This site needs JavaScript to work properly. Archive Like ATR, ataxia telangiectasia-mutated (ATM) has both DNA damageinduced checkpoint and repair functions. Menu Contact Dictionary Search. Participants must have fully recovered from the acute toxic effects of all prior anti-cancer therapy. In all pts, nausea and anaemia were the most common adverse events (AEs). Overall response rate was 8.3% and CBR was 62.5% among the entire cohort. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. A second patient with primary adenoid cystic carcinoma of minor salivary gland and germline ATM mutation with LOH has had an ongoing 22% reduction in target lesions and has also remained on treatment for 26+ months. McMullen M, Karakasis K, Loembe B, Dean E, Parr G, Oza AM. Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations). The research study procedures include screening for eligibility, study treatment, evaluations and follow-up visits. All rights reserved. We do not sell to patients. The ORR was 46% (n = 6); all 6 demonstrating a PR. Prior Therapy, Extent and Duration of Response of Patients With BRCA1/2Mutated High-Grade Serous Ovarian Cancer Post-PARP Inhibition Received Olaparib and Ceralasertib/AZD6738. Cancer is caused by changes (mutations) to genes that control the way cells function. In an interview with OncLive, Wethington, director of The Susan L. Burgert MD Gynecologic Oncology Survivorship Program and an assistant professor of Gynecology and Obstetrics at Johns Hopkins Medicine, discussed the results of the study and importance of studying combination treatments in patients with PARP-resistant ovarian cancer. Olaparib was administered at 300 mg twice daily and ceralasertib at 160 mg daily on days 1-7 in 28-day cycles until progression or unacceptable toxicities. CR was initially achieved at 4 months and has been ongoing for 26+ months. The regimen used full-dose olaparib along with ceralasertib on the basis of prior phase I data. Participants with a known hypersensitivity to olaparib or any of the excipients of the product or any contraindication to the combination anti-cancer agent as per local prescribing information. Ceralasertib is in clinical development in solid tumors as a mono-therapy (RPh2D available) and in combination with radiotherapy (RPh2D expected 2/3Q 2018), carboplatin (RPh2D available), paclitaxel (RPh2D expected 3Q 2017), olaparib (RPh2D . Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services. Loss of the wild-type ATM allele could be identified in these two patients as determined by variant allelic frequency in the tumor when compared with germline control. May 28, 2021. Receiving, or having received during the 14 days prior to Cycle 1 Day 1, corticosteroids (at a dose > 10 mg prednisone/day or equivalent) for any reason. Patients with a known diagnosis of ataxia telangiectasia. Median time on prior PARPi was 13 months (range 4-60). DNA damage response (DDR) pathway represents the most attractive synthetic lethality targets, since genomic instability is a hallmark of cancers due to the accumulation of DNA mutation during the process of DNA . Neither patient has had significant toxicity or required a dose reduction. Homologous recombination (HR) repair is a high-fidelity process used to repair DNA double-strand breaks (DSB), during the S and G2 phases.1 Germline mutations in HR genes and other genes involved in DDR and the genes giving rise to Fanconi anemia significantly increase the lifetime risk of certain cancers. Dose reescalation was not permitted. ASCO Author Services --- A serum creatinine based on age/gender as follows: Any of the following cardiac diseases currently or within the last 6 months (by New York Heart Association (NYHA) Class 2 where applicable): Corrected QT interval (QTc) 470msec obtained from 3 electrocardiograms (ECGs) 2-5 minutes apart using the Fredericia formula. Hematologic toxicity was the most common event as expected from previous clinical trials of each agent. Synthetic lethality (SL) describes a situation in which the occurrence of one genetic event maintains cell viability, whereas the co-occurrence