Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors

Semrad, Thomas J.; Kim, Edward Jae-hoon; Gong, I-Yeh; Li, Tianhong; Christensen, Scott; Arora, Mili; Riess, Jonathan W.; Gandara, David R.; Kelly, Karen

doi:10.1007/s00280-021-04293-3

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…Recent studies have shown that nuclear phosphorylation of YAP1 at Ser397 by Aurora Kinase A (AURKA), a master cell cycle regulator [ 15 ], enhances its stabilisation and improves its transcriptional activity [ 16 ]. Specific AURKA inhibitors like alisertib (MLN8237) are available [ 17 ] and are currently under clinical evaluation for the treatment of solid tumours both in monotherapy and combination [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

Rio-Vilariño,

Cenigaonandia-Campillo,

García-Bautista

et al. 2024

Br J Cancer

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Background Primary resistance to anti-EGFR therapies affects 40% of metastatic colorectal cancer patients harbouring wild-type RAS/RAF. YAP1 activation is associated with this resistance, prompting an investigation into AURKA’s role in mediating YAP1 phosphorylation at Ser397, as observed in breast cancer. Methods We used transcriptomic analysis along with in vitro and in vivo models of RAS/RAF wild-type CRC to study YAP1 Ser397 phosphorylation as a potential biomarker for cetuximab resistance. We assessed cetuximab efficacy using CCK8 proliferation assays and cell cycle analysis. Additionally, we examined the effects of AURKA inhibition with alisertib and created a dominant-negative YAP1 Ser397 mutant to assess its impact on cancer stem cell features. Results The RAS/RAF wild-type CRC models exhibiting primary resistance to cetuximab prominently displayed elevated YAP1 phosphorylation at Ser397 primarily mediated by AURKA. AURKA-induced YAP1 phosphorylation was identified as a key trigger for cancer stem cell reprogramming. Consequently, we found that AURKA inhibition had the capacity to effectively restore cetuximab sensitivity and concurrently suppress the cancer stem cell phenotype. Conclusions AURKA inhibition holds promise as a therapeutic approach to overcome cetuximab resistance in RAS/RAF wild-type colorectal cancer, offering a potential means to counter the development of cancer stem cell phenotypes associated with cetuximab resistance.

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Section: Introductionmentioning

confidence: 99%

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

Rio-Vilariño,

Cenigaonandia-Campillo,

García-Bautista

et al. 2024

Br J Cancer

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“…In combination with paclitaxel, tolerability concerns have included high rates of neutropenia, grade ≥ 3 events, SAEs, and dose reductions or discontinuations [ 17 , 31 ], although health-related quality of life appeared similar to paclitaxel alone [ 31 ]. Similarly, diarrhea, dehydration, and hematologic toxicities have been dose-limiting for alisertib plus irinotecan [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

A phase I dose escalation, dose expansion and pharmacokinetic trial of gemcitabine and alisertib in advanced solid tumors and pancreatic cancer

Chen¹,

Huynh²,

Wu³

et al. 2022

Cancer Chemother Pharmacol

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Purpose Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion. Methods Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1–4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles. Results In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1–4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration. Conclusions This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.

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“…AurKA inhibition has also been demonstrated to produce synthetic lethality in SMARCA4-mutated murine models of NSCLC [45]. However, human trials have been limited due to relatively low efficacy at tolerable drug doses, particularly with alisertib [46][47][48]. A novel AurKA inhibitor TAS-119 showed an improved safety profile in phase 1 trials, though phase 2 data are as yet unpublished [49].…”

Section: Udc: Undifferentiated Carcinomamentioning

confidence: 99%

A Rare Case of Rhabdoid Pancreatic Carcinoma: Prolonged Disease-Free Survival Following Upfront Resection and Adjuvant Chemotherapy

Land,

Van Haeringen,

Cooper

et al. 2023

Cureus

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The rhabdoid subtype of undifferentiated pancreatic carcinoma is rarely reported. The clinical course of this disease is therefore poorly understood, although it is apparently an aggressive malignancy. We herein discuss the case of a 69-year-old man presenting with a rapidly enlarging mass of the pancreatic body and tail who was diagnosed with locally advanced SMARCB1-deficient undifferentiated pancreatic carcinoma with rhabdoid features, treated with radical resection and adjuvant chemotherapy, and has achieved 18-month disease-free survival ongoing at the time of article publication. We identify and contrast our case with 15 similar tumors reported in the English literature, briefly discuss the biology of this tumor, its relationship to malignant rhabdoid tumors of childhood, the role of SMARCB1 and its parent complex switch/sucrose-non-fermentable chromatin remodeling complex (SWI/SNF) in modulating the behavior of pancreatic malignancy, and the potential therapeutic avenues available for SWI/SNF-mutated malignancies.

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Phase 1 study of alisertib (MLN8237) and weekly irinotecan in adults with advanced solid tumors

Cited by 9 publications

References 26 publications

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

Inhibition of the AURKA/YAP1 axis is a promising therapeutic option for overcoming cetuximab resistance in colorectal cancer stem cells

A phase I dose escalation, dose expansion and pharmacokinetic trial of gemcitabine and alisertib in advanced solid tumors and pancreatic cancer

A Rare Case of Rhabdoid Pancreatic Carcinoma: Prolonged Disease-Free Survival Following Upfront Resection and Adjuvant Chemotherapy

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