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

NCT ID: NCT06275958

Last Updated: 2024-10-16

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

RECRUITING

Clinical Phase

PHASE3

Total Enrollment

587 participants

Study Classification

INTERVENTIONAL

Study Start Date

2024-07-01

Study Completion Date

2028-12-31

Brief Summary

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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

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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).

Conditions

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Older Patients Colorectal Cancer Metastatic Cancer Candidates for Palliative Chemotherapy

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

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 Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Doublet therapy, full dose (low toxicity risk based on G8)

Low risk of toxicity: G8-score of 15 or higher

Group Type ACTIVE_COMPARATOR

Doublet Chemotherapy, Standard Dose (100%)

Intervention Type DRUG

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 therapy, dose-reduced (low toxicity risk based on G8)

Low risk of toxicity: G8-score of 15 or higher

Group Type EXPERIMENTAL

Doublet Chemotherapy, Dose-reduced (75%)

Intervention Type DRUG

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)

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

Group Type ACTIVE_COMPARATOR

Monotherapy, Standard Dose (100%)

Intervention Type DRUG

\- Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

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

Group Type EXPERIMENTAL

Monotherapy, Dose-reduced (75%)

Intervention Type DRUG

75% of:

\- Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

Interventions

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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)

Intervention Type 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)

Intervention Type DRUG

Monotherapy, Standard Dose (100%)

\- Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

Intervention Type DRUG

Monotherapy, Dose-reduced (75%)

75% of:

\- Capecitabine 1000mg/m2 oral at day 1-14 (every 3 weeks)

Intervention Type DRUG

Eligibility Criteria

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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
Minimum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Dutch Colorectal Cancer Group

OTHER

Sponsor Role collaborator

Leiden University Medical Center

OTHER

Sponsor Role lead

Responsible Party

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Johanna E A Portielje, MD PhD

Professor Medical Oncology

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Johanneke Portielje, Professor

Role: PRINCIPAL_INVESTIGATOR

Leiden University Medical Center

Joosje Baltussen, MD

Role: STUDY_DIRECTOR

Leiden University Medical Center

Locations

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Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Site Status NOT_YET_RECRUITING

Noordwest Ziekenhuisgroep

Alkmaar, , Netherlands

Site Status NOT_YET_RECRUITING

Ziekenhuis Amstelland

Amstelveen, , Netherlands

Site Status NOT_YET_RECRUITING

Amsterdam UMC

Amsterdam, , Netherlands

Site Status NOT_YET_RECRUITING

Rijnstate

Arnhem, , Netherlands

Site Status NOT_YET_RECRUITING

Wilhelmina Ziekenhuis

Assen, , Netherlands

Site Status NOT_YET_RECRUITING

Rode Kruis Ziekenhuis

Beverwijk, , Netherlands

Site Status NOT_YET_RECRUITING

Slingeland Ziekenhuis

Doetinchem, , Netherlands

Site Status NOT_YET_RECRUITING

Ziekenhuis Gelderse Vallei

Ede, , Netherlands

Site Status NOT_YET_RECRUITING

Catharina Ziekenhuis

Eindhoven, , Netherlands

Site Status RECRUITING

Treant

Emmen, , Netherlands

Site Status NOT_YET_RECRUITING

Admiraal de Ruyter Ziekenhuis

Goes, , Netherlands

Site Status NOT_YET_RECRUITING

Beatrixziekenhuis

Gorinchem, , Netherlands

Site Status NOT_YET_RECRUITING

Groene Hart Ziekenhuis

Gouda, , Netherlands

Site Status RECRUITING

Saxenburgh

Hardenberg, , Netherlands

Site Status NOT_YET_RECRUITING

St. Jansdal Ziekenhuis

Harderwijk, , Netherlands

Site Status NOT_YET_RECRUITING

Elkerliek Ziekenhuis

Helmond, , Netherlands

Site Status RECRUITING

Tergooi MC

Hilversum, , Netherlands

Site Status RECRUITING

Medisch Centrum Leeuwarden

Leeuwarden, , Netherlands

Site Status NOT_YET_RECRUITING

Leiden University Medical Center

Leiden, , Netherlands

Site Status RECRUITING

Alrijne Ziekenhuis

Leiderdorp, , Netherlands

Site Status NOT_YET_RECRUITING

Canisius Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

Site Status NOT_YET_RECRUITING

Laurentius Ziekenhuis

Roermond, , Netherlands

Site Status NOT_YET_RECRUITING

Bravis ziekenhuis

Roosendaal, , Netherlands

Site Status RECRUITING

Ikazia Ziekenhuis

Rotterdam, , Netherlands

Site Status RECRUITING

Maasstad Ziekenhuis

Rotterdam, , Netherlands

Site Status NOT_YET_RECRUITING

Ommelander Ziekenhuis

Scheemda, , Netherlands

Site Status NOT_YET_RECRUITING

ZorgSaam Zorggroep Zeeuws-Vlaanderen

Terneuzen, , Netherlands

Site Status RECRUITING

Haaglanden Medisch Centrum

The Hague, , Netherlands

Site Status NOT_YET_RECRUITING

Hagaziekenhuis

The Hague, , Netherlands

Site Status RECRUITING

Bernhoven

Uden, , Netherlands

Site Status NOT_YET_RECRUITING

Diakonessenhuis

Utrecht, , Netherlands

Site Status NOT_YET_RECRUITING

St Antonius

Utrecht, , Netherlands

Site Status NOT_YET_RECRUITING

VieCuri Medisch Centrum

Venlo, , Netherlands

Site Status NOT_YET_RECRUITING

Streekziekenhuis Koninging Beatrix

Winterswijk, , Netherlands

Site Status RECRUITING

Zaans Medisch Centrum

Zaandam, , Netherlands

Site Status NOT_YET_RECRUITING

Countries

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Netherlands

Central Contacts

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Joosje Baltussen

Role: CONTACT

071 - 526 35 23

Data Management: Clinical Research Center LUMC

Role: CONTACT

References

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Baltussen JC, van den Bos F, Slingerland M, Binda TRR, Liefers GJ, van den Hout WB, Fiocco M, Verschoor AJ, Cloos-van Balen M, Holterhues C, Houtsma D, Jochems A, Spierings LEAMM, van Bodegom-Vos L, Mooijaart SP, Gelderblom H, Speetjens FM, de Glas NA, Portielje JEA. DOSAGE study: protocol for a phase III non-inferiority randomised trial investigating dose-reduced chemotherapy for advanced colorectal cancer in older patients. BMJ Open. 2024 Aug 13;14(8):e089882. doi: 10.1136/bmjopen-2024-089882.

Reference Type DERIVED
PMID: 39142680 (View on PubMed)

Related Links

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Other Identifiers

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2023-506115-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2023-506115-17

Identifier Type: -

Identifier Source: org_study_id

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