Improving Peptide Receptor Radionuclide Therapy With PARP Inhibitors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Adverse events
研究概览
简要总结
This is a phase 1 dose-escalation study to determine the maximum tolerated dose of the PARP inhibitor olaparib in combination with PRRT in patients with a well-differentiated advanced gastroenteropancreatic NET (GEP NET), progressive after PRRT. As secondary objectives, efficacy, pharmacokinetics and biomarker response will be investigated.
详细描述
Rationale:
Peptide receptor radionuclide therapy (PRRT) with the beta-emitting radiopharmaceutical 177Lutetium-DOTA-Tyr3,octreotate (177Lu-DOTATATE) is an effective and safe treatment option for patients with metastatic neuroendocrine tumors (NETs). In advanced NET patients, 177Lu-DOTATATE has been proven to secure long-term survival in several large retrospective series and was superior to high-dose somatostatin analogs in a randomized phase 3 clinical trial, with a 79% decrease in the risk of progression or death. However, objective response rates are limited and fewer than 1% of the patients can achieve complete response following PRRT. Administering a higher cumulative dose than currently applied will induce more toxicity in healthy tissues and probably will be detrimental to patients. Therefore, adaptations to the currently applied PRRT regimen are needed.
The repair of PRRT-induced DNA damage constitutes a viable target to enhance its antitumor effects. In a number of preclinical models, inhibitors of the enzyme poly ADP ribose polymerase (PARP), essential for repair of single-strand DNA breaks, have been shown to improve the cytotoxic effects of PRRT without signs of added toxicity. Various PARP inhibitors are registered for the treatment of human cancers, such as ovarian cancer, and BRCA- or homologous repair deficiency (HRD)-dependent prostate and pancreatic cancer and are under investigation in several clinical trials as radiosensitizer. Based on preclinical in vitro and in vivo data, we hypothesize that PARP inhibitors can potentiate radiation-induced tumor cell death in patients treated with PRRT. This therapeutic combination has not been studied in human subjects before.
Objective:
To determine the maximum tolerated dose (MTD) of the PARP inhibitor olaparib in combination with PRRT in patients with a well-differentiated advanced NET, progressive after PRRT.
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
- •Histologically proven locally advanced or metastatic, well-differentiated (grade 1, 2 or 3) NET.
- •Disease progression based on RECIST v1.1 following initial or salvage treatment with PRRT with 177Lu-DOTATATE with a progression free interval of at least 12 months since first cycle of previous administration of PRRT or with no suitable systemic alternative treatment options.
- •The patient is eligible for two cycles of salvage PRRT.
- •Measurable disease according to RECIST v1.1 on CT/MRI.
- •Confirmed presence of somatostatin receptors on all target lesions on CT/MRI, based on positive uptake on a 68Ga-DOTATATE/-TOC/-NOC PET-CT/MRI scan.
- •Age ≥ 18 years.
- •Karnofsky Performance Score (KPS) > 60.
排除标准
- •Hb concentration <6.2 mmol/L; white blood cell count <3x109/L; platelets <100x109/L; neutrophil count <1.5x109/L.
- •Renal insufficiency defined as a creatinine clearance <50 mL/min, measured in 24-hour urine collection.
- •Liver function or enzyme abnormalities defined as a total bilirubin >3 x ULN, Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x ULN or serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
- •Pregnancy, lactation and inability to comply with effective means of contraception in females of child-bearing age.
- •Neuroendocrine carcinoma of any origin.
- •Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to inclusion in the study. Interferons, everolimus, sunitinib or other systemic therapies within 4 weeks prior to inclusion in the study.
- •Uncontrolled congestive heart failure (NYHA II, III, IV).
- •Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with the completion of the study.
- •Prior external beam radiation therapy to more than 25% of the bone marrow.
- •Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
- •Patients who use a strong CYP3A4 inhibitor within 1 week before start of the treatment or a CYP3A4 inducer within 4 weeks before start of the treatment.
- •History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
- •Known allergy or intolerance for the (non-)investigational drugs.
- •Inability to provide informed consent.
- •End of life care.
研究组 & 干预措施
PRRT + olaparib 100mg q.d.
administration of the standard therapy of 7.4GBq 177lu-dotatate with the additional study medication olaparib 100mg q.d.
干预措施: olaparib (Drug)
PRRT + olaparib 100mg b.i.d.
administration of the standard therapy of 7.4GBq 177lu-dotatate with the additional study medication olaparib 100mg b.i.d.
干预措施: olaparib (Drug)
PRRT + olaparib 200mg b.i.d.
administration of the standard therapy of 7.4GBq 177lu-dotatate with the additional study medication olaparib 200mg b.i.d.
干预措施: olaparib (Drug)
PRRT + olaparib 300mg b.i.d.
administration of the standard therapy of 7.4GBq 177lu-dotatate with the additional study medication olaparib 300mg b.i.d.
干预措施: olaparib (Drug)
结局指标
主要结局
Adverse events
时间窗: 3 years
Incidence and severity of adverse events according to CTCAE v5.0
Maximum tolerated dase
时间窗: 3 years
Determination of the MTD of olaparib in combination with standard dose PRRT
次要结局
- Survival rates(3 years)
- Best response(3 years)
- Antitumor effects(3 years)
研究者
Morticia N. Becx
coordinating investigator
Erasmus Medical Center