Selective Poly(ADP-ribose) Polymerase Inhibitor Research Articles

Olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in combination with pembrolizumab and carboplatin as first-line treatment of recurrent or metastatic head and neck squamous-cell carcinoma (RM-HNSCC): A single-arm, phase 2 trial.

6016 Background: The homologous recombination deficiency (HRD) phenotype is common in HNSCC and is due to mutation and promoter hypermethylation of DNA repair genes ( BRCA1, BRCA2, ATR, ATM, and FANC) and PTEN. In pre-clinical models of HNSCC, HRD sensitizes tumor to PARP inhibition and to additive antitumor activity of PARP inhibition in combination with platinum agents. PARP inhibitors also activate the STING pathway and upregulate PD-L1 expression, resulting in synergistic antitumor activity when given with PD-1 inhibitors. Olaparib is a highly selective PARP inhibitor that has been safely combined with pembrolizumab and carboplatin. Methods: In this single-arm phase 2 trial, patients with RM-HNSCC, no prior therapy for RM disease, and adequate performance status and organ function received up to six 21-day cycles of olaparib (200 mg bid orally days 1-10), pembrolizumab (200 mg IV day 1), and carboplatin (AUC 5 IV day 1), followed by up to twenty-nine 21-day cycles of olaparib (oral 300 mg bid days 1-21) and pembrolizumab (200 mg day 1). Treatment continued until discontinuation criteria were met. The primary endpoint was objective response, assessed by an independent radiologist using iRECIST. The primary hypothesis was that this regimen would result in a higher objective response rate (ORR) than historically reported with 5-FU, pembrolizumab and a platinum agent in similar patients. A Simon optimal two-stage design tested the null hypothesis (H0 : ORR≤36%) versus the alternative hypothesis (H1 : ORR=62%) at a type I error rate of 10% and 90% power. In the first stage, up to 13 patients could be accrued. If ≥6 responses occur, 16 additional patients will be accrued. The null hypothesis will be rejected if ≥14 responses are observed in these 29 patients. At the end of the first stage, an interim analysis was be performed to assess olaparib delivery during cycles 1 and 2 with the goal of 100% delivery in ≥ 80% of patients. We report the results of the primary endpoint and olaparib delivery for the first stage of the trial. Results: Twelve patients enrolled into the first stage of the trial. Key characteristics included median age 62 years (range 59-74), tobacco history (Y-5; N-7), primary site (oropharynx-7; oral cavity-4; larynx-1), HPV status (positive: 6; negative: 6) and PD-L1 status (CPS 0: 1; 1-19: 4; ≥20: 7). Tumor response occurred in 8 patients (ORR 67%). The best tumor response to date was CR (1), PR (7), SD (3) and PD (1). Olaparib delivery during cycles 1 and 2 was 100% for all patients. Conclusions: Among patients with RM-HNSCC, first-line treatment with olaparib, pembrolizumab and carboplatin resulted in an ORR of 67% during the first stage of the trial. Olaparib delivery was 100%. Enrollment into the second stage is ongoing. Clinical trial information: NCT04643379 .

