A Phase 1 Trial of TPI 287 as a Single Agent and in Combination With Temozolomide in Patients With Refractory or Recurrent Neuroblastoma or Medulloblastoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 18
- 试验地点
- 6
- 主要终点
- Number of Participants With Adverse Events as a Measure of Safety and Tolerability
研究概览
简要总结
The purpose of this research study is to evaluate a new investigational drug (TPI 287) for neuroblastoma and medulloblastoma both alone and in combination with temozolomide (a currently approved drug). An investigational drug is one that has not yet been approved by the Food and Drug Administration. This investigational drug is called TPI 287. This study will look at the safety and tolerability of TPI 287 both alone and in combination with temozolomide, and look to establish a safe dose of this agent. The study will also look at the tumor's response to these drugs, but this is not the primary objective of this study.
TPI 287 was shown to be effective in stopping tumor growth and was also shown to be safe in three different animal species. TPI 287 has been tested in humans in four clinical trials, and approximately 100 subjects with various types of cancers have received the drug. All of these subjects that have received TPI 287 have been adults. TPI 287 has not been tested in a pediatric population before this study.
Temozolomide was tested in recurrent neuroblastoma and showed activity in a recently published study. Preclinical studies of TPI in combination with temozolomide have shown at minimum an additive effect. The ability of temozolomide and TPI 287 to be effective in combination is suggested by these two drugs showing even greater activity when used together.
详细描述
Neuroblastoma:
Neuroblastoma is the most common pediatric extracranial solid tumor and accounts for 7% to 10% of childhood cancers (American Cancer Society 2008; Bernstein et al. 1992). Whereas the prognosis for infants with neuroblastoma is generally good, currently only 30% of children diagnosed after 12-15 months of age survive despite aggressive multimodal therapies (Brodeur et al 1993; Park et al 2008). High-dose chemotherapy (HDC) followed by hematopoietic stem cell transplantation (HSCT) and maintenance therapy with retinoic acid improves survival by 35% in children presenting with metastatic NB, but the 5-year event-free survival remains below 50% (Matthay et al, 1999; Hartmann, et al, 1999). Consequently, the evaluation of new drugs is strongly needed in this disease.
1.2
Medulloblastoma:
Medulloblastoma is the most common malignant brain tumor in children and accounts for 16% of all brain tumors in children 0-14 years old and 6% in adolescents 15-19 years old (CBTRUS 2008). Current therapies for children with disseminated disease are associated with severe long-term toxicities, and lead to cure in only a minority of cases. (Partap et al, 2007). Thus, the development of new therapies-especially ones with more favorable toxicity profiles-would represent a significant improvement in the treatment of this disease. Although there have been reports that the survival rate of children with chemosensitive relapsed medulloblastoma can approach 40% following intensive chemotherapy combined with autologous stem cell support, more recent data looking at survival of all patients relapsing after modern combination chemotherapy and radiation is also on the order of 10-15%. (Rood, et al, 2004) As such, new therapeutic approaches are needed to treat these children.
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
- 12 Months 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically proven neuroblastoma and confirmation of refractory or recurrent disease or medulloblastoma with histologic confirmation at diagnosis or at the time of recurrence/progression
- •Patients must be age >12 months and diagnosed before the age of 21
- •Life expectancy must be more than 3 months
- •If measurable disease, this must be demonstrated by residual abnormal tissue at a primary or metastatic site measuring more than 1 cm in any dimension by standardized imaging (CT or MRI). For patients with neuroblastoma who only have skeletal disease, there must be at least two persisting skeletal foci on meta-iodobenzylguanidine (MIBG) follow-up scans
- •Current disease state must be one for which there is currently no known curative therapy
- •Lansky Play Score must be more than 30 and/or ECOG performance status must be 0 to 2
- •For patients with medulloblastoma receiving steroids, the dose must be stable (i.e. not increasing) for at least one week before starting study
- •Patients without bone marrow metastases must have an ANC > 750/μl and platelet count >50,000/μl
- •Adequate liver function must be demonstrated, defined as:
- •Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age AND
- •SGPT (ALT) < 10 x upper limit of normal (ULN) for age
- •No other significant organ toxicity defined as > Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events version 3 (NCI-CTCAE V3.0 (http://ctep.cancer.gov/forms/CTCAEv3.pdf))
- •A negative urine pregnancy test is required for female participants of child bearing potential (≥13 years of age or after the onset of menses)
- •Both male and female post-pubertal study subjects need to agree to use one of the more effective birth control methods during treatment and for six months after treatment is stopped. These methods include total abstinence (no sex), oral contraceptives ("the pill"), an intrauterine device (IUD), levonorgestrol implants (Norplant), or medroxyprogesterone acetate injections (Depo-provera shots). If one of these can not be used, contraceptive foam with a condom is recommended
- •Informed Consent: All patients and/or legal guardians must sign informed written consent. Assent, when appropriate, will be obtained according to institutional guidelines
- •Patients may have received microtubulin inhibitors and/or temozolomide during previous therapies
排除标准
- •Patients who have received any chemotherapy administered within the last 21 days
- •Patients who have received radiotherapy within the last 30 days
- •Patients who have received myeloablative therapy within the previous 3 months
- •Patients receiving anti-tumor therapy for their disease or any investigational drug concurrently
- •Patients with serious infection or a life-threatening illness (unrelated to tumor) that is > Grade 2 (NCI CTCAE V3.0), or active, serious infections requiring parenteral antibiotic therapy within 4 weeks prior to screening
- •Any other medical condition, including malabsorption syndromes, mental illness or substance abuse, deemed by the Investigator to be likely to interfere with the interpretation of the results or which would interfere with a patient's ability to sign or the legal guardian's ability to sign the informed consent, and patient's ability to cooperate and participate in the study
- •Patients with known hypersensitivity to any of the components of the drugs to be administered on study
- •Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study
研究组 & 干预措施
TPI 287
干预措施: TPI 287 (Drug)
结局指标
主要结局
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
时间窗: 2 years
To determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287 as a single agent and collect exploratory data on the safety and tolerability of TPI 287 in combination with temozolomide (TMZ) in pediatric and young adult patients with refractory or recurrent neuroblastoma or medulloblastoma
次要结局
- Tmax of TPI 287in Pediatrics Using Pharmacokinetic (PK) Testing.(Cycle 3 day 1 at Pre dose, 0 (end of infusion), 0.25, 0.5, 1, 2, 4, and 6 hours post dose)
- AUC of TPI 287in Pediatrics Using Pharmacokinetic (PK) Testing.(Cycle 3 day 1 at Pre dose, 0 (end of infusion), 0.25, 0.5, 1, 2, 4, and 6 hours post dose)
- Progression Free Survival (PFS) of Participants Using Days From Start of Study Drug Until Progression(Up to 4 years)
- Number of Patients With an Overall Response Rate (ORR) of PR or CR(1 year)
- Cmax of TPI 287in Pediatrics Using Pharmacokinetic (PK) Testing.(Cycle 3 day 1 at Pre dose, 0 (end of infusion), 0.25, 0.5, 1, 2, 4, and 6 hours post dose)
研究者
Giselle Sholler
Study Chair
Milton S. Hershey Medical Center