PARP1/2

Senaparib是一种新型的选择性聚ADP核糖聚合酶-1/2抑制剂，在临床前研究中具有很强的抗肿瘤活性。 Senaparib (IMP4297) 正在研究作为胰腺癌、乳腺癌和晚期肝癌的治疗方法 [2]。Senaparib是一种口服生物可利用的核酶聚ADP核糖聚合酶（PARP）1和2抑制剂，具有潜在的抗肿瘤活性。给药后，senaparib选择性结合PARP 1和2，并通过碱基切除修复途径阻止PARP介导的单链DNA断裂的DNA修复。这增强了DNA链断裂的积累，促进了基因组的不稳定性，最终导致细胞凋亡。PARP催化核蛋白的翻译后ADP核糖基化，核蛋白发出信号并招募其他蛋白质来修复受损的DNA，并被单链DNA断裂激活。

Senaparib（前身为IMP4297）是一种新型的选择性口服PARP1和PARP2抑制剂，在临床前研究中显示出很强的抗肿瘤活性，体内活性比奥拉帕尼（目前批准的PARP中开发最完善的一种）高20倍。 Senaparib的第一阶段人体研究是在澳大利亚晚期实体瘤患者中进行的（ClinicalTrials.gov标识符NCT03507543）。研究了单剂量和多剂量番泻叶的安全性、耐受性和药代动力学（PK）特征，并记录了初步的抗肿瘤反应。[1]

---

39名患者以2至150mg的10个剂量水平入组。在任何队列中均未观察到剂量限制性毒性。大多数治疗中出现的不良事件为1-2级（91%）。7名患者（17.9%）报告了血液治疗中出现的不良事件。8名患者（20.5%）发生了与治疗相关的不良事件，最常见的是恶心（7.7%）。研究治疗结束后报告了两例死亡，其中一例被认为是与Senaparib相关的骨髓衰竭引起的并发症。药代动力学分析表明，senaparib的累积指数为1.06-1.67，吸收饱和度为每天80-150mg。在22名可评估疾病的患者中，总有效率为13.6%，疾病控制率为81.8%。BRCA突变阳性亚组的总体反应率为33.3%，非突变亚组为6.3%。 结论：Senaparib在澳大利亚晚期实体瘤患者中具有良好的耐受性，具有令人鼓舞的抗肿瘤活性信号。senaparib的推荐2期剂量确定为每日100mg。[1]

---

疗效： 在根据RECIST 1.1标准可评估肿瘤反应的22名患者中，有6名患者被确认为BRCA1或BRCA2突变携带者（见表S12）。在这22名患者中，有3名患者（均为癌症患者）出现PR（20 mg、100 mg和120 mg剂量组各1例），ORR为13.6%（95%CI，2.9%–34.9%）。其中两名应答者患有BRCA突变阳性肿瘤（20mg和100mg剂量组各一例），BRCA突变阴性亚组的ORR为33.3%（六名患者中有两名；95%CI，4.3%-77.7%）。非突变亚组的ORR为6.3%（16名患者中的一名）。另外15名患者（68.2%）总体上患有SD。DCR总体上为81.8%（95%CI，59.7%-94.8%），与BRCA突变阳性亚组相似（83.3%；95%CI，35.9%-99.6%）。在100mg组中，ORR为20%（95%置信区间，0.5%-71.6%），DCR为40%（95%置信范围，5.3%-85.3%）。图3显示了所有可评估患者的目标病变大小最佳变化的瀑布图。在数据截止日期，所有三名应答者仍然活着，没有疾病进展，BRCA野生型患者的应答持续时间为1.4个月，两名BRCA突变阳性患者的应答时间为2.8个月和22.1个月。在疗效人群中，中位无进展生存期为5.7个月（95%置信区间，2.7%-7.4%），在BRCA突变阳性亚组中为7.4个月（95%CI，1.77%未达到）（见表S13和图S2）。10名癌症前列腺患者中有1名（10%）出现PSA反应；他患有BRCA野生型，属于40mg剂量组[1]。

