A Phase 1 Adaptive Dose Escalation With Dose Expansion Study of Triapine in Combination With Temozolomide (TMZ) for Patients With Recurrent Glioblastoma
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Recommended phase 2 dose for triapine in combination with temozolomide
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of triapine in combination with temozolomide in treating patients with glioblastoma that has come back after a period of improvement (recurrent). Triapine inhibits an enzyme responsible for producing molecules required for the production of deoxyribonucleic acid (DNA), which may inhibit tumor cell growth. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Giving triapine in combination with temozolomide may be safe, tolerable, and/or effective in treating patients with recurrent glioblastoma.
详细描述
PRIMARY OBJECTIVE:
I. To evaluate the recommended phase 2 dose (RP2D) for triapine (3-AP) in combination with temozolomide (TMZ).
SECONDARY OBJECTIVES:
I. To evaluate the safety profile of triapine in combination with temozolomide (TMZ).
II. To evaluate progression-free survival (PFS). III. To evaluate overall survival (OS). IV. To evaluate the overall response rate (ORR) per RANO 2.0 criteria.
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
- •Patients must have histologically confirmed World Health Organization (WHO) grade 2-4 glioma, isocitrate dehydrogenase (IDH) wild type (WT) (by immunohistochemistry [IHC] R132H negative [neg] or sequencing). Astrocytoma with molecular features of glioblastoma (GBM). Confirmed diagnosis via molecular testing
- •Patients must have an established diagnosis of recurrent glioblastoma and:
- •Group 1 and 2: recurrent glioblastoma
- •Group 3: Surgically amenable recurrent glioblastoma
- •Patients must have stable or decreasing dose of corticosteroids equivalent to ≤ 6 mg dexamethasone, for ≥ 7 days prior to registration
- •Patients with 3 or fewer lines of prior therapy
- •Patients with a life expectancy of at least 3 months
- •Patients with disease that has progressed after a standard or investigational first-line therapy (e.g. radiotherapy [RT], RT plus temozolomide) with or without tumor treating fields therapy (TTFields)
- •Note: Patients who have received fractionated first-line radiation therapy and no prior chemotherapy (e.g. as common practice for MGMT unmethylated tumors), or who have participated in an investigational protocol substituting TMZ for a novel agent are eligible
- •Patients must be able to undergo contrast-enhanced magnetic resonance imaging (MRI)
- •Patients must be age ≥ 18 years
- •Patients must exhibit a Karnofsky performance status ≥ 70
- •Patients must have adequate organ and bone marrow function as defined below: Leukocytes (white blood cells [WBC]) ≥ 3,000/mcL, Absolute neutrophil count (ANC) ≥ 1,500/mcL, Hemoglobin (Hgb) ≥ 8 g/dL (transfusion may be used for eligibility outside of 7 days), Platelets (PLT) ≥ 100,000/mcL (transfusion or growth factor may be used for eligibility outside of 7 days), Total bilirubin ≤ 2 x institutional upper limit of normal (ULN), Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3 x institutional ULN, Creatinine ≤ 1.5 x institutional ULN, International normalized ratio (INR) ≤ 1.5 x ULN, Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 x ULN
- •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
- •Patients of child-bearing potential (POCBP) must agree to use two forms of adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation. Patients who can impregnate their partners must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) from time of informed consent and for the duration of study participation
- •Should a patient become pregnant or suspect they are pregnant while they or their partner is participating in this study, they should inform their treating physician immediately.
- •Note: At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
- •Note: A POCBP is any person with an egg-producing reproductive tract (regardless of gender, sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- •Has not undergone a hysterectomy, bilateral salpingectomy, or bilateral oophorectomy
- •Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months) (in patients > 45 years of age in the absence of other biological or physiological causes)
- •Potential POCBP who may be menopausal and are < 55 years of age must have a serum follicle-stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause
- •Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff
- •Patient must be willing and able to comply with the protocol for the duration of the study and provide written, signed, and dated informed consent prior to study registration.
