A Study of Radiation/Temozolomide and Immunotherapy With Daratumumab to Improve Antitumor Efficacy in Glioblastoma (PRIDE).
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 16
- 试验地点
- 2
- 主要终点
- Dose Limiting Toxicity (DLT) rate of Daratumumab
研究概览
简要总结
TMZ is a standard therapy for GBM. The study will demonstrate that Daratumumab can collaborate with TMZ to enhance the cytotoxicity against GBM cells. Collectively, the preclinical data along with existing in vivo studies by others provides the rationale for therapeutic targeting of CD38 in GBM and its microenvironment. Daratumumab is commercially available, is safe and well tolerated when combined with alkylating chemotherapy, radiation therapy and has attained therapeutic CSF levels. Thus, the addition of Daratumumab to the frontline treatment regimen of GBM can potentially have a significant clinical benefit. Approximately 16 subjects will be enrolled in this trial. Up to 6 will be enrolled in the phase I part and 10 to 13 in the phase II part to come up with a total of 16 patients with 2 phases combined.
详细描述
Glioblastoma (GBM) is an aggressive brain cancer. Current therapeutic strategies include maximal safe surgical resection followed by course of Temozolomide (TMZ) and radiation therapy (RT). Despite trimodality treatment, recurrence remains inevitable. Our study will use Daratumumab, an anti-CD38 monoclonal antibody, in combination with TMZ and RT in newly diagnosed GBM patients. There is pre-clinical evidence suggesting Daratumumab is cytotoxic to GBM in a multimodal fashion, its safe when combined with chemotherapy & radiation therapy as well as has the potential to cross blood brain barrier.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Subjects must have high radiological likelihood of GBM with plan for resection/biopsy for histologically confirmed GBM
- •ECOG Performance status ≤ 2
- •Subjects must have normal organ and marrow function as defined below:
- •Leukocytes ≥ 3,000/mcL
- •Absolute neutrophil count ≥ 1,500/mcL
- •Platelet count ≥ 100,000/mcL
- •Total bilirubin within normal institutional limits
- •AST (SGOT) ≤ 3 X institutional upper limit of normal
- •ALT (SGPT) ≤ 3 X institutional upper limit of normal
- •Serum Creatinine within normal institutional limits OR glomerular filtration rate (GFR) 60 mL/min/1.73 m2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2
- •The effects of Daratumumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.
- •Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
- •Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Daratumumab and TMZ administration.
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
- •Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •Patients who received prior treatment for GBM.
- •Patients who are receiving any other investigational agents.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to Daratumumab and TMZ.
- •BCG (Intravesical), Deferiprone, and Dipyrone are risk X category and should be avoided when Daratumumab is used. Chloramphenicol (Ophthalmic), promazine and Clozapine are in the risk category C and myelosuppression signs should be monitored when used in combination with Daratumumab.
- •Avoid category Risk X drugs such as BCG (Intravesical), Deferiprone, Dipyrone, Natalizumab, Tacrolimus (Topical), Vaccines (Live) and Pimecrolimus concurrently with TMZ. Consider therapy modifications of category D drugs such as Baricitinib, Echinacea, Fingolimod, Leflunomide, Lenograstim, Lipegfilgrastim, Nivolumab, Palifermin, Roflumilast, Tofacitinib, Vaccines (Inactivated when used with TMZ. Monitor therapy for category risk C drugs such as Chloramphenicol (Ophthalmic), CloZAPine, Coccidioides immitis Skin Test, Denosumab, Ocrelizumab, Pidotimod, Promazine, Sipuleucel-T, Trastuzumab, and Valproate Products.
- •Patients with uncontrolled intercurrent illness.
- •Patients with psychiatric illness/social situations that would limit compliance with study requirements.
- •Pregnant women are excluded from this study because there are no animal and human data to assess the risk of Daratumumab during pregnancy. On the other hand, TMZ is a category D drug where adverse events are observed in animal reproduction studies. May cause fetal harm when administered to pregnant females. Male and female patients should use effective contraception to avoid pregnancy while receiving temozolomide. May impair male fertility based on animal data).
- •Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) <50% of predicted normal.
- •o Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is <50% of predicted normal.
- •Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification.
- •o Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate in the study.
- •Clinically significant cardiac disease, including:
- •Myocardial infarction within 6 months before randomization, or unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV).
- •Uncontrolled cardiac arrhythmia
研究组 & 干预措施
Daratumumab
Daratumumab, IV, 16 mg/KG -
1 dose prior to surgery or biopsy; Weeks 1 - 8 = 1 dose weekly; Weeks 9 - 24 = 1 dose every other week; Weeks 25 onward (determined by disease progression) = 1 dose every 4 weeks
干预措施: Daratumumab (Drug)
结局指标
主要结局
Dose Limiting Toxicity (DLT) rate of Daratumumab
时间窗: Up to 6 weeks
Rate of subjects that experience DLT. Subjects will be evaluated for DLTs after 6 doses of Daratumumab. If there is no DLT in the first 3 patients, the investigators will move forward to conduct the phase II clinical trial. If there is a DLT, another three patients will be enrolled. The study may be suspended with additional discussions in the data monitoring committee if there are ≥2 identified DLTs in the first 3 patients or ≥2 DLTs in the first 6 patients. The sample size justification is based on the standard 3+3 design.
Phase II - Median overall survival of newly diagnosed GBM patients
时间窗: Up to 12 months
Evaluate the median overall survival of newly diagnosed GBM patients. All patients in phase I part will be included in the efficacy analysis on overall survival (OS) in phase II part. If the 1-year survival rate of the study subjects is above 50% (median survival rate), it will be considered that the new intervention is promising.
次要结局
- Phase II - Estimate the tumor response rate(Up to 12 months)
- Phase I - Median overall survival of newly diagnosed GBM patients(Up to 6 weeks)
- Phase I - Estimate the tumor response rate(Up to 6 weeks)
- Phase II - Assess the treatment-emergent adverse events(Up to 12 months)
- Phase I - Evaluate the Progression-Free Survival (PFS)(Up to 6 weeks)
- Phase I - Assess the treatment-emergent adverse events(Up to 6 weeks)
- Phase II - Evaluate the Progression-Free Survival (PFS)(Up to 12 months)
研究者
Sonikpreet Aulakh
Assistant Professor
West Virginia University