A Phase Ib/II Trial of Combined SGN-35 (BrentuximabVedotin) Therapy With Cyclophosphamide, Procarbazine, Prednisone, Etoposide and Mitoxantrone (BrEPEM) for Older Patients With Untreated Hodgkin Lymphoma (HL)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 41
- 试验地点
- 15
- 主要终点
- Phase II: Complete response rate
研究概览
简要总结
The purpose of the phase Ib of the study is to identify the maximum tolerated dose (MTD) of Brentuximab Vedotin (BV) in combination with EPEM and to assess the toxicity of the combination of BV with EPEM. In the phase II efficacy will be evaluated.Besides, progression-free survival (PFS), event-free survival (EFS), overall survival (OS), the duration of response, the overall response rate (ORR) based on best response will be evaluated
详细描述
Hodgkin lymphoma (HL) is a lymphoid neoplasm characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells in a background of inflammatory cells. The majority of patients with HL have a good outcome with first-line chemotherapy such as ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine,procarbazine and prednisone) sometimes combined with radiation therapy. However, the same lymphoma has different results in the older than 60 years-old patients. This population of 60 years of age or older accounts for 20% of all HL cases. Age at diagnosis is an independent adverse prognostic factor for HL. The poor outcome in this group is due to both toxicity of chemo and radiotherapy resulting in higher treatment-related mortality and insufficient dosing of the applied treatment.
Most clinical trials exclude older patients with HL because older patients have more unfavorable risk profiles and the approaches to treat older patients with HL with intensive regimens resulted in treatment associated mortality of up to 21%. More effective treatments to get better results in this patient population are required.
In 2001 the problem about the need for effective treatments with acceptable toxicity for the older patients with HL was discussed. After that different international groups accepted the challenge of trial organization for older patients with HL.
Two phase 2 studies were developed with modified chemotherapy regimens. The first, BACOPP (Bleomycin, doxorubicin, Cyclophosphamide, vincristine, prednisolone and procarbazine), was a BEACOPP regimen modified, used in younger patients. In this study, 65 patients with early unfavorable or advanced stage HL aged between 60 and 75 years were included.
Eighty-five percent of patients achieved complete remission, 3% achieved partial remission, and 7% developed progressive disease. Eighteen patients died (30%), including 7 treatment-associated deaths. This chemotherapy regimen although was effective, had an important toxicity in this older HL patient population. The second trial was PVAG (regimen composed of gemcitabine, prednisone, vincristine and adriamycin). The treatment was used in elderly HL patients in early unfavorable and advanced stages. Fifty-nine patients were enrolled in this study; 78% of patients achieved complete remission (CR) o CR uncertain; 3,4% responded with partial response; 25% didn't achieve a response or relapsed. Seventeen deaths were observed, but only 1 of them was secondary to treatment-related toxicity.
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
- 60 Years 至 95 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Males or females of 60 years of age or older.
- •Previously untreated classical Hodgkin lymphoma (i.e., nodular sclerosis, mixed cellularity, lymphocyte depleted, lymphocyte-rich, and not otherwise specified [NOS]).
- •Stage IIB, III, and IV disease by Ann Arbor classification.
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or
- •Patients must have bi-dimensional measurable disease documented in the lymphoma baseline tumor assessment form (PET-CT report) within 30 days prior to Screening (at least 1.5 cm)
- •Patients must have a bone marrow biopsy within 60 days prior to screening.
- •Patients must have a multi gated acquisition scan (MUGA) or echocardiogram within 60 days prior to study screening and the ejection fraction must be >= 50%.
- •Adequate hematologic function, defined as Absolute neutrophil count (ANC) ≥ 1,500/mm3 / 1x109/L and Platelet count ≥75,000/mm3 / 75x109/L unless there is known marrow involvement of the disease
- •Serum Creatinine < 2.0 mg/dl and/or creatinine clearance or calculated creatinine clearance > 40 mL/minute.
