A Phase 1 Adaptive Dose Escalation With Dose Expansion Study of Triapine in Combination With Temozolomide (TMZ) for Patients With Recurrent Glioblastoma
概览
- 阶段
- 1 期
- 干预措施
- Questionnaire Administration
- 疾病 / 适应症
- Recurrent Glioblastoma, IDH-Wildtype
- 发起方
- Northwestern University
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Recommended phase 2 dose for triapine in combination with temozolomide
- 状态
- 招募中
- 最后更新
- 昨天
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 Response Assessment in Neuro-Oncology (RANO) criteria. EXPLORATORY OBJECTIVES: I. To investigate the distribution of triapine within tumor and peritumoral areas post oral administration and correlation with serum levels. II. To investigate the potential interaction of drug absorption when administrating oral triapine and temozolomide together by measuring plasma levels triapine and temozolomide post administration. III. To evaluate oral triapine plasma pharmacokinetics and corresponding methemoglobin level by venous blood gas proportion. IV. To evaluate the quality of life per Functional Assessment of Cancer Therapy-Brain (FACT-Br) for patients treated with triapine and temozolomide. OUTLINE: This is a dose-escalation study of triapine in combination with temozolomide. Patients with recurrent glioblastoma not planning to undergo surgery are assigned to group 1 or group 2. Patients with recurrent glioblastoma planning to undergo surgery are assigned to group 3. GROUPS 1 AND 2: Patients receive temozolomide orally (PO) once daily (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 magnetic resonance imaging (MRI) at screening and on study and undergo collection of blood samples on study. GROUP 3: 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. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 24 months.
研究者
入排标准
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 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
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 cytotoxic 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
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: Questionnaire Administration
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
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
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
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
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
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
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
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
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
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
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)