PARP1/2

Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. Senaparib (IMP4297) is being studied as a therapy for pancreatic, breast, and advanced liver cancer [2]. Senaparib is an orally bioavailable inhibitor of the nuclear enzymes poly (ADP-ribose) polymerase (PARP) 1 and 2, with potential antineoplastic activity. Upon administration, senaparib selectively binds to PARP 1 and 2 and prevents PARP-mediated DNA repair of single-strand DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks and promotes genomic instability and eventually leads to apoptosis. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by single-strand DNA breaks.

Senaparib (formerly IMP4297) is a novel, selective, oral PARP1 and PARP2 inhibitor that has shown strong antitumor activity in preclinical studies, with 20-fold higher in vivo activity than olaparib (the most well developed of the currently approved PARPis). A phase 1, first-in-human study of senaparib was conducted in Australian patients with advanced solid tumors (ClinicalTrials.gov identifier NCT03507543). The safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple doses of senaparib were explored, and preliminary antitumor responses were documented. [1]

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Thirty-nine patients were enrolled at 10 dose levels ranging from 2 to 150 mg. No dose-limiting toxicities were observed in any cohort. Most treatment-emergent adverse events were grade 1-2 (91%). Seven patients (17.9%) reported hematologic treatment-emergent adverse events. Treatment-related adverse events occurred in eight patients (20.5%), and the most frequent was nausea (7.7%). Two deaths were reported after the end of study treatment, one of which was considered a complication from Senaparib-related bone marrow failure. Pharmacokinetic analysis indicated that senaparib the accumulation index was 1.06-1.67, and absorption saturation was 80-150 mg daily. In 22 patients with evaluable disease, the overall response rate was 13.6%, and the disease control rate was 81.8%. The overall response rate was 33.3% for the BRCA mutation-positive subgroup and 6.3% for the nonmutated subgroup. Conclusions: Senaparib was well tolerated in Australian patients with advanced solid tumors, with encouraging signals of antitumor activity. The recommended phase 2 dose for senaparib was determined to be 100 mg daily. [1]

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Efficacy: Of the 22 patients who were evaluable for tumor response by RECIST 1.1 criteria, six patients were confirmed as carriers of BRCA1 or BRCA2 mutations (see Table S12). Among these 22 patients, three (all with ovarian cancer) experienced a PR (one each in the 20-mg, 100-mg, and 120-mg dose groups), with an ORR of 13.6% (95% CI, 2.9%–34.9%). Two of the responders had BRCA mutation-positive tumors (one each in the 20-mg and 100-mg dose groups), for an ORR in the BRCA mutation-positive subgroup of 33.3% (two of six patients; 95% CI, 4.3%–77.7%). The ORR was 6.3% (one of 16 patients) for the nonmutated subgroup. An additional 15 patients (68.2%) overall had SD. The DCR was 81.8% (95% CI, 59.7%–94.8%) overall and was similar for the BRCA mutation-positive subgroup (83.3%; 95% CI, 35.9%–99.6%). In the 100-mg group, the ORR was 20% (95% CI, 0.5%–71.6%), and the DCR was 40% (95% CI, 5.3%–85.3%). A waterfall plot of the best change in target lesion size for all evaluable patients is shown in Figure 3. All three responders were still alive without disease progression at the data cutoff date, with response durations of 1.4 months for the patient with BRCA wild type and 2.8 and 22.1 months for the two patients with BRCA mutation-positive disease. Median PFS was 5.7 months (95% CI, 2.7%–7.4%) in the efficacy population and 7.4 months (95% CI, 1.77% to not reached) in the BRCA mutation-positive subgroup (see Table S13 and Figure S2). One of the 10 patients (10%) with prostate cancer experienced a PSA response; he had BRCA wild-type and was in the 40-mg dose group [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.

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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.

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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]

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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]

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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]

C24H21CLF2N6O3

514.911750555038

514.133172

C, 55.98; H, 4.11; Cl, 6.88; F, 7.38; N, 16.32; O, 9.32

1401683-39-3

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

89927080

Typically exists as solid at room temperature

2

8

4

36

804

0

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

IBDAAVBRRAWCKS-UHFFFAOYSA-N

InChI=1S/C24H20F2N6O3.ClH/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);1H

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

Senaparib hydrochloride; IMP-4297 hydrochloride; IP7DV1DQ1R; UNII-IP7DV1DQ1R; 1401683-39-3; 2,4(1H,3H)-Quinazolinedione, 5-fluoro-1-((4-fluoro-3-((4-(2-pyrimidinyl)-1-piperazinyl)carbonyl)phenyl)methyl)-, hydrochloride (1:1); SCHEMBL15420063;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)