Study design [1]
Details of the dose-escalation protocol can be found in the Supporting Methods. Patients were initially administered one dose of oral Senaparib; after a 7-day washout period, senaparib was administered once daily in 3-week cycles (from day 1 [D1] to D21). If no dose-limiting toxicity (DLT) emerged, the dose was increased from 6 to 40 mg once daily in dose cohorts in a stepwise manner. For subsequent dose levels, the study followed a conventional 3 + 3 design24 to determine the maximum tolerated dose (MTD; the maximum dose at which one in six patients from a single cohort experienced a DLT during the first treatment cycle [C1]) or the recommended phase 2 dose (RP2D; based on the toxicity end point—the MTD or one dose level below; Figure S1 and Table S2). Treatment with Senaparib continued for up to 1 year until disease progression or unacceptable toxicity or until the investigator determined there was no benefit to the patient.

This study was conducted in accordance with the protocol, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use good clinical practice guidelines, applicable regulations and guidelines governing clinical study conduct, and the ethical principles originating in the Declaration of Helsinki. All patients provided written informed consent to participate before their inclusion in the study.

---

End points [1]
Primary end points were the incidence and nature of DLTs, and the incidence, nature, relatedness, and severity of treatment-emergent adverse events (TEAEs). The secondary end point was the PK parameters of Senaparib. Exploratory efficacy end points were the overall response rate (ORR), the disease control rate (DCR; complete responses [CRs] + partial responses [PRs] + stable disease [SD] lasting ≥6 weeks), the duration of response, progression-free survival (PFS), and, where applicable, serum prostate-specific antigen (PSA) and cancer antigen 125 (CA-125) concentrations. A full list of all efficacy end points and their definitions can be found in Table S3.

---

Study assessments [1]
TEAEs and serious adverse events (SAEs) were recorded throughout the study, and patients were followed for safety for 30 days after the last dose of Senaparib or at treatment discontinuation, whichever occurred later. All TEAEs were graded for severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03),25 and their relatedness was investigator assessed according to protocol-defined criteria Tables (see S4 and S5). Dose modifications to manage any toxicities were allowed after C1 (see Table S6). The window for DLT assessment was C1D1 to C1D21. DLTs were defined as the occurrence of any of the following during the assessment window: any grade ≥3 nonhematologic toxicity, grade 4 neutropenia lasting >7 days, febrile neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3 and fever ≥38.5°C) or documented grade ≥3 infection with an absolute neutrophil count ≤1000 cells/mm3, grade 4 thrombocytopenia lasting >48 hours or requiring intervention or associated with increased bleeding, or dose interruption for >14 days because of toxicity. Any patient experiencing a DLT was treated according to standard clinical practice and discontinued from the study treatment.

Blood sampling for measurement of PK and PSA/CA-125 concentrations and assessments for antitumor efficacy are described in the Supporting Methods. Antitumor efficacy was assessed in patients with a measurable lesion using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1

Pharmacokinetics [1]
Single-dose pharmacokinetic data for sennaparib are shown in Figure 2A and Table S10. The median time to reach peak plasma concentration (Cmax) for sennaparib was 1.00–2.08 hours. Sennaparib exposure parameters (Cmax and AUC) increased with increasing dose in the 2–80 mg dose range, but showed no significant difference in the 80–150 mg dose range. The relationship between dose and sennaparib exposure indicated that exposure plateaued after an 80 mg daily dose.
Multiple-dose pharmacokinetic data for sennaparib are shown in Figure 2B and Table S11. The pharmacokinetic pattern of sennaparib after multiple doses was the same as that after a single dose (Figure 2B). In the multiple-dose phase (D1), the median time to reach peak plasma concentration (Cmax) after a single dose of 2–150 mg sennaparib was 1.97–2.13 hours. The mean elimination half-life was 5.86–13.30 hours on day 1 and 5.68–8.39 hours on day 15. No significant accumulation of sennaparib was observed in the body after multiple administrations (accumulation index 1.06–1.67).

