The DOI matches its Crossref record; 27 of the 28 references it cites were found in a registry or an index.
Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of SAR245408 (XL147), an Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors
Published version of a preprint
Abstract
Purpose: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy. Experimental Design: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies. Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%–80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non–small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations. Conclusions: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. Clin Cancer Res; 20(1); 233–45. ©2013 AACR.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“For example, the PI3K inhibitor XL147 was reported to inhibit the PI3K pathway with a 40–80% reduction in the phosphorylation of AKT and 4EBP1 in tumours and unexpectedly inhibited the MEK/ERK pathway in a phase I trial [111].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [111]
Citations
Cites
New Guidelines to Evaluate the Response to Treatment in Solid Tumors
Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., et al. (2000) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/92.3.205 · Cited by 15,660
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621
High Frequency of Mutations of the PIK3CA Gene in Human Cancers
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., Yan, H., Gazdar, A. F., Powell, S. M., Riggins, G. J., et al. (2004) · Science · doi:10.1126/science.1096502 · Cited by 3,448
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330
Targeting the phosphoinositide 3-kinase pathway in cancer
Liu, P., Cheng, H.-L. M., Roberts, T. M., & Zhao, J. J. (2009) · Nature Reviews Drug Discovery · doi:10.1038/nrd2926 · Cited by 2,785
Phosphatidylinositol-3-OH kinase direct target of Ras
Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., & Downward, J. (1994) · Nature · doi:10.1038/370527a0 · Cited by 1,954
Carracedo, A., Ma, L., Teruya-Feldstein, J., Rojo, F., Salmena, L., Alimonti, A., Egia, A., Sasaki, A. T., Thomas, G., Kozma, S. C., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34739 · Cited by 1,381
Self-citationThe PI3K Pathway As Drug Target in Human Cancer
Courtney, K. D., Corcoran, R. B., & Engelman, J. A. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2009.25.3641 · Cited by 1,268
Rodriguez‐Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A. J., & Downward, J. (1997) · Cell · doi:10.1016/s0092-8674(00)80226-3 · Cited by 1,060
PTEN loss in the continuum of common cancers, rare syndromes and mouse models
Hollander, M. C., Blumenthal, G. M., & Dennis, P. A. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3037 · Cited by 793
Research works printed but not linked: 1
- Sidhu, 2013, Antitumor activity of pimasertib in combination with SAR245409 or SAR245408 in human primary colorectal cancer xenograft models bearing PI3K/KRAS and KRAS mutations [abstract]
Cited by
Sorted by citations
Items 101–154 of 154
Treating non-small cell lung cancer by targeting the PI3K signaling pathway
Jiang, L., Zhang, J., Xu, Y., Xu, H., & Wang, M. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000002195 · Cited by 23
Self-citationSheng, Y., Li, W., Zhu, F., Liu, K., Chen, H., Yao, K., Reddy, K., Lim, D. Y., Oi, N., Li, H., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.593475 · Cited by 21
Rahman, M. M., Islam, M. R., Akash, S., Hossain, M. E., Tumpa, M. A. A., Ishtiaque, G. M. A., Ahmed, L., Rauf, A., Khalil, A. A., Abdulmonem, W. A., et al. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e18090 · Cited by 23
RetractedTargeting the PI3K/Akt/mTOR Pathway in Malignancy: Rationale and Clinical Outlook
Cho, D. (2014) · BioDrugs · doi:10.1007/s40259-014-0090-5 · Cited by 23
Edelman, G. M., Rodon, J. A., Lager, J. J., Castell, C., Jiang, J., Allen, E. M. V., Wagle, N., Lindeman, N. I., Sholl, L. M., & Shapiro, G. I. (2018) · The Oncologist · doi:10.1634/theoncologist.2017-0691 · Cited by 20
Self-citationMEK inhibitors beyond monotherapy: current and future development.
