DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients with Metastatic Colorectal Cancer (DOSAGE)

DOSAGE Study: a Multicenter Randomized Phase III Trial of DOSe-reduced Chemotherapy for Advanced Colorectal Cancer in Older Patients

The goal of this phase III, open-label, non-inferiority randomized controlled clinical trial is compare upfront dose-reduced chemotherapy with the standard dose chemotherapy in older patients ( ≥70 years) with metastasized colorectal cancer, with regard to progression-free survival (PFS). The choice between monotherapy (a fluoropyrimidine) and doublet chemotherapy (a fluoropyrimidine with oxaliplatin) will be made for each individual patient based on expected risk of chemotherapy toxicity (according to the G8 screening). Patients classified as low risk of toxicity will be randomized between doublet chemotherapy in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between monotherapy in either full-dose or upfront dose-reduction.

Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Metastatic Cancer; Older Patients; Candidates for Palliative Chemotherapy
• Intervention / Treatment: Drug: Doublet Chemotherapy, Standard Dose (100%); Drug: Doublet Chemotherapy, Dose-reduced (75%); Drug: Monotherapy, Standard Dose (100%); Drug: Monotherapy, Dose-reduced (75%)

Detailed Description

Treating older adults with chemotherapy remains a challenge, as they are strongly underrepresented in clinical trials and no robust guidelines for treating older patients exist. Moreover, older adults are at increased risk of chemotherapy-related toxicity, resulting in decreased quality of life (QoL), increased hospital admissions and high health care costs. Therefore, the aim of the DOSAGE study is to demonstrate that upfront dose-reduced chemotherapy in patients with metastasized colorectal cancer is non-inferior to full-dose treatment with regard to progression-free survival (PFS). Treatment plans (monotherapy or doublet chemotherapy) will be based on expected risk of treatment toxicity for the individual patient (according to the Geriatric 8 (G8) questionnaire). The investigators expect that this treatment strategy will lead to less grade ≥3 toxicity, less early treatment continuation and hospitalizations and a better QoL and physical functioning.

The DOSAGE study is a phase III, open-label, non-inferiority, randomized controlled clinical trial in patients aged ≥70 years with metastasized colorectal cancer eligible for palliative chemotherapy. All participating patients will undergo geriatric screening by the G8 questionnaire and will be classified as "low risk of toxicity" (G8-score of 15 or higher) or "high risk of toxicity" (G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist). Patients classified as low risk will be randomized between a fluoropyrimidine and oxaliplatin in either full-dose, or with an upfront dose-reduction of 25%. Patients classified as high risk will be randomized between fluoropyrimidine monotherapy in either full-dose or upfront dose-reduction. Addition of targeted treatment (bevacizumab or epidermal growth factor receptor (EGFR) inhibition) is allowed. Patients with a moderate renal impairment (GFR 30- 50 mL/min) will be treated with 25% reduced starting dose of capecitabine when randomized for full dose treatment and treated with 40% reduced starting dose when randomized for upfront dose reduction.

Primary outcome is PFS. Secondary endpoints include grade ≥3 toxicity, QoL, physical functioning, overall survival, number of treatment cycles, dose reductions, hospital admissions, cumulative received dosage and cost-effectiveness. Given a non-inferiority margin of 8 weeks, 587 patients will be included (293/292 patients per arm).

• Study Type: Interventional
• Enrollment (Estimated): 587
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Joosje Baltussen; Phone Number: 071 - 526 35 23; Email: DOSAGE@lumc.nl
• Study Contact Backup: Name: Data Management: Clinical Research Center LUMC; Email: ClinicalResearchCenter@lumc.nl