of two genetic events lead to cell death. Thirteen patients (54.2%) had SD for at least 16 weeks with a CBR of 62.5% (Fig 1). Patient has had prescription or non-prescription drugs or other products known to be CYP3A4 and/or CYP2B6 substrates or CYP3A4 and/or CYP2B6 substrates with a narrow therapeutic index. Drugs. No treatment-related deaths occurred. These were durable, confirmed responses that occurred among the first 16 patients, allowing the study to progress to the second stage. The ASCO Post, ASCO eLearning complete left bundle branch block, third degree heart block, Significant ventricular or supraventricular arrhythmias e.g. In patients with recurrent disease, PARP inhibitors have been used in patients with tumors harboring BRCA alterations with response rates typically exceeding 30%.11-14 Additionally, these agents are now commonly considered irrespective of BRCA mutation in the second-line maintenance setting, after a response to a platinum-based chemotherapy.8-10 Recent work has also examined PARP inhibition in the first-line maintenance setting.15,16 More common PARP inhibitors use has highlighted the importance of both acquired and de novo resistance. Prior PARPi indication was 1st line maintenance in 8% (n = 1), 2nd line maintenance in 38% (n = 5) and recurrence in 54% (n = 7). We conducted a phase II trial of ceralasertib plus durvalumab in patients with previously treated advanced gastric cancer (AGC) to . Five patients with ATM mutations were included. Preclinical data suggest that ATR inhibition targets PARP inhibitor resistance through two potential mechanisms, including disruption of BRCA1-independent RAD51 loading to sites of DSB and reversal of BRCA1-independent replication fork protection.20 Combined ATR-CHK1 axis and PARP inhibition has been shown to be cooperative in the PARP inhibitorresistant setting, with synergistic increases in replication fork stalling, DSB, and apoptosis, coupled with compromised HR repair, translating to improved survival in preclinical ovarian cancer models.20,21. Two patients with PDAC and ATM mutation (unknown LOH status) progressed rapidly. Eligible patients had to have received standard first-line therapy for metastatic cancer (except for tumors for which no first-line therapy exists) with progressive disease at the time of study entry. DOI: 10.1200/JCO.2021.39.15_suppl.5516 Journal of Clinical Oncology A second patient with grade 4 neutropenia also required a dose reduction for olaparib alone. Cookies. Apply to this Phase 2 clinical trial treating Metastatic Triple-Negative Breast Carcinoma, Breast Neoplasms, Anatomic Stage IV Breast Cancer AJCC . No pt discontinued treatment due to toxicity. My main role is as pre-clinical bioscience lead for ceralasertib (AZD6738) ATR inhibitor which is late stage Phase II/III pivotal clinical trials. K12 CA076917/CA/NCI NIH HHS/United States, P50 CA240243/CA/NCI NIH HHS/United States, NCI CPTC Antibody Characterization Program, Tubbs A, Nussenzweig A: Endogenous DNA damage as a source of genomic instability in cancer. In the olaparib and ceralasertib treatment arm (SUKSES-N2, n = 26), ORR was 3.8% (n = 1) and DCR was 42.3% (n = 11). In Module 2 Part A2, patients will receive either a single or twice daily dose of ceralasertib followed by 4 to 6 days washout, before multiple dosing with ceralasertib and olaparib. The patient can receive a stable dose of bisphosphonates or denosumab for bone metastases, before and during the study as long as these were started at least 5 days prior to the study treatment. Prior TOTAL lung radiation. 2022 MJH Life Sciences and OncLive - Clinical Oncology News, Cancer Expert Insights. -, Knijnenburg TA, Wang L, Zimmermann MT, et al. However, efficacy is limited by both intrinsic and acquired resistance. Initially, 16 eligible patients were to be treated. Only the most severe grade for each individual patient toxicity is entered. Although we were able to determine biallelic loss in a few of the tumors, we lacked information about the activity of the nonmutated alleles in most cases. 