Templeton, I. E., & Musib, L. (2015) · Current opinion in pharmacology (Print) · doi:10.1016/j.coph.2015.05.012 · Cited by 20
Rationale-based therapeutic combinations with PI3K inhibitors in cancer treatment
Castel, P., Toska, E., Zumsteg, Z. S., Carmona, F. J., Elkabets, M., Bosch, A., & Scaltriti, M. (2014) · Molecular & Cellular Oncology · doi:10.4161/23723548.2014.963447 · Cited by 22
Therapeutic Approaches to RAS Mutation
Scott, A. J., Lieu, C. H., & Messersmith, W. A. (2016) · The Cancer Journal · doi:10.1097/ppo.0000000000000187 · Cited by 19
Pandey, R., & Kapur, R. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0388-z · Cited by 18
Disentangling the Complexity of HGF Signaling by Combining Qualitative and Quantitative Modeling
D’Alessandro, L. A., Samaga, R., Maiwald, T., Rho, S., Bonefas, S., Raue, A., Iwamoto, N., Kienast, A., Robichon, K., Meyer, R., et al. (2015) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1004192 · Cited by 18
Current perspectives of KRAS in non-small cell lung cancer
Harris, E., & Thawani, R. (2024) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2024.101106 · Cited by 17
Trono, P., Modugno, F. D., Circo, R., Spada, S., Benedetto, A. D., Melchionna, R., Palermo, B., Matteoni, S., Soddu, S., Mottolese, M., et al. (2015) · Oncogene · doi:10.1038/onc.2015.143 · Cited by 16
Mehnert, J. M., Edelman, G. M., Stein, M. N., Camisa, H., Lager, J. J., Dedieu, J.-F., Ghuysen, A.-F., Sharma, J., Liu, L., & LoRusso, P. M. (2017) · Investigational New Drugs · doi:10.1007/s10637-017-0467-7 · Cited by 14
Self-citationE-cadherin downregulation sensitizes PTEN-mutant tumors to PI3Kβ silencing
Millán‐Uclés, Á., Zuluaga, S., Marqués, M., Vallejo-Díaz, J., Sanz, L., Cariaga-Martínez, A. E., Real, F. X., & Carrera, A. C. (2016) · Oncotarget · doi:10.18632/oncotarget.13414 · Cited by 13
Spagnuolo, A., Maione, P., & Gridelli, C. (2022) · Translational Lung Cancer Research · doi:10.21037/tlcr-21-948 · Cited by 15
Targeting the PI3K/AKT/mTOR Pathway in Cancer Cells
Guimarães, I. D. S., Tessarollo, N. G., Junior, P. C. M. L., dos Santos, D. Z., Zampier, R. C., de Oliveira, L. F. R. L., Siqueira, K. V., Silva, I. V., & Rangel, L. B. A. (2015) · InTech eBooks · doi:10.5772/61676 · Cited by 13
Ramesh, A., Natarajan, S. K., Nandi, D., & Kulkarni, A. A. (2019) · Cellular and Molecular Bioengineering · doi:10.1007/s12195-019-00576-1 · Cited by 13
Choi, J., Kim, K. H., Roh, K.-H., Jung, H., Lee, A., Lee, J. Y., Song, J. Y., Park, S. J., Kim, I. H., Lee, W. S., et al. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1421890 · Cited by 12
Isoform-Selective Phosphatidylinositol 3-Kinase Inhibition in Cancer
Bergholz, J. S., Roberts, T. M., & Zhao, J. J. (2018) · Journal of Clinical Oncology · doi:10.1200/jco.2017.77.0891 · Cited by 12
Welt, A., Wiesweg, M., Theurer, S., Abenhardt, W., Groschek, M., Müller, L., Schröder, J., Tewes, M., Chiabudini, M., Potthoff, K., et al. (2020) · Cancer Medicine · doi:10.1002/cam4.3092 · Cited by 11
The Clinical Pharmacology and Toxicity Profile of Rapalogs
Su, D. W., Mita, M. M., & Mita, A. C. (2015) · Springer eBooks · doi:10.1007/978-2-8178-0492-7_8 · Cited by 9