- •Patients must have the ability to understand and the willingness to sign a written informed consent document
排除标准
- •Patients who have a prior or concurrent malignancy that may interfere with study treatment or safety
- •NOTE: 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, per principal investigator (PI) discretion
- •Patients who are receiving any other investigational agents.
- •Exceptions: COVID-19 vaccine and treatment is allowed, per PI's discretion
- •Patient's interval since last therapy ≥ 1 cycle or ≥ 2 biological half-lives, i.e.
- •≥ 28 days since start of last cycle of temozolomide (cycle length-28 days)
- •≥ 42 days since start of last cycle of lomustine or other nitrosourea (cycle length-42 days)
- •≥ 21 days since start of last cycle of a small molecule targeted agent (cycle length-21 days)
- •≥ 42 days from last bevacizumab infusion (cycle length-42 days)
- •Patients who have a history of allergic reactions attributed to compounds of similar chemical composition to temozolomide or triapine
- •Patients with brainstem, spinal cord and diffuse leptomeningeal dissemination.
- •Patients with gliomatosis or multifocal disease
- •Patients with a history of G6PD deficiency or other congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD levels prior to registration
- •Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following:
- •Have uncontrolled epilepsy
- •Have an uncontrolled intercurrent illness
- •Are pregnant or nursing
- •Concurrent malignancy (outside of glioblastoma) that requires tumor directed treatment
- •Known concurrent shingles, herpes, cytomegalovirus (CMV) infection
- •Known concurrent opportunistic fungal infection
- •Known immunodeficiency that could lead to opportunistic infections
- •Psychiatric illness/social situations that would limit compliance with study requirements
- •Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints
- •Patients who are pregnant or nursing. Pregnant patients are excluded from this study because temozolomide is an alkylating agent with potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with temozolomide, breastfeeding should be discontinued if the mother is treated with temozolomide
- •Patients who are unable to swallow oral medication or have problems/diseases that affect absorption or oral medication
- •Patients with a known history of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV). If patient does not have a known history testing will not be conducted
- •Note: Temozolomide is an immunosuppressive agent. Patients with a known history of HIV, HBV, and HCV, and unexplained opportunistic infections are not eligible due to safety reasons
研究组 & 干预措施
Groups 1 and 2 (temozolomide, triapine)
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Triapine (Drug)
Groups 1 and 2 (temozolomide, triapine)
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Questionnaire Administration (Other)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Questionnaire Administration (Other)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Resection (Procedure)
Groups 1 and 2 (temozolomide, triapine)
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Biospecimen Collection (Procedure)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Biospecimen Collection (Procedure)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Groups 1 and 2 (temozolomide, triapine)
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Triapine (Drug)
Group 3 (triapine, surgical resection, temozolomide)
Patients receive triapine PO QD for 5 days prior to surgical resection. After surgical resection, patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Temozolomide (Drug)
Groups 1 and 2 (temozolomide, triapine)
Patients receive temozolomide PO QD and triapine PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI at screening and on study and undergo collection of blood samples on study.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Recommended phase 2 dose for triapine in combination with temozolomide
时间窗: At the end of Cycle 1 (each cycle is 28 days) + 7 days (up to cycle 2 day 7)
The recommended phase 2 dose will be based on treatment-emergent and drug-related toxicity. Dose limiting toxicities and adverse events (AEs) will be assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 5.0.
次要结局
- Incidence of AEs and serious AEs(Up to 30 days after last administration of study drug)
- Progression free survival (PFS)(From baseline until the patient experiences disease progression, initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause, assessed at 6, 12, and 24 months)
- Overall survival(From time of diagnosis until the patient initiates subsequent anti-cancer therapy, completes study participation, or experiences death from any cause, assessed at 6, 12, and 24 months)
- Overall response rate (ORR)(From baseline until the response has been confirmed, the patient experiences disease progression, the patient initiates, subsequent anti-cancer therapy, or the patient completes study participation, assessed up to 24 months)