Safety and Tolerability [1] Overall, 38 patients (97.4%) experienced at least one treatment-emergent adverse event (TEAE) during treatment (267 total; Table 2). The incidence and severity of TEAEs appeared to be dose-independent. The most common TEAEs of each grade were fatigue, headache (n = 10; 25.6% each), and nausea (n = 9; 23.1%; Table 3). Most TEAEs were grade 1 or 2 (n = 25; 64.1%; Table 2). TEAEs led to discontinuation of treatment in 6 patients (15.4%) or interruption of treatment in 8 patients (20.5%). Two deaths were reported, both occurring at the end of the study treatment. One of the deaths was attributed to progression of metastatic breast cancer and was considered unrelated to senaparib: the patient died 27 days after discontinuation of treatment. Another death involved a patient with non-BRCA-mutated ovarian cancer, whose cause of death was attributed to a grade 5 bone marrow failure event related to sennaparib. Bone marrow biopsy did not reveal myelodysplastic syndrome (MDS). This patient also had grade 3 anemia, grade 4 neutropenia, and grade 4 thrombocytopenia. The patient had stable disease (SD) and was progression-free for 10.9 months after treatment with 80 mg daily, and died 96 days after discontinuation of treatment. Treatment-related adverse events (AEs) were reported in 8 patients (20.5%), the most common being nausea (n = 3; 7.7%), fatigue, and thrombocytopenia (n = 2; both 5.1%; see Table S8). A total of 28 serious adverse events (SAEs) occurred in 15 patients (38.5%) (see Table S9), of which 22 events in 14 patients (78.6%) were grade 2 or 3. The most common SAEs were hematuria (occurring twice in 2 patients, both grade 3 [5.1%]) and pulmonary embolism (occurring twice in 2 patients, grade 2 and grade 3 respectively [5.1%]). Almost all reported SAEs were considered unrelated to or unlikely to be related to sennaparib; the only exception was the aforementioned grade 5 bone marrow failure SAE.
Seven patients (17.9%) experienced TEAEs during hematologic therapy. Four patients (10.3%; three grade 2, one grade 3) reported anemia, three patients (7.7%; two grade 1, one grade 3) reported thrombocytopenia, and one patient (2.6%; grade 4) reported neutropenia. The last TEAE during hematologic therapy was grade 5 bone marrow failure, considered possibly related to the study drug. The patient was diagnosed with a Grade 4 serious adverse event (SAE) – decreased platelet count – on day 239 of the study, leading to discontinuation of the study drug; and was further diagnosed with bone marrow failure on day 263 of the study, ultimately dying on day 353. No cases of secondary hematologic malignancies occurred in this study.
No DLT was observed at any dose level during the dose-limiting toxicity (DLT) observation period specified in the protocol. Therefore, the maximum tolerated dose (MTD) was not reached. Considering that the absorption of sennaparib tends to saturate in the dose range of 80–150 mg, and the initial ORR was 20% at a 100 mg dose, the RP2D for sennaparib was determined to be 100 mg daily.

[1]. A phase 1 dose-escalation study of the poly(ADP-ribose) polymerase inhibitor senaparib in Australian patients with advanced solid tumors. Cancer . 2023 Apr 1;129(7):1041-1050.

[2]. 574P Updated results of phase I study of senaparib (IMP4297) in Australian patients with advanced solid tumours. ABSTRACT ONLY| VOLUME 31, SUPPLEMENT 4, S490, SEPTEMBER 01, 2020.

Senapanib is an orally bioavailable inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2 with potential antitumor activity. After administration, senapanib selectively binds to PARP 1 and 2, blocking PARP-mediated single-strand DNA break repair (via the base excision repair pathway). This enhances the accumulation of DNA strand breaks, promotes genomic instability, and ultimately leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nucleoproteins, which signal and recruit other proteins to repair damaged DNA and are activated by single-strand DNA breaks. Drug Indication Treatment of metastatic castration-resistant prostate cancer. Background: Senapanib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor that has shown potent antitumor activity in preclinical studies. This first-in-human, phase I dose-escalation study aims to evaluate the safety and preliminary efficacy of senapanib in patients with advanced solid tumors.
Methods: A traditional 3+3 design was used to recruit patients with advanced solid tumors from three centers in Australia. The dose escalation cohort continued until the maximum tolerated dose or the recommended phase II dose was determined. Patients received a single oral dose of sennapanib, and if no dose-limiting toxicity occurred within 7 days, sennapanib was administered orally once daily for 3 weeks. The primary endpoints were safety and tolerability. [1]