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands
    • Not yet recruiting
    • Jeroen Bosch Ziekenhuis
  • Alkmaar, Netherlands
    • Not yet recruiting
    • Noordwest Ziekenhuisgroep
  • Amstelveen, Netherlands
    • Not yet recruiting
    • Ziekenhuis Amstelland
  • Amsterdam, Netherlands
    • Not yet recruiting
    • Amsterdam UMC
  • Arnhem, Netherlands
    • Not yet recruiting
    • Rijnstate
  • Assen, Netherlands
    • Not yet recruiting
    • Wilhelmina ziekenhuis
  • Beverwijk, Netherlands
    • Not yet recruiting
    • Rode Kruis Ziekenhuis
  • Den Haag, Netherlands
    • Recruiting
    • Hagaziekenhuis
  • Den Haag, Netherlands
    • Not yet recruiting
    • Haaglanden Medisch Centrum
  • Doetinchem, Netherlands
    • Not yet recruiting
    • Slingeland Ziekenhuis
  • Ede, Netherlands
    • Not yet recruiting
    • Ziekenhuis Gelderse Vallei
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Ziekenhuis
  • Emmen, Netherlands
    • Not yet recruiting
    • Treant
  • Goes, Netherlands
    • Not yet recruiting
    • Admiraal De Ruyter Ziekenhuis
  • Gorinchem, Netherlands
    • Not yet recruiting
    • Beatrixziekenhuis
  • Gouda, Netherlands
    • Recruiting
    • Groene Hart Ziekenhuis
  • Hardenberg, Netherlands
    • Not yet recruiting
    • Saxenburgh
  • Harderwijk, Netherlands
    • Not yet recruiting
    • St. Jansdal Ziekenhuis
  • Helmond, Netherlands
    • Recruiting
    • Elkerliek Ziekenhuis
  • Hilversum, Netherlands
    • Recruiting
    • Tergooi Mc
  • Leeuwarden, Netherlands
    • Not yet recruiting
    • Medisch Centrum Leeuwarden
  • Leiden, Netherlands
    • Recruiting
    • Leiden University Medical Center
  • Leiderdorp, Netherlands
    • Not yet recruiting
    • Alrijne Ziekenhuis
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Canisius Wilhelmina Ziekenhuis
  • Roermond, Netherlands
    • Not yet recruiting
    • Laurentius Ziekenhuis
  • Roosendaal, Netherlands
    • Recruiting
    • Bravis ziekenhuis
  • Rotterdam, Netherlands
    • Recruiting
    • Ikazia Ziekenhuis
  • Rotterdam, Netherlands
    • Not yet recruiting
    • Maasstad Ziekenhuis
  • Scheemda, Netherlands
    • Not yet recruiting
    • Ommelander Ziekenhuis
  • Terneuzen, Netherlands
    • Recruiting
    • ZorgSaam Zorggroep Zeeuws-Vlaanderen
  • Uden, Netherlands
    • Not yet recruiting
    • Bernhoven
  • Utrecht, Netherlands
    • Not yet recruiting
    • Diakonessenhuis
  • Utrecht, Netherlands
    • Not yet recruiting
    • St Antonius
  • Venlo, Netherlands
    • Not yet recruiting
    • VieCuri Medisch Centrum
  • Winterswijk, Netherlands
    • Recruiting
    • Streekziekenhuis Koninging Beatrix
  • Zaandam, Netherlands
    • Not yet recruiting
    • Zaans Medisch Centrum

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged 70 years or older with colorectal cancer and distant metastases without localized treatment options.
• Patients who are candidates for first-line palliative chemotherapy as judged by their treating oncologist
• Being able to understand the Dutch language
• Adequate bone marrow and organ function: Absolute neutrophil count (ANC) > 1.5 x 10^9 mmol/L, Hemoglobin (Hb) > 6.0 mmol/L, Platelets >100 x 109 / L, Serum bilirubin ≤ 2 x upper limit of normal (ULN), serum transaminases ≤ 3 x ULN without presence of liver metastases or ≤ 5x ULN with presence of liver metastases.

Exclusion Criteria:

• Patients who received prior palliative chemotherapy
• Patients in whom local treatment of metastases is scheduled (i.e. liver surgery or stereotactic radiotherapy)
• Candidates for triple chemotherapy
• Patients who received prior adjuvant chemotherapy in the one year before inclusion in the study (chemotherapy before that time is allowed)
• Patients with complete or incomplete dihydropyrimidine dehydrogenase (DPD) deficiency
• Patients with Microsatellite instable (MSI)-high colorectal cancer
• Patients with HIV or active hepatitis
• Patients with severe kidney failure (defined as GFR ≤30ml/min)
• Patients with severe cognitive deficits making informed consent not possible

