Phase II trial of the PARP inhibitor, niraparib, in BRCA1-Associated Protein 1 (BAP1) and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS354-TPS354
Author(s):  
Thomas J. George ◽  
David L. DeRemer ◽  
Ji-Hyun Lee ◽  
Stephen Staal ◽  
Merry Jennifer Markham ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Dna Damage Response ◽  
Group Performance ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Mutant Cell ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Damage Response

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS591-TPS591 ◽  
Author(s):  
Thomas J. George ◽  
David L. DeRemer ◽  
Hiral D. Parekh ◽  
Ji-Hyun Lee ◽  
Merry Jennifer Markham ◽  
...  
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Mutant Cell ◽  
Performance Status ◽  
Objective Response ◽  
Functional Protein ◽  
Damage Response

TPS591 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks on treatment. Enrollment continues to a maximum of 47 evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

scholarly journals Dancing with the DNA damage response: next-generation anti-cancer therapeutic strategies

2018 ◽  
Vol 10 ◽  
pp. 175883591878665 ◽  
Author(s):  
Anna Minchom ◽  
Caterina Aversa ◽  
Juanita Lopez
Keyword(s):  
Cell Cycle ◽  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Genomic Stability ◽  
Critical Determinant ◽  
Potential Biomarker ◽  
Damage Response

Maintenance of genomic stability is a critical determinant of cell survival and relies on the coordinated action of the DNA damage response (DDR), which orchestrates a network of cellular processes, including DNA replication, DNA repair and cell-cycle progression. In cancer, the critical balance between the loss of genomic stability in malignant cells and the DDR provides exciting therapeutic opportunities. Drugs targeting DDR pathways taking advantage of clinical synthetic lethality have already shown therapeutic benefit – for example, the PARP inhibitor olaparib has shown benefit in BRCA-mutant ovarian and breast cancer. Olaparib has also shown benefit in metastatic prostate cancer in DDR-defective patients, expanding the potential biomarker of response beyond BRCA. Other agents and combinations aiming to block the DDR while pushing damaged DNA through the cell cycle, including PARP, ATR, ATM, CHK and DNA-PK inhibitors, are in development. Emerging work is also uncovering how the DDR interacts intimately with the host immune response, including by activating the innate immune response, further suggesting that clinical applications together with immunotherapy may be beneficial. Here, we review recent considerations related to the DDR from a clinical standpoint, providing a framework to address future directions and clinical opportunities.

Phase II trial of the PARP inhibitor, niraparib, in BAP1 and other DNA damage response (DDR) pathway deficient neoplasms (NCT03207347).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22061-e22061
Author(s):  
azka ali ◽  
David L. DeRemer ◽  
Ji-Hyun Lee ◽  
Hiral D. Parekh ◽  
Stephen Staal ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Cell Carcinoma ◽  
Dna Damage Response ◽  
Renal Cell ◽  
Clear Cell ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Cell Renal Cell Carcinoma ◽  
Damage Response

e22061 Background: BRCA-associated protein-1 (BAP1) is a ubiquitin ligase associated with regulating cell cycle, cell proliferation, DNA damage pathway, and cell death. It also acts as a tumor suppressor gene as seen in hereditary cancer syndrome associated with germline mutations in BAP1. Preclinical studies have shown that PARP-inhibitor treatment of BAP1 mutant cell lines demonstrated significant synthetic lethality, independent of underlying BRCA status suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of several solid tumors including cholangiocarcinoma, mesothelioma, uveal melanoma, and clear cell renal cell carcinoma. Methods: This phase 2, open-label, single arm study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in two biologically distinct cohorts. Eligible patients (pts) with measurable metastatic and incurable solid tumors are assigned to one of the two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via Next Generation Sequencing (NGS); or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Key inclusion criteria also include age ≥18 years, adequate cardiac, renal, hepatic function and ECOG PS of 0 to 1. Key exclusion criteria include known BRCA1 or BRCA2 mutations or prior PARPi exposure. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate (ORR), and secondary endpoints are progression free survival (PFS), overall survival (OS), toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort B enrollment is closed. Enrollment in Cohort A continues. A maximum of 47 evaluable subjects is planned with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. Clinical trial information: NCT03207347. [Table: see text]