- •Total Bilirubin < 1.5 x the upper limit of normal (ULN) unless elevation is known to be due to Gilbert syndrome.
- •ALT or AST must be < 3 x the upper limit of the normal range. AST and ALT may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of hematologic/solid tumour in liver.
- •Hemoglobin must be ≥ 8g/dL
- •Patients must not have received prior chemotherapy or radiation therapy for the treatment of Hodgkin lymphoma.
- •Female patient is either post-menopausal for at least 2 years before the screening visit or surgically sterile or if of childbearing potential must agree to use two effective contraceptive methods, at the same time, from the time of signing the informed consent and for 6 months following the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
- •Male patients, even if surgically sterilized, (i.e., status post vasectomy) must agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
- •Patients must sign the informed consent form before screening. Voluntary written informed consent must be signed before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
排除标准
- •Nodular lymphocyte predominant Hodgkin lymphoma
- •Previous treatment with BV or any other prior anti-CD30-based antibody therapy
- •Female patient who is both lactating and breast-feeding or has a positive pregnancy test during the screening period or a positive pregnancy test on Day 1 before the first dose of study drug
- •History of another primary malignancy that has not been in remission for at least 3 years; (the following are exempt from the 3-year limit: early stage [stage I or II] breast cancer treated with surgery and radiation +/- hormones [without adjuvant chemotherapy], non-melanoma skin cancer, fully excised melanoma in situ [stage 0], curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou test [PAP smear])
- •Known cerebral/meningeal disease (HL or any other etiology), including signs or symptoms of progressive multifocal leukoencephalopathy (PML)
- •Any active systemic viral, bacterial, or fungal infection requiring treatment with antimicrobial therapy within 1 week prior to first dose
- •Known or suspected hepatitis B infection, or known or suspected active hepatitis C infection Known human immunodeficiency virus (HIV) positive
- •Patients with a known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximab vedotin
- •Patients with dementia or an altered mental state that would preclude the understanding and rendering of informed consent
- •Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
- •Any sensory or motor peripheral neuropathy greater than or equal to 2
- •Known history of any of the following cardiovascular conditions;
- •Myocardial infarction within 2 years of enrollment
- •New York Heart Association (NYHA) Class III or IV heart failure
- •Evidence of uncontrolled cardiovascular conditions, including cardiac arrhythmias,congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
研究组 & 干预措施
Experimental: Brentuximab vedotin plus EPEM
Brentuximab Vedotin dose will start at 1.2 mg/kg by intravenous (IV) infusion on Day1 and Day15 plus Cyclophosphamide 500mg/m2 IV on Day1 plus Procarbazine 100mg/m2 by mouth (OR) on Day1 through 5 plus Etoposide 60mg/m2 OR on Day15 through 19 plus Mitoxantrone 6mg/m2 IV on Day15 and Prednisone 30mg/m2 on Day1 through 5 of each 28-day treatment cycles for up to 6 total treatment cycles (approximately 24 weeks or 6 months)
干预措施: BrentuximabVedotin (BV) (Drug)
结局指标
主要结局
Phase II: Complete response rate
时间窗: 6 months after last patient start treatment
To assess the percentage of patients with complete response rate after BV-EPEM treatment.
Phase Ib: maximum tolerated dose (MTD)
时间窗: Up to 28 days after start of each cycle
To identify the maximum tolerated dose (MTD) of Brentuximab Vedotin (BV) in combination with EPEM
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
时间窗: Up to 28 days after start of each cycle
To evaluate the toxicity of the treatment by measure of number of treatment-related adverse events according to CTCAE v4.0
次要结局
- Overall response rate (ORR)(At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)
- event-free survival (EFS)(At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)
- overall survival (OS)(At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)
- progression-free survival (PFS)(At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)
- Incidence of Treatment Adverse Events [Safety and Tolerability](At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)
- Duration of response(At the end of eache cycle (every cycle is 28 days) and then every 3 months up to 3 years in the study)