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]
The senaparib single-dose PK data are presented in Figure 2A and Table S10. The median time to reach Cmax of senaparib was 1.00–2.08 hours across dose levels. Senaparib exposure parameters (Cmax and AUC) demonstrated an increasing trend with increasing doses in the dose range from 2 to 80 mg but were comparable in the range from 80 to 150 mg. The relationships between dose and senaparib exposure supported a plateau commencing at 80 mg daily.
Data for the senaparib multiple-dose PK parameters are presented in Figure 2B and Table S11. The PKs of senaparib after multiple-dose administration followed the same pattern as the single-dose administration (Figure 2B). The median time to reach Cmax of senaparib was 1.97–2.13 hours after single-dose administration of 2–150 mg during this multiple-dose stage (D1). The mean elimination half-life ranged from 5.86 to 13.30 hours for D1 and from 5.68 to 8.39 hours for D15. There was no apparent accumulation of senaparib in the body after multiple dosing (accumulation index, 1.06–1.67).

Safety and tolerability [1]
Overall, 38 patients (97.4%) experienced at least one TEAE (267 events in total; Table 2). The incidence and severity of TEAEs did not appear to be dose-dependent. The most common TEAEs of any grade were fatigue, headache (n = 10; 25.6% for each), and nausea (n = 9; 23.1%; Table 3). The majority of TEAEs were grade 1 or 2 (n = 25; 64.1%; Table 2). TEAEs resulted in dose discontinuation or interruption in six patients (15.4%) and eight patients (20.5%), respectively. Two deaths were reported, and both occurred after the end of study treatment. One death was attributed to progression of metastatic breast cancer and was considered unrelated to senaparib: the patient died 27 days after the withdrawal of treatment. The other death occurred to a patient with non-BRCA–mutated ovarian cancer, and it was attributed to a grade 5 event of bone marrow failure related to senaparib, for which the bone marrow biopsy did not indicate myelodysplastic syndrome (MDS); this patient also had grade 3 anemia, grade 4 neutropenia and grade 4 thrombocytopenia. The patient had a response of SD to the treatment at dose level of 80 mg daily, 10.9 months free of disease progression, and died 96 days after the withdrawal of treatment. Eight patients (20.5%) reported treatment-related AEs; the most common were nausea (n = 3; 7.7%), fatigue, and thrombocytopenia (n = 2; 5.1% for each; see Table S8). In total, 15 patients (38.5%) experienced 28 SAEs (see Table S9), of which 22 events (78.6%) in 14 patients were grade 2 or 3. The most frequent SAEs were hematuria (two events in two patients [5.1%], both grade 3) and pulmonary embolism (two events in two patients [5.1%], one each at grades 2 and 3). Almost all reported SAEs were considered either not related or unlikely to be related to senaparib; the exception was the SAE of grade 5 bone marrow failure already mentioned.

Hematologic TEAEs occurred in seven patients (17.9%). Anemia was reported in four patients (10.3%; three at grade 2 and one at grade 3), thrombocytopenia in three patients (7.7%; two at grade 1 and one at grade 3), and neutropenia in one patient (2.6%; grade 4). The final hematologic TEAE was the grade 5 bone marrow failure, which was considered to be probably related to the study drug. This patient was diagnosed with a grade 4 SAE of decreased platelet count on study day 239, leading to study drug discontinuation, and was further diagnosed with bone marrow failure on study day 263, leading to death on day 353. There were no cases of secondary hematologic malignancies among the patients in this study.

No DLTs were observed during the protocol-defined DLT period at any dose level. Therefore, the MTD was not reached. Considering the absorption of senaparib tended to be saturated during the 80–150 mg dose range, and the preliminary efficacy was a 20% ORR at 100 mg, the RP2D of senaparib 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.

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.

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Drug Indication
Treatment of metastatic castrate-resistant prostate cancer.

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Background: Senaparib is a novel, selective poly(ADP-ribose) polymerase-1/2 inhibitor with strong antitumor activity in preclinical studies. This first-in-human, phase 1, dose-escalation study examined the safety and preliminary efficacy of senaparib in patients with advanced solid tumors.

Methods: Patients with advanced solid tumors were enrolled from three centers in Australia, using a conventional 3 + 3 design. Dose-escalation cohorts continued until the maximum tolerated dose or a recommended phase 2 dose was determined. Patients received one dose of oral senaparib and, if no dose-limiting toxicity occurred within 7 days, they received senaparib once daily in 3-week cycles. The primary end points were safety and tolerability. [1]

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Overall, senaparib was well tolerated in Australian patients with advanced, pretreated solid tumors and demonstrated preliminary evidence of antitumor activity. The current findings support further phase 2 and 3 investigations of senaparib in patients with solid tumors at the RP2D of 100 mg daily.[1]

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PARP inhibitors are promising anti-cancer agents with proven clinical activity based on mechanism of synthetic lethality. Senaparib (previously known as IMP4297) is a novel highly potent and selective oral PARP1/2 inhibitor with strong antitumor activity in preclinical studies. This first in human study investigated the tolerability, safety, PK, and preliminary antitumor activity of senaparib in Australia.

Methods
Adults with advanced, refractory solid tumours received senaparib orally QD, starting at 2mg. Dose escalation used a traditional 3+3 design and a modified Fibonacci sequence with 3-6 patients per cohort. DLT was evaluated in the first cycle. Dose expansion cohort enrolled patients with BRCA mutated (BRCA+) advanced solid tumors.

Results
As of Feb 25, 2020, 39 patients were enrolled in 10 dose levels (2 to 150mg). No DLTs were observed. The most frequent treatment emergent adverse events (TEAE) 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 (TRAE) were observed in 8 (21%) patients starting from 40mg dose group. The most frequent TRAEs were nausea (8%), thrombocytopenia (5%) and fatigue (5%). An event of grade 4 thrombopenia in 80mg was the only serious TRAE. Four (10%) patients interrupted and 6 (15%) patients discontinued therapy due to AEs. The overall ORR and DCR was 15% and 85% respectively. In 8 evaluable ovarian cancer patients, ORR was 38% and DCR was 75%. A prolonged (> 20 months) PR response was observed in one BRCA+ ovarian cancer patient and a > 50% decrease of PSA for 11 months was observed in one BRCA- prostate cancer patients. The plasma exposure increased proportionally with doses ranging from 2mg to 80mg and became nonlinear ranging from 80mg to150mg cohorts.

Conclusions
Senaparib demonstrated encouraging clinical benefit and a favorable tolerability profile in patients with advanced solid tumour. The 100 mg orally QD was selected as the RP2D in Australia based on safety, pharmacokinetics and clinical activity. 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);

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.)