2022 Apr 12;27(8):2491. doi: 10.3390/molecules27082491. Published online If there were < 2 responses, accrual would be terminated on the basis of the likelihood of an ORR of 10%. Exposure of other drugs metabolised by CYP3A4 and/or CYP2B6 may be reduced and additional monitoring may be required The use of herbal supplements or 'folk remedies' (and medications and foods that significantly modulate CYP3A activity) should be discouraged. FIG 1. Although we did see a 31% rate of grade 3 or grade 4 toxicities and 4 dose reductions, no patient had to come off therapy because of toxicity. This study is the first to suggest the potential of ATR inhibitors to overcome PARPi resistance in an HRD patient population. Lansky/Karnofsky performance status 60% for participants 16 years of age and Lansky 60% for participants <16 years of age (see Appendix B) within 28 days prior to enrollment with no deterioration over the previous 2 weeks. Ceralasertib is an oral inhibitor of ATR, ataxia-telangiectasia receptor (ATR). An event is defined as the occurrence of relapse, disease progression as defined by RECIST 1.1, or death from any cause. I have experience across the drug discovery and development pipeline from target discovery, lead generation/optimisation-candidate drug nomination through to translational science and phase III . Methods: We conducted a non-randomized trial (NCT03462342) in platinum sensitive HGSOC immediately following prior PARPi treatment of a 28 day cycle of olaparib 300mg orally twice daily and ceralasertib 160mg orally once daily on days 1-7. Patients with relative hypotension (less than 5th percentile for age/height/sex or systolic and/or diastolic blood pressure >15% below baseline) or clinically relevant orthostatic hypotension (a fall in systolic blood pressure of at least 20 mm Hg within 3 minutes of standing compared to blood pressure obtained from sitting/supine position). Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer. Background Targeting the DNA damage repair (DDR) pathways is an attractive strategy for boosting cancer immunotherapy. Preclinical studies show the addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARPi overcome PARPi-resistance. Olaparib With Ceralasertib in Recurrent Osteosarcoma; SARC038: Phase 2 Study of Regorafenib and Nivolumab in Osteosarcoma; Study of Onivyde With Talazoparib or Temozolomide in Children With Recurrent Solid Tumors and Ewing Sarcoma; STRIvE-02: B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults ClinicalTrials.gov Identifier: NCT04417062, Interventional The duration of benefit from olaparib and ceralasertib exceeded the initial duration of response to the PARP inhibitor in these patients (median 8 months, range 2-18 months v 4 months, range 2-12 months; Table 4). Patients with HGSOC harboring germline or somatic mutations in BRCA1/2 genes and who had prior progression on PARP inhibitors were also permitted to enroll. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising therapy in cancers with homologous recombination repair deficiency. Efficacy of ceralasertib and olaparib in a subset of patients with ATM mutation. In the VIOLETTE trial, addition of ceralasertib to olaparib did not increase objective response rates (ORRs) compared with olaparib monotherapy in patients with BRCA mutations (50.0% versus 44.2%) or patients with HRR pathway mutations (20.0% versus 15.0%). Among four patients with PALB2 mutations, one with metastatic adenoid cystic carcinoma of salivary gland has had ongoing disease stability at 14+ months. Shah PD, Wethington SL, Pagan C, Latif N, Tanyi J, Martin LP, Morgan M, Burger RA, Haggerty A, Zarrin H, Rodriguez D, Domchek S, Drapkin R, Shih IM, Smith SA, Dean E, Gaillard S, Armstrong D, Torigian DA, Hwang WT, Giuntoli R, Simpkins F. Gynecol Oncol. Patients who had received a prior PARP inhibitor in the frontline maintenance, second-line maintenance, and treatment settings had ORRs of 8% (n = 1), 38% (n = 5), and 54% (n = 7), respectively. olaparib and ceralasertib inhibit key dna repair targets within different dna damage response pathways and individually may be able to reduce the rate of dna repair in cells, thereby increasing dna