Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer

Kim, Seung Tae; Smith, Simon A.; Mortimer, Peter G.; Loembé, Arsene-Bienvenu; Cho, Heejin; Kim, Kyoung‐Mee; Smith, Claire; Willis, Sophie E.; Irurzun-Arana, Itziar; Berges, Aliénor; Hong, Jung Yong; Park, Se Hoon; Park, Joon Oh; Park, Young Suk; Lim, Ho Yeong; Kang, Won Ki; Kozarewa, Iwanka; Pierce, Andrew J.; Dean, Emma; Lee, Jeeyun

doi:10.1158/1078-0432.ccr-21-0251

Cited by 54 publications

(31 citation statements)

References 40 publications

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“…Published trials involving ceralasertib in solid tumors showed a generally encouraging toxicity profile, with myelosuppression being the major dose-limiting toxicity when used with chemotherapy [137,138]. However, one must be mindful of the potential longer-term effects of sublethal targeting of tumor cells with ATR/Chk1 inhibitors that may promote genomic instability and clonal evolution, if these cells are allowed to accumulate replication stress-induced DNA damage but escape death [139].…”

Section: Targeting Replication Stress Through Atr/chk1 Inhibitionmentioning

confidence: 99%

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Kwok

Agathanggelou

Davies

et al. 2021

Cancers

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The p53 pathway is a desirable therapeutic target, owing to its critical role in the maintenance of genome integrity. This is exemplified in chronic lymphocytic leukemia (CLL), one of the most common adult hematologic malignancies, in which functional loss of p53 arising from genomic aberrations are frequently associated with clonal evolution, disease progression, and therapeutic resistance, even in the contemporary era of CLL targeted therapy and immunotherapy. Targeting the ‘undruggable’ p53 pathway therefore arguably represents the holy grail of cancer research. In recent years, several strategies have been proposed to exploit p53 pathway defects for cancer treatment. Such strategies include upregulating wild-type p53, restoring tumor suppressive function in mutant p53, inducing synthetic lethality by targeting collateral genome maintenance pathways, and harnessing the immunogenicity of p53 pathway aberrations. In this review, we will examine the biological and clinical implications of p53 pathway defects, as well as our progress towards development of therapeutic approaches targeting the p53 pathway, specifically within the context of CLL. We will appraise the opportunities and pitfalls associated with these therapeutic strategies, and evaluate their place amongst the array of new biological therapies for CLL.

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Section: Targeting Replication Stress Through Atr/chk1 Inhibitionmentioning

confidence: 99%

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Kwok

Agathanggelou

Davies

et al. 2021

Cancers

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“…In an open-label, phase I study, which aimed to assess the safety, pharmacodynamics, and preliminary efficacy of ceralasertib in combination with weekly paclitaxel in patients with refractory advanced solid tumors, 33 patients with melanoma, resistant to previous anti-PD1 therapy, were enrolled (NCT02630199). In the melanoma cohort, the ORR was 33.3%, the mPFS was 3.6 months, the median DOR was 9.9 months, and the mOS was 7.4 months [ 108 ]. Similarly, a phase II study (NCT03780608) was designed to assess the efficacy and safety of ceralasertib in combination with durvalumab in patients with MM who had progressed on anti-PD-1 therapy.…”

Section: Resultsmentioning

confidence: 99%

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Comito

Pagani

Grilli

et al. 2022

Cancers

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The prognosis of patients with advanced cutaneous melanoma has radically changed in the past decade. Nevertheless, primary or acquired resistance to systemic treatment occurs in many cases, highlighting the need for novel treatment strategies. This review has the purpose of summarizing the current area of interest for the treatment of metastatic or unresectable advanced cutaneous melanoma, including data from recently completed or ongoing clinical trials. The main fields of investigation include the identification of new immune checkpoint inhibitors (anti-LAG3, GITR agonist and anti-TIGIT), adoptive cell therapy, vaccines, engineered TCR therapy, IL-2 agonists, novel targets for targeted therapy (new MEK or RAF inhibitors, HDAC, IDO, ERK, Axl, ATR and PARP inhibitors), or combination strategies (antiangiogenetic agents plus immune checkpoint inhibitors, intra-tumoral immunotherapy in combination with systemic therapy). In many cases, only preliminary efficacy data from early phase trials are available, which require confirmation in larger patient cohorts. A more in-depth knowledge of the biological effects of the molecules and identifying predictive biomarkers remain crucial for selecting patient populations most likely to benefit from novel emerging treatment strategies.

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“…Similarly, a trial of ATR inhibitor ceralasertib evaluating its combination with paclitaxel in patients with a variety of solid organ malignancies showed upregulation of PD-L1 expression in paired tumor samples following treatment with ceralasertib (98).…”

Section: Combination With Dna Repair Targeting Agentsmentioning

confidence: 94%

Immunotherapy in Lung Cancer: Current Landscape and Future Directions

et al. 2022

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Over the past decade, lung cancer treatment has undergone a major paradigm shift. A greater understanding of lung cancer biology has led to the development of many effective targeted therapies as well as of immunotherapy. Immune checkpoint inhibitors (ICIs) have shown tremendous benefit in the treatment of non-small cell lung cancer (NSCLC) and are now being used as first-line therapies in metastatic disease, consolidation therapy following chemoradiation in unresectable locally advanced disease, and adjuvant therapy following surgical resection and chemotherapy in resectable disease. Despite these benefits, predicting who will respond to ICIs has proven to be difficult and there remains a need to discover new predictive immunotherapy biomarkers. Furthermore, resistance to ICIs in lung cancer is frequent either because of a lack of response or disease progression after an initial response. The utility of ICIs in the treatment of small cell lung cancer (SCLC) remains limited to first-line treatment of extensive stage disease in combination with chemotherapy with modest impact on overall survival. It is thus important to explore and exploit additional targets to reap the full benefits of immunotherapy in the treatment of lung cancer. Here, we will summarize the current state of immunotherapy in lung cancer, discuss novel targets, and explore the intersection between DNA repair defects and immunotherapy.

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Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer

Abstract: are former employees of AstraZeneca JL has served a consultant/advisory role for Mirati and Oncologie.All remaining authors have no conflicts of interest to declare. Grant SupportThis investigator-initiated trial was funded by a study-drug donation and partial funding from AstraZeneca.

Cited by 54 publications

References 40 publications

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Targeting the p53 Pathway in CLL: State of the Art and Future Perspectives

Emerging Novel Therapeutic Approaches for Treatment of Advanced Cutaneous Melanoma

Immunotherapy in Lung Cancer: Current Landscape and Future Directions

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