Abstract CT218: A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas

Abstract Objectives: Small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas (NECs) share many clinical features, including limited response to immune checkpoint inhibitors (ICIs). However, preclinical data suggest synergistic response with combined ICI and poly (ADP-ribose) polymerase inhibitors (PARPi) in SCLC models. This single-institution, phase II trial (NCT04701307) assessed the efficacy of a combination of the anti-PD-1 monoclonal antibody, dostarlimab, with the selective PARPi, niraparib, in patients with relapsed SCLC or NECs. Methods: Eligible patients with SCLC (Cohort 1) or NECs (Cohort 2) had received at least one prior line of therapy and were treated with niraparib 300 mg (or 200 mg if <77kg or platelets < 150,000/µL) PO daily, and dostarlimab 500 mg IV q21d (1000mg IV q42d starting with Cycle 5). Co-primary endpoints were objective response rate (ORR) by RECISTv1.1 and 6-month progression free-survival (PFS6). Using a Bayesian Optimal Phase 2 (BOP2) design, interim futility analyses were planned after enrolling up to 15 SCLC and 9 NEC patients (NEC), respectively. Adverse events (AE) were monitored continuously. Patients underwent biopsies, if feasible, at Cycle 1 and Cycle 3, as well as longitudinal plasma collection for translational studies. Results: From Feb 2021 to Aug 2021, 14 and 9 patients enrolled with SCLC and NEC, respectively. NECs included tumors from gynecological, head/neck, and gastrointestinal sites. In Cohort 1 (SCLC), 12 of 14 patients were evaluable by RECISTv1.1, including 1 complete response (CR), while 4 patients not achieving partial response (PR) had minor responses (-2%, -14%, -19%, and -24% from baseline). Only 1 patient in this cohort achieved PFS6, though 2 additional patients progressed between 5 and 6 months. In Cohort 2 (NEC), 6 of 9 patients were evaluable by RECISTv1.1 and no CR/PRs were observed. One patient did experience durable minor response (-21%), but no patients achieved PFS6. Dose-limiting, niraparib-related hematological AEs, typically thrombocytopenia, occurred in 12 of 23 patients. Non-hematological, treatment-related serious AEs occurred in only 1 patient (Grade 3 inflammatory arthritis), while 1 additional patient experienced brief dose-interruption due to Grade 2 pneumonitis. Preliminary translational data, including bulk and single-cell RNAseq, indicate molecular features, such as transcriptional subtype, are shared across SCLC and NECs and may predict response to this combination. Conclusions: In heavily pre-treated patients across SCLC and NEC cohorts, combined niraparib and dostarlimab failed to exceed interim futility criteria. However, multiple SCLC patients experienced durable disease control, including one patient with sustained CR and associated translational studies point to potential biomarker-driven approaches in the future. Trial supported by GlaxoSmithKline. Citation Format: Carl M. Gay, C. Allison Stewart, Michael Frumovitz, Junya Fujimoto, Yuann xi, Qi Wang, Runsheng Wang, Veronica Novegil, Mehmet Altan, Tina Cascone, Arvind Dasari, Yasir Y. Elamin, Frank V. Fossella, Bonnie S. Glisson, Charles S. Lu, Marcelo V. Negrao, Ferdinandos Skoulidis, Natalie Vokes, Robert J. Cardnell, Ignacio I. Wistuba, Jing Wang, John V. Heymach, Lauren A. Byers. A phase II trial of niraparib plus dostarlimab in relapsed small cell lung cancer and other high-grade neuroendocrine carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT218.

A multi-task FP-GNN framework enables accurate prediction of selective PARP inhibitors.

PARP (poly ADP-ribose polymerase) family is a crucial DNA repair enzyme that responds to DNA damage, regulates apoptosis, and maintains genome stability; therefore, PARP inhibitors represent a promising therapeutic strategy for the treatment of various human diseases including COVID-19. In this study, a multi-task FP-GNN (Fingerprint and Graph Neural Networks) deep learning framework was proposed to predict the inhibitory activity of molecules against four PARP isoforms (PARP-1, PARP-2, PARP-5A, and PARP-5B). Compared with baseline predictive models based on four conventional machine learning methods such as RF, SVM, XGBoost, and LR as well as six deep learning algorithms such as DNN, Attentive FP, MPNN, GAT, GCN, and D-MPNN, the evaluation results indicate that the multi-task FP-GNN method achieves the best performance with the highest average BA, F1, and AUC values of 0.753 ± 0.033, 0.910 ± 0.045, and 0.888 ± 0.016 for the test set. In addition, Y-scrambling testing successfully verified that the model was not results of chance correlation. More importantly, the interpretability of the multi-task FP-GNN model enabled the identification of key structural fragments associated with the inhibition of each PARP isoform. To facilitate the use of the multi-task FP-GNN model in the field, an online webserver called PARPi-Predict and its local version software were created to predict whether compounds bear potential inhibitory activity against PARPs, thereby contributing to design and discover better selective PARP inhibitors.

92 (PB082) - RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, synergizes with SOC therapy in preclinical models of solid tumors

Background: Poly (ADP-ribose) polymerase (PARP) activity involves synthesis of Poly-ADP ribose (PAR) polymers that recruit host DNA repair proteins leading to correction of DNA damage and maintenance of cell viability. Several PARP inhibitors have been approved for the treatment of BRCA-mutated ovarian, breast and pancreatic cancer. In addition to BRCA-mutated cancers, therapeutic role of PARP inhibitors as monotherapy agent or in combination with established therapy can be expanded to other types of solid tumors through ‘synthetic lethality’ mechanism. Herein, we describe the efficacy of RP12146 as a single agent and in combination with approved therapies in preclinical models of solid tumors. Material & Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 as a single agent or in combination with approved agents in various solid tumor cell lines. Apoptosis & Cell cycle was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD or Propidium Iodide, and analysis by flow cytometry. Anti-tumor potential of RP12146 as a single agent or in combination with chemotherapeutic agents was tested in OVCAR-3 and NCI-H69 Xenografts. Expression of downstream markers were determined in cell lines and xenograft tumor samples by Western blotting. Results: RP12146 inhibited PARP1 (0.6 nM) & PARP2 (0.5 nM) with equal potency with several fold selectivity over the other members of the PARP family. In addition, RP12146 demonstrated selective PARP1-Trapping with ∼20-fold selectivity over PARP2. RP12146 caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 μM to 9.6 μM. Combination of RP12146 with Temozolomide, SN-38, Topotecan, and Lurbinectedin demonstrated either additive or synergistic effects manifested by an inhibition in growth, induction of apoptosis and cell cycle arrest in Breast, Gastric, Glioma, Lung Cancer, and Ovarian cancer cell lines. RP12146 exhibited anti-tumor potential with TGI of 28% and 21.8% as a single agent in OVCAR-3 and NCI-H69 Xenograft model respectively. In NCI-H69 xenograft model, RP12146 in combination with cisplatin exhibited TGI of 69.3%. Conclusion: Data demonstrate the therapeutic potential of RP12146 as single agent and in combination in solid tumors. RP12146 is currently being evaluated in Phase 1 clinical trials in patients with locally advanced or metastatic solid tumors (NCT05002868). No conflict of interest.

