DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients With Metastatic Colorectal Cancer

Colorectal Cancer Clinical Trial

— DOSAGE  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06275958
• Other study ID #: 2023-506115-17
• Secondary ID: 2023-506115-17
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 2024
• Est. completion date: December 2028

Study information

• Verified date: February 2024
• Source: Leiden University Medical Center
• Contact: Joosje Baltussen
• Phone: 071 - 526 35 23
• Email: DOSAGE[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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).

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 587
• Est. completion date: December 2028
• Est. primary completion date: June 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 70 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Metastatic Cancer
• Older Patients

Intervention

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)
• 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)
• Monotherapy, Standard Dose (100%)
- Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)
• Monotherapy, Dose-reduced (75%)
75% of: - Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

Locations

Country	Name	City	State
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Noordwest Ziekenhuisgroep	Alkmaar
Netherlands	Ziekenhuis Amstelland	Amstelveen
Netherlands	Amsterdam UMC	Amsterdam
Netherlands	Rijnstate	Arnhem
Netherlands	Wilhelmina Ziekenhuis	Assen
Netherlands	Rode Kruis Ziekenhuis	Beverwijk
Netherlands	Haaglanden Medisch Centrum	Den Haag
Netherlands	Hagaziekenhuis	Den Haag
Netherlands	Slingeland Ziekenhuis	Doetinchem
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Treant	Emmen
Netherlands	Admiraal de Ruyter Ziekenhuis	Goes
Netherlands	Beatrixziekenhuis	Gorinchem
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Saxenburgh	Hardenberg
Netherlands	St. Jansdal Ziekenhuis	Harderwijk
Netherlands	Elkerliek Ziekenhuis	Helmond
Netherlands	Tergooi MC	Hilversum
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Alrijne Ziekenhuis	Leiderdorp
Netherlands	Canisius Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Laurentius Ziekenhuis	Roermond
Netherlands	Bravis ziekenhuis	Roosendaal
Netherlands	Ikazia Ziekenhuis	Rotterdam
Netherlands	Maasstad Ziekenhuis	Rotterdam
Netherlands	Ommelander Ziekenhuis	Scheemda
Netherlands	ZorgSaam Zorggroep Zeeuws-Vlaanderen	Terneuzen
Netherlands	Bernhoven	Uden
Netherlands	Diakonessenhuis	Utrecht
Netherlands	St Antonius	Utrecht
Netherlands	VieCuri Medisch Centrum	Venlo
Netherlands	Streekziekenhuis Koninging Beatrix	Winterswijk
Netherlands	Zaans Medisch Centrum	Zaandam

Sponsors (3)

Lead Sponsor	Collaborator
Leiden University Medical Center	Dutch Colorectal Cancer Group, Stichting Darmkanker

Country where clinical trial is conducted

Netherlands, 

Outcome

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

External Links

•   DCCG Website