Randomized, Double-Blind, Phase II Trial of Vitamin D Supplementation in Patients With Previously Untreated Metastatic Colorectal Cancer
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 139
- 试验地点
- 16
- 主要终点
- Median Progression-free Survival (PFS)
研究概览
简要总结
This is a prospective, randomized, double-blind phase II trial to evaluate the efficacy and safety of two doses of vitamin D supplementation in combination with standard chemotherapy in participants with previously-untreated metastatic colorectal adenocarcinoma.
详细描述
In this research study, the investigators are comparing standard and higher dose Vitamin D treatment when given in combination with standard treatment for metastatic colorectal cancer. Standard treatment includes the chemotherapy combination of 5-FU, Leucovorin and Oxaliplatin (FOLFOX) with bevacizumab.
Participants will be randomized into one of the study groups-Arm A: Vitamin D (standard dose of 400 IU/day), FOLFOX and Bevacizumab or Arm B: Vitamin D (higher dose of 8000 IU/day for 2 weeks followed by 4000 IU/day), FOLFOX and Bevacizumab.
Study Treatment (A cycle of treatment is 14 days):
Vitamin D
Cycle 1: You will take two capsules of Vitamin D orally, once a day (at the same time), every day. Participants randomized to Arm A will be taking one capsule with 400 IU of Vitamin D and one capsule with placebo (pills with no medicine) so that neither you nor your doctor will know what group you have been assigned to. Participants randomized to Arm B will be taking two capsules of 4000 IU each.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed adenocarcinoma of the colon or rectum that is metastatic or locally advanced (unresectable)
- •Measurable disease
- •KRAS wild-type and KRAS mutant patients are eligible
- •No prior systemic treatment for advanced or metastatic colorectal cancer is allowed
- •No prior radiotherapy to more than 25% of bone marrow
- •No surgery or major biopsy within 4 weeks of randomization
- •Paraffin-embedded and/or snap-frozen tumor tissue samples must be available
排除标准
- •Not pregnant or breastfeeding
- •No prior chemotherapy, systemic therapy or investigational agent
- •No concurrent use of other anti-cancer therapy
- •No known brain metastases
- •No history of other malignancies except adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, curatively treated lobular or ductal carcinoma in situ of the breast or other cancer curatively treated with no evidence of disease for more than 3 years prior to randomization
- •No regular use of vitamin D supplements greater than 2000 IU per day in the past year
- •No history of allergic reactions attributed to compounds of similar chemical or biologic composition to 5-FU, capecitabine, oxaliplatin, leucovorin, bevacizumab and/or vitamin D3
- •No significant history of bleeding events, pre-existing bleeding diathesis, coagulopathy or gastrointestinal perforation
- •No arterial thrombotic events within 6 months of randomization
- •No serious non-healing wound, ulcer or bone fracture
- •No history of uncontrolled hypertension
- •No clinically significant peripheral neuropathy
- •No predisposing colonic or small bowel disorders in which the symptoms are uncontrolled
- •No uncontrolled seizure disorder or active neurological disease
- •No pre-existing hypercalcemia
- •No known active hyperparathyroid disease
- •No regular use of thiazide diuretics
- •No malabsorption, uncontrolled vomiting or diarrhea
- •No known co-morbid disease that would increase the risk of toxicity
- •No use of chronic oral corticosteroid therapy or any other therapy that can cause vitamin D depletion
- •No clinically significant cardiovascular disease
- •No uncontrolled intercurrent illness
- •No history of any medical or psychiatric condition or addictive disorder or laboratory abnormality that may increase the risks associated with study participation
研究组 & 干预措施
Chemotherapy + Standard Dose Vitamin D
FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 400 IU vitamin D3 orally once daily
Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons.
干预措施: FOLFOX + bevacizumab (Drug)
Chemotherapy + Standard Dose Vitamin D
FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 400 IU vitamin D3 orally once daily
Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons.
干预措施: Vitamin D (Dietary Supplement)
Chemotherapy + Higher Dose
FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 8000 IU daily x 2 weeks as loading dose, followed by 4000 IU daily as maintenance dose.
Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons.
干预措施: FOLFOX + bevacizumab (Drug)
Chemotherapy + Higher Dose
FOLFOX-bevacizumab: intravenously on Day 1 (+/- 7 days) of every two-week cycle per institutional standards + 8000 IU daily x 2 weeks as loading dose, followed by 4000 IU daily as maintenance dose.
Participants were treated until disease progression, unacceptable toxicity or withdrawal for other reasons.
干预措施: Vitamin D (Dietary Supplement)
结局指标
主要结局
Median Progression-free Survival (PFS)
时间窗: Disease was evaluated every 4 cycles on treatment and off treatment every 8-16 weeks until PD or non-protocol therapy start if discontinued for reason other than PD. Participants were observed up to 28.5 months with maximum follow-up of 56.7 months.
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. Patients who discontinued treatment to pursue potentially curative resection were censored for progression-free survival at the time of surgery. Patients who had not experienced cancer progression or died were censored at their last known follow-up date.
次要结局
- Number of Participants With Vitamin D Deficiency at Baseline(Baseline)
- Vitamin D Sufficiency Rate(Plasma samples were collected at 3 timepoints on treatment: first restaging (cycle 5, day 1), second restaging (cycle 9, day 1) and at treatment discontinuation. Median (maximum) treatment duration was 7.3 (28.5) months.)
- Hazard Ratio Between Baseline Plasma 25(OH)D Level and PFS(Baseline Plasma 25(OH)D Level and up to 28.5m for evaluation of PFS.)
- Median Overall Survival (OS)(Participants were followed for survival by clinic visit or telephone every 3 months post-treatment discontinuation up to 36 months from the date that the last participant was enrolled. Median follow-up was 22.9 months with maximum 56.7 months.)
- Objective Response Rate(Disease was evaluated every 4 cycles on treatment. Median (maximum) treatment duration was 7.3 (28.5) months.)
- Grade 3-5 Treatment-Related Neutropenia Toxicity Rate(AEs were evaluated at day 1 of each cycle on treatment and up to 30 days after the last dose. Maximum treatment duration is 28.5 months with median 7.3 months.)
- Plasma 25-hydroxyvitamin D Levels(Plasma samples were collected at 4 timepoints on study: baseline, first restaging (cycle 5, day 1), second restaging (cycle 9, day 1) and at treatment discontinuation. Median (maximum) treatment duration was 7.3 (28.5) months.)
- Hazard Ratio Between Baseline Plasma 25(OH)D Levels and OS(Baseline Plasma 25(OH)D Level and up to maximum 56.7 months for evaluation of OS.)
研究者
Kimmie Ng, MD
Principal Investigator
Dana-Farber Cancer Institute