A Phase 2 Study of the PARP Inhibitor Olaparib (AZD2281) in IDH1 and IDH2 Mutant Advanced Solid Tumors
概览
- 阶段
- 2 期
- 干预措施
- Biopsy Procedure
- 疾病 / 适应症
- Advanced Malignant Solid Neoplasm
- 发起方
- National Cancer Institute (NCI)
- 入组人数
- 89
- 试验地点
- 99
- 主要终点
- Overall response rate
- 状态
- 进行中（未招募）
- 最后更新
- 2个月前
概览
简要总结
This phase II trial studies how well olaparib works in treating patients with glioma, cholangiocarcinoma, or solid tumors with IDH1 or IDH2 mutations that has spread from where it first started (primary site) to other places in the body (metastatic) and that does not respond to treatment (refractory). Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVE: I. To estimate the overall response rates of olaparib in subjects with recurrent/progressive IDH1/2-mutant solid tumors, who will be recruited to 3 cohorts: a. glioma, b. cholangiocarcinoma, c. other solid malignant tumors. SECONDARY OBJECTIVES: I. To estimate the distribution of progression free survival (PFS) of olaparib in adults with recurrent/progressive IDH1/2-mutant glioma and cholangiocarcinoma. II. To estimate the overall survival (OS) in adults with recurrent/progressive IDH1/2- mutant glioma and cholangiocarcinoma. III. To determine the duration of response in adults with recurrent/progressive IDH1/2-mutant glioma, cholangiocarcinoma or other solid malignant tumors. IV. To confirm the safety and tolerability of olaparib monotherapy. EXPLORATORY OBJECTIVES: I. To describe 2HG concentration in plasma by mass spectrometry at baseline and at specific timepoints and correlate with treatment response. II. To describe 2HG levels in tumor biopsies from prior to the beginning of treatment and at specific timepoints and correlate with treatment response. III. To evaluate in tumor biopsies and in liquid biopsies performed at baseline and at specific timepoints if co-occurring alterations detected via multiplexed immunofluorescence, mass cytometry (CyTOF)-imaging mass cytometry (IMC), ribonucleic acid (RNA) sequencing and/or deoxyribonucleic acid (DNA) sequencing can be associated with differential levels of 2HG production, treatment response and resistance. OUTLINE: Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a computer tomography (CT) scan and/or magnetic resonance imaging (MRI), as well as a tumor biopsy and blood sample collection on study. After completion of study treatment, patients are followed up for 30 days.
研究者
入排标准
入选标准
- •Subjects must be able to understand the nature of this trial and provide written informed consent, prior to any study specific procedures; patients with Impaired Decision Making Capacity (IDMC) who have a close caregiver or legally authorized representative (LAR) may be considered eligible for this study at the treating physician's discretion, provided that the physician is reasonably sure that the possible risks and benefits of the study are clear and that the patient will take the drug as prescribed
- •Subjects must be diagnosed with a glioma, cholangiocarcinoma or other solid malignant tumor that has progressed despite standard therapy, or for which no effective standard therapy exists, with biopsy-confirmed evidence of an IDH1 or IDH2 mutation associated with neomorphic activity of the encoded proteins; patients must have IDH1 or IDH2 mutation which must be detected in a clinical accredited laboratory using a Food and Drug Administration (FDA)-approved molecular test or a validated deoxyribonucleic acid (DNA)-based assay conducted in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory; only specific mutations that lead to a neomorphic phenotype will be eligible for enrollment, and include IDH1: R132V, R132G, R132S, R132L, R132C and R132H; IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K
- •Patients must have tumors determined to be easily accessible for biopsy and must be willing to have serial biopsies (with a third biopsy upon evidence of disease progression); in case of multiple lesions, tumor biopsies will be performed on the most accessible site of disease; all possible precautions to avoid complications will be taken, including discussions in multidisciplinary meetings, if needed; patients affected by glioma will not be considered for study biopsies
- •Patients must be willing to undergo extra blood sampling for correlative studies
- •Subjects with extracranial disease must have evaluable disease by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); subjects affected by glioma must have evaluable disease by Response Assessment in Neuro-Oncology Criteria (RANO) criteria
- •For subjects with glioma, specific inclusion criteria are as follows:
- •The disease should be recurrent or transformed glioma; subjects must not have had prior surgery (biopsy allowed) or radiation therapy within 3 weeks of enrollment
- •There must be an enhancing component of disease, as evaluated on pre-treatment magnetic resonance imaging (MRI)
- •For patients with World Health Organization (WHO) grade III or IV glioma and progressive disease \< 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria:
- •New enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line)
排除标准
- •Patients should not enter the study if any of the following exclusion criteria are fulfilled
- •Involvement in the planning and/or conduct of the study
- •Previous enrollment in the present study
- •Participation in another clinical study with an investigational product during the last 30 days or five half-lives of the drug (whichever is less) prior to the initiation of study treatment (6 weeks for nitrosoureas or mitomycin C)
- •Any previous treatment with PARP inhibitor, including olaparib
- •Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment
- •Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma, or other solid tumors including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for \>= 5 years; patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
- •Resting electrocardiogram (ECG) with corrected QT interval (QTc) \> 470 msec or family history of long QT syndrome
- •Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil); the required washout period prior to starting olaparib is 2 weeks; because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated drug information reference; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil); the required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents; because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated drug information reference; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
研究组 & 干预措施
Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a CT scan and/or MRI, as well as a tumor biopsy and blood sample collection on study.
干预措施: Biopsy Procedure
Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a CT scan and/or MRI, as well as a tumor biopsy and blood sample collection on study.
干预措施: Biospecimen Collection
Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a CT scan and/or MRI, as well as a tumor biopsy and blood sample collection on study.
干预措施: Computed Tomography
Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a CT scan and/or MRI, as well as a tumor biopsy and blood sample collection on study.
干预措施: Magnetic Resonance Imaging
Treatment (olaparib)
Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity, withdrawal of consent or death. Patients undergo a CT scan and/or MRI, as well as a tumor biopsy and blood sample collection on study.
干预措施: Olaparib
结局指标
主要结局
Overall response rate
时间窗: Up to completion of 8 weeks of treatment
Will be determined by investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1 for extracranial solid tumors, Response Assessment in Neuro-Oncology criteria for intracranial glioma. Overall response rate and a 90% creditable interval in each cohort will be estimated using the approach described by Koyama. For the other solid tumors cohort, descriptive statistics and graphical displays will be used to summarize results within tumor types.
次要结局
- Progression-free survival(From start of treatment to time of progression or death, whichever occurs first, assessed up to 3.6 years)
- Incidence of adverse events(Up to 3.6 years)