damage and causing cell death.8therefore, the mechanistic rationale for the combination of these compounds is that the simultaneous inhibition of two JCO Clinical Cancer Informatics Please see Appendix E for further details. Body weights and tumor sizes were measured every other day. Three patients discontinued treatment due to drug related grade 5 pneumonia, grade 3 drug-induced pneumonitis and grade 2 anemia. Efficacy of ceralasertib and olaparib in all patients enrolled in the study. Contact Us The objective of this arm of the OLAPCO trial was to assess the efficacy of the combined regimen of olaparib and the ATR inhibitor ceralasertib in previously treated patients with DDR-deficient solid tumors. Among 13 evaluable patients, the objective response rate (ORR) was 46% (n = 6), and the progression-free survival was 7.5 months (95% CI, 4.7not reached). and transmitted securely. ASCO Meetings - Cohort 1: Participants with unresectable osteosarcoma (unable to remove with surgery) - Cohort 2: Participants with lung only resectable osteosarcoma (able to remove with surgery . Cookies. In this small series, we saw excellent tolerance and a very intriguing response rate. Primary objective: The primary objective is to assess the efficacy of ceralasertib + olaparib combination, and olaparib monotherapy, compared with placebo, as second maintenance therapy in platinum-sensitive . Other Name: AZD2281 Intervention Type: Drug Intervention Name: Ceralasertib. Description. Refractory nausea and vomiting, chronic gastrointestinal diseases or previous significant bowel resection, with clinically significant sequelae that would preclude adequate absorption of ceralasertib. Five patients required dose reductions for myelosuppression. Conquer Cancer Foundation Conception and design: Juliane Jrgensmeier, Brunella Felicetti, Peter Mortimer, Geoffrey I. Shapiro, Joseph Paul Eder, Provision of study materials or patients: Haider Mahdi, Navid Hafez, Davendra Sohal, Khanh T. Do, Patricia LoRusso, Geoffrey I. Shapiro, Collection and assembly of data: Haider Mahdi, Navid Hafez, Deborah Doroshow, Davendra Sohal, Vickie Keedy, Khanh T. Do, Patricia LoRusso, Manuel Avedissian, Jeffrey Sklar, Geoffrey I. Shapiro, Joseph Paul Eder, Data analysis and interpretation: Haider Mahdi, Navid Hafez, Deborah Doroshow, Davendra Sohal, Vickie Keedy, Patricia LoRusso, Juliane Jrgensmeier, Jeffrey Sklar, Colin Glover, Brunella Felicetti, Emma Dean, Geoffrey I. Shapiro, Joseph Paul Eder, Final approval of manuscript: All authors, Accountable for all aspects of the work: All authors. If among the first 16 patients, 4 experienced unacceptable toxicity, enrollment would be terminated early. or Bulk Inquiry * Please select Quantity before adding items. What sequence do we complete the testing in? Other eligibility criteria include measurable disease by RECIST v1.1 and age 18 years with life expectancy 16 weeks. This is one thats somewhat easier to assay for using available commercial tests. (May 20, 2021) Individual Participant Data (IPD) Sharing Statement: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. If prior radiation included lung then radiation must have been completed 12 weeks before Cycle 1 Day 1 AND V20 (% of lung that received 20Gy) must not exceed 25% OR the mean lung dose must be less than 5Gy. Female participants must have a negative serum or urine pregnancy test within 28 days of study treatment and confirmed prior to treatment on Cycle 1 Day 1. Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Combining ceralasertib with olaparib as second- or third-line therapy does not improve outcomes for patients with triple-negative breast cancer (TNBC), a phase 2 trial suggests. published online before print 2022 Mar 10;14(6):1420. doi: 10.3390/cancers14061420. We present results of an investigator-initiated study of the combination PARPi (olaparib) and ATRi (ceralasertib) in patients who were on a PARPi and experienced disease progression. Study record managers: refer to the Data Element Definitions if submitting registration or results information.
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