---

Overall, sennapanib was well tolerated in previously treated patients with advanced solid tumors in Australia and showed preliminary antitumor activity. The current findings support further phase II and phase III studies of sennapanib in patients with solid tumors at a daily RP2D dose of 100 mg. [1]

---

PARP inhibitors are a class of promising anticancer drugs with proven clinical activity and a mechanism of action based on synthetic lethality. Senaparib (formerly known as IMP4297) is a novel, highly potent, and selective oral PARP1/2 inhibitor that has demonstrated potent antitumor activity in preclinical studies. This first-in-human study aimed to investigate the tolerability, safety, pharmacokinetics, and preliminary antitumor activity of Senaparib in Australia.
Methods
Adult patients with advanced, refractory solid tumors were given Senaparib orally once daily, starting at a dose of 2 mg. Dose escalation followed a conventional 3+3 design and a modified Fibonacci sequence, with 3–6 patients in each group. Dose-limiting toxicities (DLTs) were assessed during the first treatment cycle. A dose expansion cohort included patients with BRCA mutations (BRCA+) in advanced solid tumors.
Results
As of February 25, 2020, 39 patients were enrolled and randomly assigned to 10 dose groups (2–150 mg). No dose-limiting toxicities (DLTs) were observed. The most common treatment-related adverse events (TEAEs) during treatment were headache (25.6%), fatigue (25.6%), constipation (17.9%), diarrhea (15.4%), nausea (12.8%), vomiting (12.8%), and anemia (10.3%). Treatment-related adverse events (TRAEs) were observed in 8 patients (21%) starting with the 40 mg dose group. The most common TRAEs were nausea (8%), thrombocytopenia (5%), and fatigue (5%). One case of grade 4 thrombocytopenia occurred in the 80 mg dose group, which was the only serious TRAE. Treatment was discontinued in 4 patients (10%) due to adverse events, and treatment was discontinued in 6 patients (15%) due to adverse events. The overall objective response rate (ORR) and disease control rate (DCR) were 15% and 85%, respectively. In the 8 evaluable patients with ovarian cancer, the ORR was 38% and the DCR was 75%. One patient with BRCA-positive ovarian cancer achieved a partial response (PR) lasting more than 20 months, and one patient with BRCA-negative prostate cancer achieved a PSA decrease of more than 50% lasting 11 months. Plasma exposure increased proportionally with the dose from 2 mg to 80 mg, but increased non-linearly in the dose range of 80 mg to 150 mg.
Conclusion
Sennapanib showed encouraging clinical benefit and good tolerability in patients with advanced solid tumors. Based on safety, pharmacokinetics and clinical activity, Australia selected 100 mg orally once daily as the recommended Phase II dose (RP2D). Clinical trial information: NCT03507543. [2]

C24H20F2N6O3

478.450811386108

478.16

C, 60.25; H, 4.21; F, 7.94; N, 17.57; O, 10.03

1401682-78-7

1401682-78-7; 1401683-39-3 (HCl)

68389008

White to off-white solid powder

2

98.7

1

8

4

35

804

0

FC1=CC=C(C=C1C(N1CCN(C2N=CC=CN=2)CC1)=O)CN1C(NC(C2C(=CC=CC1=2)F)=O)=O

VBTUJTGLLREMNW-UHFFFAOYSA-N

InChI=1S/C24H20F2N6O3/c25-17-6-5-15(14-32-19-4-1-3-18(26)20(19)21(33)29-24(32)35)13-16(17)22(34)30-9-11-31(12-10-30)23-27-7-2-8-28-23/h1-8,13H,9-12,14H2,(H,29,33,35)

5-fluoro-1-[[4-fluoro-3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4-dione

IMP4297; IMP-4297; Senaparib; 1401682-78-7; Senaparib [INN]; MNZ4OP95CF; UNII-MNZ4OP95CF; 5-fluoro-1-[[4-fluoro-3-(4-pyrimidin-2-ylpiperazine-1-carbonyl)phenyl]methyl]quinazoline-2,4-dione; IMP 4297; Senaparib

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~83.3 mg/mL (~174.2 mM)

配方 1 中的溶解度: 2.08 mg/mL (4.35 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 悬浮液；超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

---

配方 2 中的溶解度: ≥ 2.08 mg/mL (4.35 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。