Haagensen, E. J., Thomas, H. D., Schmalix, W. A., Payne, A. C., Kevorkian, L., Allen, R. A., Bevan, P., Maxwell, R. J., & Newell, D. R. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3186-4 · Cited by 9
Liu, J., Hong, J., Ahn, K.-S., Go, J., Han, H., Park, J., Kim, D., Park, H., Koh, Y., Shin, D., et al. (2019) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2019.1594211 · Cited by 9
Bułakowska, A., Slawinski, J. J., Siedlecka-Kroplewska, K., Stasiłojć, G., Serocki, M., & Heldt, M. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.104309 · Cited by 8
Invention of a novel photodynamic therapy for tumors using a photosensitizing PI3K inhibitor
Hayashida, Y., Ikeda, Y., Sawada, K., Kawai, K., Kato, T., Kakehi, Y., & Araki, N. (2016) · International Journal of Cancer · doi:10.1002/ijc.30097 · Cited by 7
RASpecting the oncogene: New pathways to therapeutic advances
Stout, M. C., & Campbell, P. M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.10.022 · Cited by 7
Cernaj, I. E. (2016) · Cancer Cell International · doi:10.1186/s12935-016-0363-9 · Cited by 7
Bechter, O. E., Dumez, H., Costermans, J., Punie, K., Hsu, K., Dedieu, J.-F., Ghuysen, A.-F., Francesconi, E., Sharma, J., Liu, L., et al. (2016) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-016-3056-0 · Cited by 6
Synthesis and biological activity of imidazo[4,5-c]quinoline derivatives as PI3K/mTOR inhibitors
Li, Y., Zhang, X., Niu, S., Zhao, Y., Yang, L., Shao, X., & Wang, E. (2017) · Chemical Research in Chinese Universities · doi:10.1007/s40242-017-7074-1 · Cited by 5
Attenuating PI3K isoforms in pancreatic cancer: Focus on immune PI3Kγ
Basset, C., & Guillermet‐Guibert, J. (2017) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2017.04.013 · Cited by 5
BCL-2 Family Inhibition Enhances mTORC1/2 Inhibition in PIK3CA -Mutant Colorectal Cancer
DeStefanis, R. A., Schmitz, A. E., Steimle, A. K., Payne, S. N., Sha, G. C., Olson, A. M., Cornelio, A. B., Lippert, A. E. L., Kraus, S. G., Johnson, K. A., et al. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-24-1096 · Cited by 4
Emerging Therapies in Kirsten Rat Sarcoma Virus (+) Non-Small-Cell Lung Cancer
Karachaliou, A., Kotteas, E. A., Fiste, O., & Syrigos, K. (2024) · Cancers · doi:10.3390/cancers16081447 · Cited by 3
Vella, L. J., Andrews, M. C., Behren, A., Cebon, J. S., & Woods, K. (2014) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2014.929943 · Cited by 2
Targeted Therapy and Prevention of Endometrial Cancer
Shiozaki, T., & Westin, S. N. (2017) · Molecular pathology library · doi:10.1007/978-3-319-57985-6_10 · Cited by 1
Liu, M., Fu, L., Fu, H., Chen, Y., Wu, M., & Liu, H. (2024) · Journal of Holistic Integrative Pharmacy · doi:10.1016/j.jhip.2024.04.006 · Cited by 1
The PI3K-mTOR Pathway in Prostate Cancer: Biological Significance and Therapeutic Opportunities
Wu, B. J., & Chung, L. W. K. (2016) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-319-34211-5_9 · Cited by 1
Cancers of the Respiratory System
Parsyan, A. E., & Reckamp, K. L. (2014) · Springer eBooks · doi:10.1007/978-94-017-9078-9_27 · Cited by 1
Toward High-Precision Genomic Biomarkers
Tan, D. S. W., & Adjei, A. A. (2015) · Journal of Thoracic Oncology · doi:10.1097/jto.0000000000000633 · Cited by 1
Synergy of NVP-BEZ235 and enzastaurin in mantle cell lymphoma