Abstract 5493: Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in solid tumors

Abstract Introduction: The Poly (ADP-ribose) polymerase (PARP) family plays an important role in the regulation of transcription, apoptosis and DNA damage response. Several PARP inhibitors have been approved for the treatment of BRCA-mutated ovarian, breast and pancreatic cancer. Through ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects either as monotherapy or in combination with established therapy across various solid tumor types. Herein, we describe the efficacy of RP12146 as a single agent and in combination with approved therapies in preclinical models of solid tumors. Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 as a single agent or in combination with approved agents in various solid tumor cell lines. Apoptosis was evaluated following incubation of cell lines with compound for 48 or 72 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. Anti-tumor potential of RP12146 as a single agent or in combination with chemotherapeutic agents was tested in OVCAR-3 and NCI-H69 Xenografts. Expression of downstream PAR, PARP-trapping, and cleaved PARP expression were determined in cell lines and xenograft tumor samples by Western blotting. Plasma and tumor concentration of RP12146 in NCI-H69 xenograft samples were also determined. Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Combination of RP12146 with Temozolomide, Topotecan, Lurbinectedin, and Abemaciclib demonstrated either additive or synergistic effects manifested by an inhibition in growth of solid tumor cell lines. RP12146 exhibited anti-tumor potential with TGI of 28% and 21.8% as a single agent in OVCAR-3 and NCI-H69 Xenograft model respectively. In NCI-H69 xenograft model, RP12146 in combination with cisplatin exhibited TGI of 69.3 %. Conclusion: Data demonstrate the therapeutic potential of RP12146 as single agent and in combination in solid tumors. RP12146 is currently being evaluated in Phase 1 clinical trials in patients with locally advanced or metastatic solid tumors (NCT05002868). Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Haritha Polimati, Sridhar Veeraraghavan, Swaroop Vakkalanka. Activity of RP12146, a novel, selective, and potent small molecule inhibitor of PARP 1/2, in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5493.

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Phase 1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with CD33+ Relapsed or Refractory Acute Myeloid Leukemia

Could the spanning of NAM-AD subsites by poly (ADP ribose) polymerase inhibitors potentiate their selective inhibitory activity in breast cancer treatment? Insight from biophysical computations

ABSTRACT Poly (ADP-ribose) polymerase (PARP) inhibition by pharmacological agents has been a useful cancer treatment in recent times. PARP inhibitors represent a category of anticancer drugs that function by blocking PARP catalytic activity. The design of highly selective and effective PARP inhibitors has significant therapeutic advantages and remains an integral part of several PARP-based drug discovery research. We employed conformational landscape and binding energy analyses to decipher the mechanisms underlying the inhibitory potencies and selectivity of Cpd81 towards PARP enzymes. Relatively, the thermodynamics analysis revealed that pp2-cpd81 (−55.38 kcal/mol) had a higher ΔGbind than pp1-cpd81 (−27.97 kcal/mol), indicating high selective binding activity of Cpd81 towards PARP-2. The binding activity of Cpd81 to PARP-2 was potentiated by the high effects of van der Waal. Moreso, the NAM-AD positioning of Cpd81 facilitated its optimal orientation for multiple high-affinity complementary interactions with key site residues. Resultantly, Cpd81 could span the two subsites of the PARP binding pocket effectively, as seen in the multiple interactions exhibited by the compound. These interactions serve as the basis for the selective inhibitory potential of Cpd81. We believe the findings here would pave the way for developing PARP inhibitors that are selective in breast cancer treatment.