Combination olaparib and durvalumab for patients with recurrent IDH-mutated gliomas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14026-e14026
Author(s):  
Ronald Ramos ◽  
Seth Andrew Climans ◽  
Ashley Adile ◽  
Pegah Ghiassi ◽  
Stephanie Baker ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Group Performance ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Parp Inhibitors ◽  
Solid Cancer ◽  
Low Grade ◽  
Idh Mutations

e14026 Background: Isocitrate dehydrogenase (IDH) mutations are frequently observed in low grade gliomas and secondary glioblastoma. Mutant IDH enzymes aberrantly convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG). Accumulation of 2HG inhibits αKG-dependent dioxygenases, many of which are involved in epigenetic regulation. This can lead to cellular dedifferentiation and tumor formation. IDH-mutated cancer cells exhibit defective homologous recombination repair, providing the rationale for investigating poly (adenosine 5’-diphophate-ribose) polymerase (PARP) inhibitors in these tumors. Blockade of programmed cell death ligand 1 (PD‐L1) re‐sensitizes PARP inhibitor treated cancer cells to T‐cell killing. We report the preliminary results of the glioma arm of a clinical trial of a PARP inhibitor, olaparib plus PD-L1 inhibitor, durvalumab, for IDH-mutated solid cancer. Methods: This is a single arm phase II basket study (NCT03991832). Patients with IDH-mutated solid tumors are divided into three cohorts; A: glioma; B: cholangiocarcinoma; C: all other solid tumors. Major eligibility criteria include IDH mutation by immunohistochemistry or sequencing, progressive disease with maximum two prior systemic therapies, Eastern Cooperative Oncology Group performance status (ECOG) 0 –1 and adequate organ function. Patients were excluded if they had received prior PARP inhibitors or anti-PD-1/PD-L1 antibodies. Patients were treated with olaparib 300 mg orally twice daily continuously and durvalumab 1500 mg IV every 4 weeks. Each cycle was 4 weeks. Tumor response was evaluated by MRI after every 2 cycles of study treatments using response evaluation criteria in solid tumors (RECIST). Results: As of Jan 2021, 9 patients were enrolled in Arm A, 7 men and 2 women. The median age was 42 years. Eight patients had IDH1 mutations and 1 had an IDH2 mutation. There were two patients with 1p/19q codeletion. Two patients had grade 2 tumors, four had grade 3, and three had grade 4 tumors. Median time since tumor diagnosis was 7 years. Objective response was seen in 1 patient with an IDH-mutated glioblastoma who remains on study treatments after 8 cycles. Six patients (67%) had tumor progression after two cycles. Two patients had stable disease as per RECIST but had clinical deterioration and did not continue the combined treatment. Common treatment emergent adverse events were all grade 1: fatigue (8 patients), nausea (6), abdominal pain (3), anemia (3), thrombocytopenia (3), and diarrhea (2). Median progression free survival was 2.5 months (range 1.9–8 months). Updated analysis and correlative studies will be presented at the meeting. Conclusions: Combination treatment with olaparib and durvalumab for patients with IDH-mutated glioma is well tolerated but appears to lack adequate antitumor activity. Clinical trial information: NCT03991832.

scholarly journals Predictive and Prognostic Value of DNA Damage Response Associated Kinases in Solid Tumors

2020 ◽  
Vol 10 ◽  
Author(s):  
Mariam Gachechiladze ◽  
Josef Skarda ◽  
Katerina Bouchalova ◽  
Alex Soltermann ◽  
Markus Joerger
Keyword(s):  
Dna Damage ◽  
Solid Tumors ◽  
Dna Damage Response ◽  
Prognostic Value ◽  
Damage Response ◽  
Predictive And Prognostic Value

scholarly journals EGFR Amplification Induces Increased DNA Damage Response and Renders Selective Sensitivity to Talazoparib (PARP Inhibitor) in Glioblastoma

2019 ◽  
Vol 26 (6) ◽  
pp. 1395-1407 ◽  
Author(s):  
Shaofang Wu ◽  
Feng Gao ◽  
Siyuan Zheng ◽  
Chen Zhang ◽  
Emmanuel Martinez-Ledesma ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Egfr Amplification ◽  
Damage Response ◽  
Selective Sensitivity

scholarly journals Effect of DNA damage response mutations on prostate cancer prognosis: a systematic review

2019 ◽  
Vol 15 (28) ◽  
pp. 3283-3303 ◽  
Author(s):  
Stephanie L Swift ◽  
Shona H Lang ◽  
Heath White ◽  
Kate Misso ◽  
Jos Kleijnen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Systematic Review ◽  
Dna Damage ◽  
Clinical Outcomes ◽  
Dna Damage Response ◽  
Parp Inhibitor ◽  
Cancer Prognosis ◽  
Castration Resistant ◽  
Damage Response ◽  
Brca1 Brca2

The prognosis of men with prostate cancer (PC) with mutations in DNA damage response ( DDR) genes undergoing different treatments is unclear. This systematic review compared clinical outcomes in PC patients with DDR mutations ( DDR+) versus no mutations ( DDR-). 14 resources plus gray literature were searched for studies in PC and subgroups (castration-resistant PC, metastatic PC and metastatic castration-resistant PC) by DDR gene ( ATM, ATR, BRCA1, BRCA2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C) mutation status. From 11,648 records, 26 studies were included. For mCRPC, six studies reported comparative efficacy for key outcomes. Improvements in several clinical outcomes were observed for DDR+ (vs DDR-) after PARP inhibitor therapy or immunotherapy. DDR+ PC patients may have improved outcomes depending on the treatment they undergo.

Sign in / Sign up

Export Citation Format

Share Document