Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

Maitland, Michael L.; Piha-Paul, Sarina A.; Kurzrock, Razelle; Nguyen, Ly M.; Janisch, Linda; Karovic, Sanja; McKee, Mark D.; Hoening, Elizabeth; Wong, Shekman; Munasinghe, Wijith; Palma, Joann P.; Donawho, Cherrie K.; Lian, Guinan; Ansell, Peter; Ratain, Mark J.; Hong, David S.

doi:10.1038/s41416-018-0020-2

Cited by 20 publications

(10 citation statements)

References 30 publications

(33 reference statements)

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“…In particular, CDK4/6 inhibitors palbociclib, ribociclib (Frankell et al 2019) and abemaciclib have shown efficacy in in vitro models of EAC (Frankell et al 2019; Kosovec et al 2017) and promising results in breast cancer, non-small cell lung cancer and melanoma patients (Patnaik et al 2016). Similarly, the use of ABT-348, a multitarget Aurora kinase and VEGFR inhibitor (Maitland et al 2018), is currently being explored in phase I and II clinical trials in patients with CDKN2A -deficient tumors (Sharma 2015; Hong 2015), suggesting additional targeted therapies to this axis are closer to clinical adoption.…”

Section: Discussionmentioning

confidence: 99%

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Izadi

Sharpe

Breininger

et al. 2021

Preprint

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Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

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Section: Discussionmentioning

confidence: 99%

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Izadi

Sharpe

Breininger

et al. 2021

Preprint

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“…Phase I trial with ilorasertib showed two clinical responses among 58 treated patients, and confirmed a good tolerability and safety profile of the drug (Maitland et al, 2018). Palbociclib, together with abemaciclib and ribociclib, have already been approved for the treatment of metastatic breast cancer, after several studies showing their activity in a spectrum of solid tumors including melanoma.…”

Section: Cdkn2a and Cdk4: A Clinical Perspectivementioning

confidence: 66%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.

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“…The current trial raises a further important issue surrounding cancer drugs that can, by virtue of inhibiting multiple kinases, target the cardiovascular system (e.g., VEGFR or vasculardisrupting agents). In these instances, it could be hypothesized that cells of the vasculature are likely to be exposed to the drug earlier than cells of tumors and possibly at a higher concentration, resulting in cardiovascular adverse events being limiting; for example, the multikinase inhibitor, ilorasertib, targeted the VEGFR and Aurora kinase families resulting in the VEGR-related adverse events being limiting (42). In the case of AT13148, it is difficult to know if the cardiovascular side effects occurred at lower concentrations required for AKT inhibition because the drug inhibits ROCK more potently or because cells in the vascular system are likely to be exposed to such drugs earlier, and to a possibly higher concentration, than cancer cells in the tumor.…”

Section: Discussionmentioning

confidence: 99%

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors

McLeod

Kumar

Papadatos-Pastos

et al. 2020

Clinical Cancer Research

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Purpose: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity. Patients and Methods: The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon-Wed-Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3b levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies. Results: Fifty-one patients were treated on study. The safety of 5-300 mg of AT13148 was studied. Further, the doses of 120-180-240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean C max and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies. Conclusions: AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.

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Clinical pharmacodynamic/exposure characterisation of the multikinase inhibitor ilorasertib (ABT-348) in a phase 1 dose-escalation trial

Cited by 20 publications

References 30 publications

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

First-in-Human Study of AT13148, a Dual ROCK-AKT Inhibitor in Patients with Solid Tumors

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