270P Phase Ib study of venadaparib, a potent and selective PARP inhibitor, in homologous recombination repair (HRR) mutated breast cancer

Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors and are currently approved for ovary, breast, pancreas and prostate cancers. VASTUS study (NCT04174716) is a basket trial investigating the safety and efficacy of venadaparib in 6 cohorts of different tumors, including breast cancer.

Abstract 2054: Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models

Abstract Objective: Homology-directed repair (HDR) pathway is the major DNA double-strand break repair pathway. BRCA-deficiency impairs this pathway, and combination with Poly(ADP-ribose) polymerase (PARP) inhibition results in cell death. This process is known as “synthetic lethality”. A proportion of breast cancer, ovarian cancer and other solid tumor patients carrying BRCA-mutated gene receive benefits from PARP inhibitors. In this study, we present in vitro activity and in vivo efficacy data of a novel small molecule PARP inhibitor, TQB3823 to support it as our clinical candidate. Method: Enzyme inhibition activities of TQB3823 were determined in PARP1/PARP2/Tankyrase 1 assays. Cellular anti-proliferative activity and selectivity were evaluated in MDA-MB-436 cell line with BRCA1 mutation and BRCA wild type MDA-MB-231 cell line. Antitumor efficacy of TQB3823 was investigated in BRCA1 mutated MDA-MB-436 breast cancer CDX model. Result: TQB3823 showed high potency and selectivity at both enzymatic and cellular level. IC50 of TQB3823 in PARP1/PARP2/Tankyrase 1 assays are 2.8/0.9/629.3 nM, respectively. It inhibited proliferation of BRCA1 mutant MDA-MB-436 cell with IC50 of 9.6 nM. In contrast, TQB3823 showed little anti-proliferative activity in BRCA-wild type MDA-MB-231 cell with IC50 >10 μM. TQB3823 demonstrated antitumor efficacy in dose dependent fashions with tumor regression was observed at 25 mg/kg in MDA-MB-436 CDX model. The level of antitumor effects was superior to niraparib at the same dose in the same study. DNA trapping experiments revealed similar potency to olaparib indicative of low toxicity. Conclusion: We have identified a novel, potent and selective PARP inhibitor TQB3823, which inhibits the proliferation of BRCA mutant cells but spares the wild type cells. In vivo study in a BRCA-deficiency tumor model confirms the high in vivo efficacy of this molecule. In conclusion, TQB3823 represents a promising differentiated clinical candidate for treating solid cancers with homology directed repair. Citation Format: Hu Yanbin, Zhang Xiquan, Yang Ling, Tian Xin, Li Gang, Hu Lihong, Charles Z. Ding, Xia Yuanfeng, Li Wei, Yin Shanshan, Chen Ying, Wu Songliang, Chen Shuhui. Characterization of TQB3823, a differentiated PARP inhibitor with anti-tumor activity in BRCA-deficiency cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2054.

First-in-human dose-finding study of venadaparib (IDX-1197), a potent and selective PARP inhibitor, in patients with advanced solid tumors.

3107 Background: Poly ADP-ribose polymerase (PARP) is an enzyme that is central to the repair of DNA replication errors known as single-strand breaks (SSBs). PARP inhibitors are currently approved for ovary, breast, pancreatic and prostate cancers which harbor germline or somatic BRCA1/2 mutations (g/sBRCAmt) and/or homologous recombinant repair mutation (g/sHRRmt). In this phase 1 dose finding study of venadaparib, we determined the maximum tolerated dose for venadaparib monotherapy and explored the safety, tolerability, pharmacokinetics, pharmacodynamics and anticancer efficacy of venadaparib in patients with advanced solid tumor which progressed after an attempt of standard-of-care therapy and for which effective therapy does not exist. Methods: Subjects who satisfied all of the inclusion/exclusion criteria and provided written informed consent were enrolled in this study. The investigational product was administered orally once daily continuously in a 3 weekly cycle. Enrolled subjects were assessed for safety and evaluated on tumor response using RECIST 1.1. The study was carried out in a conventional 3+3 design, starting from 2 mg up to 240 mg. Dose limiting toxicities (DLTs) and pharmacokinetics were assessed during the first cycle. Results: As of 08 Feb 2021, enrollment is completed with 32 patients enrolled. Most common tumor types enrolled are breast cancer (16 patients) and ovarian cancer (11 patients). Other tumor types include cancers of endometrium, fallopian tube, uterus and prostate. No DLTs were observed up to the maximum tested dose of 240 mg. Frequently observed adverse drug reactions were as follows – Anemia (56%), nausea (38%) and neutropenia (25%). Overall objective response rate (ORR) was 16% and clinical benefit rate (CBR) was 47%. Partial response was observed starting from 40 mg and clinical benefit was observed from the lowest dose of 2 mg. From optional tumor tissue samples, venadaparib exhibited ≥ 90% PAR inhibitory effect in pharmacodynamic analysis from 10 mg. For patients with known germline or somatic BRCA status either from local lab results or examined at a central lab retrospectively, ORR and CBR was 22% and 44% respectively for BRCAm(+) (9) patients. Interestingly, clinical efficacy was observed in BRCAm(-) (18) patients also, with ORR and CBR of 17% and 50% respectively. Conclusions: Safety and tolerability of the venadaparib monotherapy was confirmed with preliminary efficacy signals observed, even in BRCAm(-) patients. Clinical benefit was observed from the lowest tested dose, suggesting the potential to combine with other chemotherapeutic agents. Further studies to explore efficacy and safety of venadaparib in other tumor types and combinations, as well as to explore adequate biomarkers are warranted. Clinical trial information: NCT03317743.

AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC).

TPS176 Background: Clinical benefit has been observed with poly(ADP-ribose) polymerase (PARP) inhibition in patients with metastatic castration-resistant prostate cancer tumors that carry HRR gene defects. Niraparib is a highly selective and potent PARP inhibitor, with activity against PARP-1 and PARP-2 deoxyribonucleic acid (DNA)-repair polymerases. The objective of AMPLITUDE is to assess the efficacy and safety of niraparib/placebo added to AAP with androgen deprivation therapy (ADT) in a biomarker-selected population with mCSPC. Methods: AMPLITUDE (NCT04497844) is a phase 3, randomized, double-blind, placebo-controlled study with an expected enrollment of 788 patients at ~350 sites in ~30 countries. Clinical trial information: NCT04497844. [Table: see text]

In silico family-wide profiling and 3D modelling of the poly(ADP-ribose) polymerase superfamily.

Background: Due to the conserved nature of the poly(ADP-ribose) polymerase (PARP) catalytic domain, the identification of unique residues is critical for the design of selective inhibitors. With inhibitors of the DNA-dependent PARP members already clinically approved, new efforts lie in discovering selective inhibitors for PARP5a and beyond. Targeting the noncatalytic domains, such as the macro2 and WWE domains may also provide a way to achieve selectivity. Methodology &results: This paper details the in silico profiling of x-ray crystal structures and homology models of the PARP catalytic, WWE and macro2 domains. PARP10 was the least conserved catalytic domain, with the macro2 and WWE domains possessing more unique residues than their catalytic counterparts. Conclusion: Overall, we identify unique residues to target when designing selective PARP inhibitors including HIS1610, TYR1620, ALA1627 and ARG1658 of the PARP14 catalytic domain, along with multiple unique residues across the PARP WWE and macro2 domains.

Design, synthesis and evaluation of potential inhibitors for poly(ADP-ribose) polymerase members 1 and 14.

Poly(ADP-ribose) polymerase (PARP) members PARP1 and PARP14 belong to an 18-member superfamily of post-translational modifying enzymes. A library of 9 novel non-NAD analog amine compounds was designed, synthesized and evaluated for inhibitory activity against PARP1 and PARP14. Both in silico studies and in vitro assays identified compound 2 as a potential PARP1 inhibitor, inhibiting activity by 93 ±2% (PARP14 inhibition: 0 ±6%), and 7 as a potential PARP14 inhibitor, inhibiting activity by 91 ±2% (PARP1 inhibition: 18 ±4%), at 10-μm concentration. Key in silico interactions with TYR907 in PARP1 and TYR1620 and TYR1646 in PARP14 have been identified. Compound 2 and compound 7 have been identified as potential leads for the development of selective PARP inhibitors.

