Clinical trial NCT06275958: DOSAGE Study: Upfront Dose-Reduced Chemotherapy in Older Patients with Metastatic Colorectal Cancer
Official title: DOSAGE Study: a Multicenter Randomized Phase III Trial of DOSe-reduced Chemotherapy for Advanced Colorectal Cancer in Older Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Older Patients
Colorectal Cancer
Metastatic Cancer
Candidates for Palliative Chemotherapy
Keywords: Dose-reduced Chemotherapy
Upfront Reduction
Palliative Chemotherapy
Non-inferiority
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
Collaborators: name: Dutch Colorectal Cancer Group
First posted: 2024-02-23
Enrollment: 587
Sex: ALL
Minimum age (years): 70
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A phase III, open-label, non-inferiority, randomized controlled clinical trial comparing dose-reduced chemotherapy versus standard dose chemotherapy in older adults with metastasized colorectal cancer
Primary purpose: TREATMENT

Brief 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.

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).

Eligibility criteria: 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

Primary outcomes:
measure: Progression-Free Survival
timeFrame: Time from randomization until either radiological or clinical progression or death, whichever occurs first, assessed up to at least one year.
Secondary outcomes:
measure: Quality of Life Questionnaire
timeFrame: At 1, 3, 6 and 12 months after randomization
measure: Quality of Life Questionnaire
timeFrame: At 1, 3, 6 and 12 months after randomization
measure: Physical functioning Questionnaire
timeFrame: At 1, 3, 6 and 12 months after randomization
measure: Physical functioning Questionnaire
timeFrame: At 1, 3, 6 and 12 months after randomization
measure: Grade 3-5 chemotherapy-related toxicity
timeFrame: Through study duration, an average of 8 months
measure: Overall Survival
timeFrame: Time between randomization until death, assessed up to at least one year.
measure: Number of completed treatment cycles
timeFrame: Through study duration, an average of 8 months
measure: Dose reductions during treatment
timeFrame: Through study duration, an average of 8 months
measure: Dose delay during treatment
timeFrame: Through study duration, an average of 8 months
measure: Unplanned hospitalizations
timeFrame: The first year after treatment initiation
measure: Cumulative received dosage
timeFrame: Through study duration, an average of 8 months
measure: Cost-effectiveness
timeFrame: 1 year
Other outcomes:
Locations:
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep
city: Amstelveen
country: Netherlands
facility: Ziekenhuis Amstelland
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Den Haag
country: Netherlands
facility: Haaglanden Medisch Centrum
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Emmen
country: Netherlands
facility: Treant
city: Goes
country: Netherlands
facility: Admiraal de Ruyter Ziekenhuis
city: Gorinchem
country: Netherlands
facility: Beatrixziekenhuis
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Hardenberg
country: Netherlands
facility: Saxenburgh
city: Harderwijk
country: Netherlands
facility: St. Jansdal Ziekenhuis
city: Helmond
country: Netherlands
facility: Elkerliek Ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi MC
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Leiden University Medical Center
city: Leiderdorp
country: Netherlands
facility: Alrijne Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
city: Roermond
country: Netherlands
facility: Laurentius Ziekenhuis
city: Roosendaal
country: Netherlands
facility: Bravis ziekenhuis
city: Rotterdam
country: Netherlands
facility: Ikazia Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Scheemda
country: Netherlands
facility: Ommelander Ziekenhuis
city: Terneuzen
country: Netherlands
facility: ZorgSaam Zorggroep Zeeuws-Vlaanderen
city: Uden
country: Netherlands
facility: Bernhoven
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Utrecht
country: Netherlands
facility: St Antonius
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum
city: Winterswijk
country: Netherlands
facility: Streekziekenhuis Koninging Beatrix
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
Study officials:
affiliation: Leiden University Medical Center
name: Johanneke Portielje, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Leiden University Medical Center
name: Joosje Baltussen, MD
role: STUDY_DIRECTOR
References: