Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma

Brown, Jennifer R.; Davids, Matthew S.; Rodón, Jordi; Abrisqueta, Pau; Kasar, Siddha; Lager, Joanne; Jiang, Jason; Égile, Coumaran; Awan, Farrukh T.

doi:10.1158/1078-0432.ccr-14-3262

Cited by 50 publications

(28 citation statements)

References 54 publications

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“…Two patients had grade ≥3 elevated aminotransferase levels, and this incidence may have been higher than seen in the first-in-human study, where <10% of patients had grade ≥3 elevated aminotransferase levels [10]. The overall incidence and severity of gastrointestinal toxicity seen with copanlisib in the current study and in the first-in-human study are notably less than those reported for other orally administered PI3K inhibitors [12, 13, 15, 22, 23] and may be related to the route of administration and first-pass metabolism seen with orally administered drugs [10]. …”

Section: Discussionmentioning

confidence: 52%

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

Doi

Fuse

Yoshino

et al. 2016

Cancer Chemother Pharmacol

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Purpose To evaluate the safety, tolerability, pharmacokinetics, and efficacy of the intravenously administered pan-PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors.MethodsA Phase I open-label study in Japanese patients with advanced or refractory solid tumors was carried out. Patients received a single intravenous dose of either copanlisib 0.4 mg/kg or copanlisib 0.8 mg/kg, dosed intermittently on days 1, 8, and 15 of a 28-day cycle. Safety was monitored throughout the study. Plasma copanlisib levels were measured for pharmacokinetic analysis. ResultsTen patients were enrolled and treated; three received copanlisib 0.4 mg/kg and seven received copanlisib 0.8 mg/kg. Overall, median duration of treatment was 6.2 weeks. No patients treated at 0.4 mg/kg experienced a dose-limiting toxicity, and the maximum tolerated dose in Japanese patients was determined to be 0.8 mg/kg. Adverse events were recorded in all ten patients; the most common were hyperglycemia, hypertension, and constipation. Copanlisib pharmacokinetic exposures displayed near dose-proportionality, with no accumulation. No patients achieved a complete or partial response, and disease control rate was 40.0%.ConclusionsCopanlisib was well tolerated in Japanese patients with advanced or refractory solid tumors, and the maximum tolerated dose was determined to be 0.8 mg/kg. Copanlisib demonstrated near dose-proportional pharmacokinetics and preliminary disease control, warranting further investigation.Clinical trial registration numberNCT01404390.

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Section: Discussionmentioning

confidence: 52%

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

Doi

Fuse

Yoshino

et al. 2016

Cancer Chemother Pharmacol

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“…Additional PI3K inhibitors are currently under development, including duvelisib, also called IPI-145, a potent PI3K γ–δ inhibitor, which antagonizes BCR and microenvironment interactions in vitro [192], even in cells carrying the BTK C481S mutation [193], and has been tested either alone [194, 195] or in combination with anti-CD20 antibodies. Additional small molecule inhibitors in early clinical development include the pan-PI3K inhibitor pilaralisib, also called SAR245408 [196], the PI3K β,δ inhibitor GS-9820, and the PI3Kδ inhibitors ACP-319 and TGR-1202 [197, 198]. …”

Section: B-cell Receptor Signaling In Cllmentioning

confidence: 99%

“…Interference with the BCR signaling axis can be obtained with inhibitors of SYK kinase, including fostamatinib [200], GS-9973 [202], and PRT-2070, of BTK kinase, including ibrutinib [163–180], ACP-196 and ONO-4059 [181], and of PI3K kinases, including idelalisib (δ inhibitor) [165, 183], duvelisib (also called IPI-145, γ,δ inhibitor) [192], pilaralisib (also called SAR245408, pan-PI3K inhibitor) [196], GS-9820 (β,δ inhibitor), TGR-1202 (δ inhibitor) [197], and ACP-319 (δ inhibitor).…”

Section: Figurementioning

confidence: 99%

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

Hacken

Burger

2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

190

208

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Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions.

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“…XL147 could induce an upregulation of HER3 expression and phosphorylation in HER2-overexpressing breast cancer cells, and it synergizes with trastuzumab or lapatinib to suppress xenograft growth [44, 45]. Currently, XL147 has entered phase I/II clinical trials in a variety of cancers including breast, endometrial, lymphoma and GBM [46–49]. A phase I exploratory pharmacodynamic study using XL147 and XL765 (Voxtalisib, a dual PI3K/mTOR inhibitor) was performed in patients with recurrent GBM prior to surgical resection (NCT01240460).…”

Section: Introductionmentioning

confidence: 99%

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

et al. 2017

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Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary tumor in the central nervous system. One of the most widely used chemotherapeutic drugs for GBM is temozolomide, which is a DNA-alkylating agent and its efficacy is dependent on MGMT methylation status. Little progress in improving the prognosis of GBM patients has been made in the past ten years, urging the development of more effective molecular targeted therapies. Hyper-activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is frequently found in a variety of cancers including GBM, and it plays a central role in the regulation of tumor cell survival, growth, motility, angiogenesis and metabolism. Numerous PI3K inhibitors including pan-PI3K, isoform-selective and dual PI3K/mammalian target of rapamycin (mTOR) inhibitors have exhibited favorable preclinical results and entered clinical trials in a range of hematologic malignancies and solid tumors. Furthermore, combination of inhibitors targeting PI3K and other related pathways may exert synergism on suppressing tumor growth and improving patients’ prognosis. Currently, only a handful of PI3K inhibitors are in phase I/II clinical trials for GBM treatment. In this review, we focus on the importance of PI3K/Akt pathway in GBM, and summarize the current development of PI3K inhibitors alone or in combination with other inhibitors for GBM treatment from preclinical to clinical studies.

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Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma

Cited by 50 publications

References 54 publications

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

A Phase I study of intravenous PI3K inhibitor copanlisib in Japanese patients with advanced or refractory solid tumors

Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment

Recent advances in the use of PI3K inhibitors for glioblastoma multiforme: current preclinical and clinical development

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