Phase 1/1b Trial of Talazoparib and Gemtuzumab Ozogamicin in Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Poly (ADP-ribose) polymerase (PARP) enzymes are involved in repair of single-strand DNA breaks through base excision repair pathways. Inhibitors of PARP are approved for the treatment of BRCA1/2-mutant malignancies where they result in compromise of dual DNA damage repair pathways, leading to induction of double-strand DNA breaks during replication and ultimately cell death. We have previously demonstrated (Portwood et al, ASH 2019 abstract) that PARP inhibitors can reduce in vitro acute myeloid leukemia (AML) growth and can synergistically enhance the anti-leukemic activity of antibody-drug conjugates containing DNA-damaging cytotoxic agents in preclinical human AML models. Talazoparib (Tala) is a novel selective PARP inhibitor which has been shown to exert more potent growth inhibitory effects across a panel of human AML cell lines than four other PARP inhibitors (veliparib, olaparib, rucaparib, niraparib). Gemtuzumab ozogamicin (GO) is an approved drug consisting of an antibody against human CD33 (gemtuzumab) linked to a cytotoxic component (calicheamicin). Hypothesis: We hypothesize that the combination of Tala + GO will be well tolerated and will result in improved clinical efficacy as compared with historical outcomes of GO monotherapy in patients with relapsed or refractory (R/R) AML. Objectives: The primary objectives of this study are (a) to determine the safety and tolerability of Tala + GO therapy in R/R AML; (b) to determine the overall response rate (ORR = complete remission (CR) + complete remission with incomplete hematologic recovery (CRi)) of combination therapy in patients with R/R AML. Additional anti-leukemic effects will be reported including complete remission rate, best response rate, duration of remission, leukemia-free survival, transfusion independence, and overall survival. Exploratory aims include measurable residual disease, evidence of PARP inhibition and DNA damage, feasibility of subsequent allogeneic stem cell transplant, and quality of life. Study Design: This open-label multi-center, Phase 1/1b trial is designed to determine whether the combination of Tala and GO represents a safe and effective approach for R/R AML. Eligible patients are adults aged ≥18 years with CD33-positive AML whose disease has failed to respond to and/or has recurred following at least one prior line of chemotherapy. There are two parts of the study: dose escalation and dose expansion. The dose escalation portion will establish the recommended Phase 2 dose (RP2D) of Tala in combination with GO. Cohorts of 3 subjects will be treated at one of three dose levels of Tala (0.5 mg, 0.75 mg, and 1 mg orally daily) in combination with fixed doses of GO (3 mg/m2/day on days 1,4, and 7, capped to one 4.5 mg vial) using a standard 3+3 subject cohort dose evaluation. Treatment will be given in 28-day cycles. The dose limiting toxicity (DLT) window will be Cycle 1 Day 1 to 28. Therapy may be given in the outpatient setting. Following determination of the RP2D, an expansion cohort of patients will be treated with the combination of Tala + GO for preliminary assessment of toxicities and anti-leukemic efficacy. Bone marrow assessment will be performed on Day 28 of Cycles 1 and 2. Safety and activity will be assessed using descriptive statistical analysis. If a patient achieves CR/CRi after cycles 1-2, the GO dose will be reduced to a maintenance dose of 2 mg/m2 on day 1 only of every subsequent cycle until disease progression or for a maximum of 6 total cycles of therapy. Patients not achieving a clinical response after 2 cycles will stop treatment. Treatment duration will be up to six months. This trial was activated in July 2020 and is registered at ClinicalTrials.gov (NCT04207190). Accrual is ongoing. Disclosures Griffiths: Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Boston Biomedical: Honoraria; Persimmune: Research Funding; AbbVie Inc: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Emadi:Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Wang:Stemline: Speakers Bureau; Astellas: Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau.

Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor

Pamiparib, an investigational Poly (ADP-ribose) polymerase (PARP) inhibitor in clinical development, demonstrates excellent selectivity for both PARP1 and PARP2, and superb anti-proliferation activities in tumor cell lines with BRCA1/2 mutations or HR pathway deficiency (HRD). Pamiparib has good bioavailability and is 16-fold more potent than olaparib in an efficacy study using BRCA1 mutated MDA-MB-436 breast cancer xenograft model. Pamiparib also shows strong anti-tumor synergy with temozolomide (TMZ), a DNA alkylating agent used to treat brain tumors. Compared to other PARP inhibitors, pamiparib demonstrated improved penetration across the blood brain barrier (BBB) in mice. Oral administration of pamiparib at a dose as low as 3 mg/kg is sufficient to abrogate PARylation in brain tumor tissues. In SCLC-derived, TMZ-resistant H209 intracranial xenograft model, combination of pamiparib with TMZ overcomes its resistance and shows significant tumor inhibitory effects and prolonged life span. Our data suggests that combination of pamiparib with TMZ has unique potential for treatment of brain tumors. Currently, the combination therapy of pamiparib with TMZ is evaluated in clinical trial [NCT03150862].

NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors.

e14640 Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B). Dose escalation is by 3+3 design. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone. Each schedule will have a 6 pt dose expansion at the MTD. The dose level (DL) 1 for schedule B is the previously reported MTD from schedule A (T 250mcg with C AUC 6 + P 80mg/m2). Results: Schedule B results are reported: 15 pts (median age 56 yrs [range 43-76]) have been enrolled. Primary malignancies include colorectal (4), pancreas (4), prostate (2), urothelial (2), and other (3). Dose was initiated at Schedule A MTD. DL2 (T 350mcg with C AUC 6 + P 80mg/m2) exceeded the MTD with 2 of 6 pts experiencing hematologic dose limiting toxicities (DLTs). DL1 is the confirmed schedule B MTD. Dose expansion to 6 pts is ongoing. Of the 11 pts with measurable disease, 3 (27%) had PR and 5 (45%) had SD. Pts were on study a median of 10 weeks (range 5-36+). Most common grade 3/4 AEs include leukopenia (53%), neutropenia (47%), and anemia (47%). One grade 5 AE of intracranial hemorrhage occurred, possibly related to therapy in the setting of grade 3 thrombocytopenia and concern for CNS disease. Conclusions: The schedule B MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m2. Data from the full dose expansion will be presented. This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874.

Abstract 4845: Preclinical evaluation of HWH340, a novel PARP inhibitor

Abstract Objective: Poly-ADP-ribose polymerase (PARP) participates in DNA repair, replication and transcription, and is important to maintaining genome stability and integrity. PARP inhibitors have proven to be efficacious in the clinic to treat BRCA-deficient cancers. PARP inhibitors may also be used as sensitizing agent in combination with other antitumor agents. The purpose of this study is to investigate in preclinical models the antitumor activity of HWH340, a novel potent and selective PARP inhibitor currently undergoing clinical investigation. Method: HWH340 was evaluated for its PARP1/2 enzymatic activity in corresponding enzyme assays and its cellular PARylation inhibitory activity in HCC1937 cells. The anti-proliferative activity and the synergistic effect in combination with temozolamide (TMZ) were evaluated in vitro in a BRCA-deficient cell line MDA-MB-436 and BRCA proficient cell line MDA-MB-231. Antitumor activity was evaluated by daily oral administration of in xenograft tumor models. Synergistic effect in combination with TMZ was also determined. The animal models used were PARP highly expressed patient-derived xenograft (PDX) model of small cell lung cancer (SCLC) LU-01-0547 and BRCA1/2-deficient CDX models of breast cancer MDA-MB-436 and pancreatic cancer CAPAN-1. Result: HWH340 displayed potent PARP1/2 enzymatic inhibitory activity with IC50 1.14 nM and 1.72 nM respectively. It also potently inhibited cellular PARylation in HCC1937 cell with IC50 2.77 nM. In BRCA proficient cell line MDA-MB-231, HWH340 showed no synergistic effect when combined with TMZ and a weak anti-proliferative activity with IC50 5.83 uM and 4.86 uM. In contrast, it displayed potent anti-proliferative activity and a synergistic effect in combination with TMZ with IC50 of 71 nM and 7 nM in the BRCA1/2-deficient MDA-MB-436 cells, respectively. HWH340 showed excellent in vivo antitumor efficacy in PARP overexpressed SCLC LU-01-0547 PDX model (TGI=81.69%@50mpk, QD). In BRCA-deficient breast cancer MDA-MB-436 CDX model, HWH340 showed potent antitumor efficacy as single agent (TGI=122% @12.5mpk, QD). In BRCA-deficient pancreatic cancer CAPAN-1 CDX model, it showed potent antitumor efficacy in combination with TMZ (TGI=79.61% @25mpk+ TMZ 30mpk, QD). Conclusion: HWH340 is a potent PARP inhibitor. Its antitumor activity in the preclinical tumor models together with its excellent pharmaceutical properties provide confidence that HWH340 may have high potential in the clinic for treatment of BRCA deficient solid cancers. Citation Format: Wenjie Sun, Yang Yue, Hailiang Chen, Ronghua Tu, Jie Shen, Gang Li, Guoqiang Ma, Zhixiang Zhang, Charles Z. Ding, Shuhui Chen. Preclinical evaluation of HWH340, a novel PARP inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4845.

Protective Functions of PJ34, a Poly(ADP-ribose) Polymerase Inhibitor, Are Related to Down-Regulation of Calpain and Nuclear Factor-κB in a Mouse Model of Traumatic Brain Injury

Poly(ADP-ribose) polymerase (PARP), calpain, and nuclear factor-κB (NF-κB) are reported to participate in inflammatory reactions in pathologic conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participates in inflammation related to calpain and NF-κB in a mouse model of controlled cortical impact (CCI). PJ34 (10 mg/kg), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. We then performed a histopathologic analysis, and we measured calpain activity and protein levels in all animals. The cytosolic, mitochondria, and nuclear fractions were prepared and used to determine the levels of PARP, calpastatin, NF-κB p65, inhibitory-κB-α, tumor necrosis factor-α, interleukin-1β, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2. We then measured blood-brain barrier disruption using electron microscopy at 6 and 24 hours after CCI. Treatment with PJ34 markedly reduced the extent of both cerebral contusion and edema, improved neurologic scores, and attenuated blood-brain barrier damage resulting from CCI. Our data showed that the cytosolic and nuclear fractions of calpain and NF-κB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and inhibitory-κB levels and decreased the levels of inflammatory mediators. PARP inhibition by PJ34 suppresses the overactivation of calpain and the production of inflammatory factors that are caused by NF-κB activation and attenuates neuronal cell death in a mouse model of CCI.