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Doublet therapy, full dose (low toxicity risk based on G8); Low risk of toxicity: G8-score of 15 or higher	Drug: Doublet Chemotherapy, Standard Dose (100%); Capecitabine 1000mg / m2 oral at day 1-14 (every 3 weeks) Oxaliplatin 130mg/m2 at day 1 (every 3 weeks) OR 5-FU 400mg/m2 IV bolus at day 1 followed by 2400mg/m2 in 46 hours (every 2 weeks) Leucovorin 400mg/m2 day 1 (every 2 weeks) Oxaliplatin 85mg/m2 day 1 (every 2 weeks)
Experimental: Doublet therapy, dose-reduced (low toxicity risk based on G8); Low risk of toxicity: G8-score of 15 or higher	Drug: Doublet Chemotherapy, Dose-reduced (75%); 75% of: Capecitabine 1000mg / m2 oral at day 1-14 (every 3 weeks) Oxaliplatin 130mg/m2 at day 1 (every 3 weeks) OR 5-FU 400mg/m2 IV bolus at day 1 followed by 2400mg/m2 in 46 hours (every 2 weeks) Leucovorin 400mg/m2 day 1 (every 2 weeks) Oxaliplatin 85mg/m2 day 1 (every 2 weeks)
Active Comparator: Fluoropyrimidine monotherapy, full dose (high toxicity risk based on G8); High risk of toxicity: G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist	Drug: Monotherapy, Standard Dose (100%); - Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)
Experimental: Fluoropyrimidine monotherapy, dose-reduced (high toxicity risk based on G8); High risk of toxicity: G8-score of 14 or lower or judged as "high toxicity risk" by their treating oncologist	Drug: Monotherapy, Dose-reduced (75%); 75% of: - Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-Free Survival	Time from randomization until either radiological or clinical progression or death, whichever occurs first, assessed up to at least one year.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost-effectiveness		1 year
Quality of Life Questionnaire	Measured by EQ-5D questionnaire	At 1, 3, 6 and 12 months after randomization
Quality of Life Questionnaire	Measured by EORTC Core QLQ-C30 questionnaire	At 1, 3, 6 and 12 months after randomization
Physical functioning Questionnaire	Measured by Lawton-Instrumental Activities of Daily Living (IADL) questionnaire	At 1, 3, 6 and 12 months after randomization
Physical functioning Questionnaire	Measured by Katz-Activities of Daily Living (ADL) questionnaire	At 1, 3, 6 and 12 months after randomization
Grade 3-5 chemotherapy-related toxicity	According to the CTCAE V5	Through study duration, an average of 8 months
Overall Survival		Time between randomization until death, assessed up to at least one year.
Number of completed treatment cycles		Through study duration, an average of 8 months
Dose reductions during treatment	Defined as ≥25% reduction of the initial dosage	Through study duration, an average of 8 months
Dose delay during treatment		Through study duration, an average of 8 months
Unplanned hospitalizations		The first year after treatment initiation
Cumulative received dosage	Adjusted for BSA	Through study duration, an average of 8 months

Collaborators and Investigators

• Sponsor: Leiden University Medical Center
• Collaborators: Dutch Colorectal Cancer Group
• Investigators: Principal Investigator: Johanneke Portielje, Professor, Leiden University Medical Center; Study Director: Joosje Baltussen, MD, Leiden University Medical Center

Publications and helpful links

Helpful Links

• DCCG Website

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: February 6, 2024
• First Submitted That Met QC Criteria: February 16, 2024
• First Posted (Actual): February 23, 2024

Study Record Updates

• Last Update Posted (Actual): October 16, 2024
• Last Update Submitted That Met QC Criteria: October 14, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: Non-inferiority; Palliative Chemotherapy; Dose-reduced Chemotherapy; Upfront Reduction
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: 2023-506115-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Which parts of your data(sets) will you select for publication?

The datasets generated during and/or analysed during the study will not be publicly available due to participant privacy but will be available from the corresponding author on reasonable request

Are there any restrictions placed on sharing/reuse of some/all of your data due to one or more of the following options? Signed informed consent Research agreement

Will you publish your data open access or with restricted access? Restricted access

Publishing your data (partly) with 'restricted access': what is the reason for this? Data contains privacy-sensitive information Contractual obligations Reuse by third-party through DSA.

Where will you publish your (meta)data? I will not publish (meta)data outside the LUMC

• IPD Sharing Time Frame: The datasets generated and/or analysed during the current study are not publicly available due to patient privacy but are available from the corresponding author on reasonable request
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No