Civallero, M., & Cosenza, M. (2014) · Clinical Management Issues · doi:10.7175/cmi.v8i1.889
Targeted Therapies For Intestinal Tumorigenesis
Chiorean, E. G., Coveler, A. L., Grim, J. E., & Grady, W. M. (2015) · Springer eBooks · doi:10.1007/978-3-319-19986-3_13
Çakar, B., & Göker, E. (2016) · Springer eBooks · doi:10.1007/978-3-319-26012-9_36
Targeted Therapy in Gynecological Malignancy
Zand, B., Westin, S. N., & Coleman, R. L. (2017) · Wiley eBooks · doi:10.1002/9781119196235.ch46
Martin, L. P., & Schilder, R. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803741-6.00008-2
Ras and Ras Signaling as a Therapeutic Target in Cancer
Sliker, B. H., & Campbell, P. M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820472-6.00006-2
Belzer, A., Bhullar, S., & Leventhal, J. S. (2022) · Current Dermatology Reports · doi:10.1007/s13671-022-00365-6
Shapiro, G. I., Bell‐McGuinn, K. M., Molina, J. R., Bendell, J. C., Spicer, J. F., Kwak, E. L., Pandya, S. S., Millham, R., Borzillo, G. V., Pierce, K. J., et al. (2023) · doi:10.1158/1078-0432.c.6523223
Self-citationCintas, C. (2017) · theses.fr (ABES) · doi:10.70675/d19569d2z4eaez4a9azae8bz1e155d6b15b3
Exploring PI3K signalling dynamics in pancreatic cancer
Delgado, C. F. R. (2020) · theses.fr (ABES) · doi:10.70675/6df9a059zc3f1z4997z9de2z34a1d24dfbeb
Contrôle de l'oncogenicité de Kras et isoforme beta de PI3K dans la cancérogenèse du pancréas
Arcucci, S. (2019) · theses.fr (ABES) · doi:10.70675/bd0f6cf8zac49z4e36zbe80z39b5e2b4e43a
BindingDB (2022) · UC San Diego · doi:10.7270/q2th8rc9
Metadata
- Authors
- Shapiro, G. I., Rodon, J., Bedell, C., Kwak, E. L., Baselga, J., Braña, I., Pandya, S. S., Scheffold, C., Laird, A. D., Nguyen, L. T., Xu, Y., Egile, C., & Edelman, G.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Authors' Affiliations: 1Dana-Farber Cancer Institute; 2Massachusetts General Hospital; 3Beth Israel Deaconess Medical Center, Boston, Massachusetts; 4Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; 5Mary Crowley Cancer Research Centers, Dallas, Texas; 6Exelixis Inc., South San Francisco, California; and 7Sanofi, Cambridge, Massachusetts, and Vitry-sur-Seine, France
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2014-01-01
- Volume
- 20
- Issue
- 1
- Pages
- 233-245
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W1979937839
- Cited by
- 152
- References
- 28
- Citations by year
- 2025: 1 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 10 · 2019: 7 · 2018: 9 · 2017: 24 · 2016: 21 · 2015: 28 · 2014: 24
- FWCI
- 10.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- phosphatidylinositol 3-kinase, maximum tolerated dose, dose-limiting toxicity, maculopapular rash, pharmacokinetics, pharmacodynamics, Akt phosphorylation, advanced solid tumors, non-small cell lung cancer, dose proportionality, tumor biopsy
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Administration, Oral, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Non-Small-Cell Lung, Dose-Response Relationship, Drug, Female, Humans, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Quinoxalines, Skin Diseases, Sulfonamides, Signal Transduction, Treatment Outcome, Area Under Curve, Maximum Tolerated Dose, Phosphatidylinositol 3-Kinase
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
