A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours

Schram, Alison M.; Gandhi, Leena; Mita, Monica; Damstrup, Lars; Campana, Frank; Hidalgo, Manuel; Grande, Enrique; Hyman, David M.; Heist, Rebecca S.

doi:10.1038/s41416-018-0322-4

Cited by 75 publications

(48 citation statements)

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“…Previous combination studies using oral PI3K and MEK inhibitors have demonstrated antitumor activity, although long-term tolerability is challenging due to frequent dose interruptions and reductions, often due to gastrointestinal toxicities [ 15 , 16 ]. Intravenous copanlisib, administered intermittently, has demonstrated manageable safety and is potentially advantageous compared with oral PI3K inhibitors, with low incidences of fatal hepatic and/or gastrointestinal toxicity [ 8 ], supporting the rationale for the study of intravenous copanlisib combined with oral refametinib.…”

Section: Introductionmentioning

confidence: 99%

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

et al. 2020

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Background Dual inhibition of PI3K and MAPK signaling is conceptually a promising anticancer therapy. Objective This phase 1b trial investigated the safety, maximum tolerated dose (MTD), recommended phase II dose, pharmacokinetics, tumor response, fluorodeoxyglucose positron emission tomography (FDG-PET) pharmacodynamics, and biomarker explorations for the combination of pan-PI3K inhibitor copanlisib and allosteric MEK inhibitor refametinib in patients with advanced solid tumors. Patients and methods This was an adaptive trial with eight dose cohorts combining dose escalation and varying schedules in repeated 28-day cycles. Patients received copanlisib (0.2–0.8 mg/kg intravenously) intermittently (days 1, 8, 15) or weekly (days 1, 8, 15, 22) each cycle, and refametinib (30–50 mg twice daily orally) continuously or 4 days on/3 days off. Patients with KRAS , NRAS , BRAF , or PI3KCA mutations were eligible for the expansion cohort. Results In the dose-escalation ( n = 49) and expansion ( n = 15) cohorts, the most common treatment-emergent adverse events included diarrhea (59.4%), nausea, acneiform rash, and fatigue (51.6% each). Dose-limiting toxicities included oral mucositis ( n = 4), increased alanine aminotransferase/aspartate aminotransferase ( n = 3), acneiform rash, hypertension ( n = 2 each), and diarrhea ( n = 1). MTD was copanlisib 0.4 mg/kg weekly and refametinib 30 mg twice daily. No pharmacokinetic interactions were identified. Decreased tumor FDG uptake and MEK-ERK signaling inhibition were demonstrated during treatment. Best response was stable disease ( n = 21); median treatment duration was 6 weeks. Conclusions Despite sound rationale and demonstrable pharmacodynamic tumor activity in relevant tumor populations, a dose and schedule could not be identified for this drug combination that were both tolerable and offered clear efficacy in the population assessed. Clinicaltrials.gov identifier NCT01392521. Electronic supplementary material The online version of this article (10.1007/s11523-020-00714-0) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

et al. 2020

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“…Moreover, a combination of imatinib and everolimus has limited activity in the treatment of patients with advanced chordoma [223]. The combination of pimasertib and voxtalisib showed a poor long-term tolerability and limited anti-tumor activity in patients with advanced solid tumors [224].…”

Section: Clinical Testing Of Mtor Inhibitorsmentioning

confidence: 99%

Targeting mTOR for cancer therapy

et al. 2019

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Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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“…In a phase Ib dose-escalation study of patients with advanced solid tumors treated with MEK inhibitor trametinib in combination with PI3K/mTOR inhibitor GSK2126458, there was poor tolerability and responses were minimal despite upregulation of PI3K/Ras pathway, likely due to toxicities [229]. In advanced solid tumors, a phase Ib clinical trial of combined MEK inhibitor (pimasertib) and PI3K/mTOR inhibitor (voxtalisib) had poor long-term tolerability and limited anti-tumor activity [262]. In a phase I trial of temsirolimus combined with pimasertib for patients with advanced solid tumors, there was unfavorable toxicity profile although some patients had some clinical benefit and stabilized disease [263].…”

Section: Combining Mtor Inhibition With Other Protein Kinase Inhibitorsmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

166

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours

Cited by 75 publications

References 19 publications

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

Phase Ib Trial of the PI3K Inhibitor Copanlisib Combined with the Allosteric MEK Inhibitor Refametinib in Patients with Advanced Cancer

Targeting mTOR for cancer therapy

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

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