A Phase I Trial of Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer (CRPC)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 43
- 试验地点
- 4
- 主要终点
- Incidence of Dose Limiting Toxicities (DLT)
研究概览
简要总结
The objective of this study is to determine the maximum safe dose of Ra-223 in combination with fractionated (split doses) docetaxel when given to subjects and to determine the best administering dose. The study will look at side effects that may happen while taking the combination treatment. A total of approximately 18 subjects will take part in the dose escalation part of the study and an additional 25 subjects will participate in the expansion cohort. This study will be conducted across four centers in the United States.
详细描述
The primary objective of this study is to assess the safety and toxicity of a fractionated docetaxel schedule in combination with standard Ra-223.
Secondary Objectives include: assessment of progression-free survival, time to treatment failure, overall survival, ability of subjects to complete 6 cycles of the combination therapy, assessment of Prostate Specific Antigen (PSA) kinetics and objective responses (measurable disease), assessment of quality of life and assessment of bone bio-marker outcomes.
The study features a 4-week lead-in period with docetaxel monotherapy to assess for docetaxel intolerance. The lead-in period is then followed by combination therapy with Ra-223 every 4 weeks for 6 cycles in a traditional Phase I dose-escalation design.
A provision has been made to include prophylactic granulocyte colony stimulating factor (G-CSF) cohorts after the lead-in period if neutropenia is the dose limiting toxicity at either dose level.
The investigators hypothesize that the fractionated dosing of docetaxel will significantly mitigate the hematologic toxicity, preserve antineoplastic activity and allow for maintenance of the 4-weekly Ra-223 schedule.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
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 or cytologically confirmed adenocarcinoma of the prostate
- •Documented metastatic castration resistant disease with PSA progression, radiographic progression, or both, despite medical or surgical castration
- •Two or more bone metastases detected on skeletal scintigraphy
- •Eligible for docetaxel chemotherapy
- •ECOG Performance Status 0-2
- •Adequate organ function:
- •Hemoglobin > 10 g/dL
- •Absolute Neutrophil Count ≥ 1,500 K/mL
- •Platelet count ≥ 150,000 x 10^9/L
- •Total bilirubin ≤ 1.5x upper limit of normal range, excluding Gilbert syndrome
- •Serum AST ≤ 1.5 x upper limit of normal range
- •Serum ALT ≤ 1.5 x upper limit of normal range
- •Estimated glomerular filtration rate (GFR) > 30mL/min
- •Ongoing castration (androgen deprivation therapy or prior orchiectomy)
- •Male subjects with female sexual partners of childbearing potential must agree to use at least one highly effective methods of birth control.
- •Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures.
- •Age ≥ 18 years
排除标准
- •Prior radionuclide therapy for CRPC
- •Prior docetaxel for CRPC. (Permitted if given for castration sensitive disease > 6 months prior).
- •Antiandrogen therapy within 4 weeks of enrollment. However, patients with primary failure of secondary anti-androgen therapy OR symptomatic progression, objective progression and/or biochemical evidence of rising PSA less than 4 weeks after discontinuation of anti-androgen therapy will not have anti-androgen withdrawal responses and will not be excluded.
- •Preexisting peripheral neuropathy grade 2 or higher.
- •Other serious medical condition as judged by the investigator.
- •Active second malignancy that requires therapy.
- •Known brain or leptomeningeal metastases
- •Concurrent enrollment in any other investigational anticancer therapy
- •Treatment with any myelosuppressive agent within 30 days of enrollment
- •Presence of bulky visceral metastases, defined as any of the following:
- •≥ 4 lung lesions (at least 1cm each in size in the longest diameter) or pulmonary lymphangitic metastasis
- •Liver metastases with sum of lesion diameters totaling ≥ 5cm
- •Evidence of neuroendocrine or small cell differentiation on prior biopsy
- •History of severe hypersensitivity reactions to docetaxel or to drugs formulated with polysorbate 80
研究组 & 干预措施
Dose escalation
There are four dose cohorts (1, 1a, 2, 2a) in this arm and two dose levels of docetaxel (40mg/m^2 [level 1] and 50mg/m^2 [level 2]). Dosing of Radium 223 remains the same in all cohorts (55 KBq/kg given every 28 days for 6 cycles).
Maximum tolerated dose (MTD) of docetaxel will be assessed. MTD is defined as the highest dose-level, among those tested, associated with a rate of less than a 33% dose limiting toxicity (DLT).
干预措施: Docetaxel (Drug)
Dose escalation
There are four dose cohorts (1, 1a, 2, 2a) in this arm and two dose levels of docetaxel (40mg/m^2 [level 1] and 50mg/m^2 [level 2]). Dosing of Radium 223 remains the same in all cohorts (55 KBq/kg given every 28 days for 6 cycles).
Maximum tolerated dose (MTD) of docetaxel will be assessed. MTD is defined as the highest dose-level, among those tested, associated with a rate of less than a 33% dose limiting toxicity (DLT).
干预措施: Radium 223 (Radiation)
Dose expansion
If the maximum tolerated dose (MTD) of docetaxel is found in arm 1, this dose level will be expanded to include an additional 25 subjects to confirm the safety and explore the preliminary anti-cancer effect. If the MTD is not identified, the study will be stopped and the expansion cohort will not be accrued.
干预措施: Docetaxel (Drug)
Dose expansion
If the maximum tolerated dose (MTD) of docetaxel is found in arm 1, this dose level will be expanded to include an additional 25 subjects to confirm the safety and explore the preliminary anti-cancer effect. If the MTD is not identified, the study will be stopped and the expansion cohort will not be accrued.
干预措施: Radium 223 (Radiation)
结局指标
主要结局
Incidence of Dose Limiting Toxicities (DLT)
时间窗: Up to 29 Days
DLT is defined as a subject in any cohort experiencing any of the following adverse events during cycle 1 of treatment, until cycle 2 day 1 of treatment: Thrombocytopenia (platelets \< 75 x 10\^9/L on C1D15 or \< 100 x 10\^9/L on C2D1), Neutropenia (ANC \< 1000 K/mL on C1D15 or ANC \< 1500 K/mL on C2D1), Grade 3 (by CTCAE v4) fatigue lasting ≥ 7 days, other non-hematologic toxicity ≥ grade 3, lasting ≥ 48 hours at least possibly related to treatment, or any toxicity (non-hematologic or hematologic) at least possibly related to treatment requiring dose reduction or dose interruption.
次要结局
- Response to Treatment, as assessed by Bone Bio-marker Outcomes(Up to 28 weeks)
- Time to Treatment Failure (TTTF)(Up to 25 years)
- Efficacy, assessed as non-progression/progression rate according to prostate cancer working group (PCWG2) criteria(From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years)
- Progression Free Survival (PFS)(Up to 25 years)
- Proportion of Randomized Subjects to Complete Combination Therapy on Schedule per Protocol(Up to 28 weeks)
- Response to treatment, as assessed by prostate-specific antigen (PSA) Kinetics and Objective Responses(From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years)
- Overall Survival(Up to 25 years)
- Satisfaction, as assessed by Quality of Life Questionnaires(From date of randomization until the date of first documented progression or death from any cause, whichever came first, assessed up to 25 years)