Abstract P4-22-21: NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors

Abstract Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor with a single agent maximum tolerated dose (MTD) of 1mg orally qd. Primary dose-limiting toxicity (DLT) was thrombocytopenia. This phase I study combines T with the commonly used chemotherapy regimen of carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. In both schedules, C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1. A 3+3 design is used for dose escalation. Key eligibility criteria include age 318 with a measurable or evaluable solid incurable malignancy. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation. Stable, treated brain metastases are allowed. No prior C for metastatic disease is allowed. Pts must have platelets>150 and no need for anticoagulation. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone with continuous daily dosing. Each schedule will have a 6 subject dose expansion at the MTD. The starting dose level for schedule B will be the MTD from schedule A. Results: Schedule A cohort results are reported: 11 pts (median age 59 [range 39-68]; 8 female; 3 male) have been enrolled. Pts had breast (6), ovarian (2), pancreatic (1), and SCC of oropharynx (1) and concurrent ovarian and pancreatic (1). Five pts are BRCA2+ and 3 pts are BRCA1+. Dose level 3 on schedule A (T 350mcg with C AUC 6 and P 80mg/m2) exceeded the MTD with 2 of 3 pts experiencing hematologic dose limiting toxicities (DLTs) including 1 pt with grade (gr) 3 neutropenic fever and gr 4 thrombocytopenia and another pt with grade 3/4 neutropenia lasting > 7 days. Most common AEs include neutropenia (grade 3-4: 7), anemia (grade 3-4: 3), and thrombocytopenia (grade 3-4: 4). Results from expansion of dose level 2 (T 250mcg with C AUC 6 and T 80mg/m2) will be presented. The 11 pts were on study a median of 9 weeks (range 9-36+). Four pts have discontinued study therapy: 1 due to need for anticoagulation for PE, 1 for prolonged cytopenias, and 2 for disease progression. Of the 8 pts with measurable disease evaluated for response to date, 4 had SD, 1 had a cPR, 1 had radiographic CR, and 2 with PD. A pt with BRCA 1+ triple negative breast cancer has maintained a prolonged PR (36+ weeks) even after dose reductions to T 100mcg with C AUC 3. One pt with ovarian cancer (BRCA WT) has radiographic CR (CA 125 remains mildly elevated) after 15+ weeks of therapy. Conclusion: PARP inhibition with talazoparib days 1-7 in combination with carboplatin and paclitaxel leads to DLT of myelosuppression. However, clinical responses are seen even with lower dose combinations. Citation Format: Turk A, Chan N, Leal T, O'Regan R, Tevaarwerk A, Rice L, Campbell T, Barroilhet L, Mehnert J, Eickhoff J, Kolesar J, Liu G, Wisinski K. NCI9782: A phase 1 study of talazoparib in combination with carboplatin and paclitaxel in patients with advanced solid tumors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-21.

Protective effects of PARP inhibitor, PJ34, is related to down-regulation of calpain and NF-κB in a mouse model of TBI.

Poly(ADP-ribose) polymerase (PARP), calpain and nuclear factor-κB (NF-κB) are reported to participate in inflammatory reactions in pathological conditions and are involved in traumatic brain injury. The objective of this study was to investigate whether PARP participated in inflammation related to calpain and NF-κB in a mouse model of controlled cortical impact (CCI). PJ34 (10 mg kg-1), a selective PARP inhibitor, was administered intraperitoneally 5 minutes and 8 hours after experimental CCI. A neurobehavioural evaluation and a histopathological analysis were then performed and the contusion volume, calpain activity and protein levels were measured in all animals. Treatment with PJ34 markedly reduced neurological deficits, decreased contusion volume and attenuated necrotic and apoptotic neuronal cell death 24 hours after CCI. The data showed that the cytosolic and nuclear fractions of calpain and NF-κB were up-regulated in the injured cortex and that these changes were reversed by PJ34. Moreover, PJ34 significantly enhanced the calpastatin and IκB levels and decreased the levels of inflammatory mediators. PARP inhibition by PJ34 suppresses the over-activation of calpain and the production of inflammatory factors that are caused by NF-κB activation and it improves neurological functioning, decreases the contusion volume and attenuates neuronal cell death in a mouse model of CCI.