patients who are unable to provide informed consent Pregnant women

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Arm<br>All patients in this single-arm study will be exposed to the experimental chemotherapy dose-adjustment algorithm. | Other: Algorithm for cytopenia-related delay and dose-reduction of mFOLFOX chemotherapy<br>* Chemotherapy dose-adjustment algorithm for FOLFOX chemotherapy<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Unplanned chemotherapy treatment delay | Number of patients with any interruption of chemotherapy leading to a cycle length of >18 days that is not anticipated as of day 3 of the preceding treatment cycle. | Through day 1 of cycle 6 of FOLFOX chemotherapy (cycle length is 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite safety endpoint | Number of patients meeting the composite endpoint of 1) febrile neutropenia (grade 3 or 4), 2) major bleeding with concurrent grade 3 thrombocytopenia (platelet count <50,000/mm3), 3) CTCAE grade 4 neutropenia (ANC <500/mm3), and/or 4) CTCAE grade 4 thrombocytopenia (platelet count <25,000/mm3) | Through day 1 of cycle 6 of FOLFOX chemotherapy (cycle length is 14 days) | 
| Relative dose intensity of chemotherapy | Relative dose intensity (RDI) of chemotherapy. RDI is defined as (planned cumulative dose/cumulative administered dose)*(actual duration/planned duration). RDI will be calculated separately for each component of the FOLFOX regimen (5-FU bolus, 5-FU infusion, oxaliplatin). | Through day 1 of cycle 6 of FOLFOX chemotherapy (cycle length is 14 days) | 
| Out of pocket costs associated with chemotherapy treatment visits | Survey-reported out-of-pocket costs will be used to estimate out-of-pocket costs associated with cytopenia-related chemotherapy treatment delays. | Single chemotherapy treatment visit on day 1 of cycle 3, 4, or 5 (cycle length is 14 days) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
neutropenia, thrombocytopenia, FOLFOX, dose adjustment