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

Официальное название

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

Обзор

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.

Подробное описание

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).

Вмешательства

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

Первичные конечные точки

• Progression-Free Survival [Срок оценки: Time from randomization until either radiological or clinical progression or death, whichever occurs first, assessed up to at least one year.]

Вторичные конечные точки (12)

• Quality of Life Questionnaire [Срок оценки: At 1, 3, 6 and 12 months after randomization]
• Quality of Life Questionnaire [Срок оценки: At 1, 3, 6 and 12 months after randomization]
• Physical functioning Questionnaire [Срок оценки: At 1, 3, 6 and 12 months after randomization]
• Physical functioning Questionnaire [Срок оценки: At 1, 3, 6 and 12 months after randomization]
• Grade 3-5 chemotherapy-related toxicity [Срок оценки: Through study duration, an average of 8 months]
• Overall Survival [Срок оценки: Time between randomization until death, assessed up to at least one year.]
• Number of completed treatment cycles [Срок оценки: Through study duration, an average of 8 months]
• Dose reductions during treatment [Срок оценки: Through study duration, an average of 8 months]
• Dose delay during treatment [Срок оценки: Through study duration, an average of 8 months]
• Unplanned hospitalizations [Срок оценки: The first year after treatment initiation]
• Cumulative received dosage [Срок оценки: Through study duration, an average of 8 months]
• Cost-effectiveness [Срок оценки: 1 year]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Нидерланды · 36 центров

• Jeroen Bosch Ziekenhuis — 's-Hertogenbosch
• Noordwest Ziekenhuisgroep — Alkmaar
• Ziekenhuis Amstelland — Amstelveen
• Amsterdam UMC — Amsterdam
• Rijnstate — Arnhem
• Wilhelmina Ziekenhuis — Assen
• Rode Kruis Ziekenhuis — Beverwijk
• Slingeland Ziekenhuis — Doetinchem
• … и ещё 28 центров

Публикации

• 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 colorec PMID 39142680

Идентификаторы

NCT: NCT06275958 · 2023-506115-17 · 2023-506115-17

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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