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
PI3K/AKT signaling pathway and cancer: an updated review
Martini, M., Santis, M. C. D., Braccini, L., Gulluni, F., & Hirsch, E. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.912836 · Cited by 1,195
Targeting the PI3K pathway in cancer: are we making headway?
Janku, F., Yap, T. A., & Meric-Bernstam, F. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.28 · Cited by 1,033
The relation between PI3K/AKT signalling pathway and cancer
Noorolyai, S., Shajari, N., Baghbani, E., Sadreddini, S., & Baradaran, B. (2019) · Gene · doi:10.1016/j.gene.2019.02.076 · Cited by 672
Targeting the PI3K/Akt/mTOR pathway in non‐small cell lung cancer (NSCLC)
Tan, A. C. (2020) · Thoracic Cancer · doi:10.1111/1759-7714.13328 · Cited by 549
Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors
LoRusso, P. M. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2014.59.0018 · Cited by 473
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
