A multicenter phase I study evaluating dual PI3K and BRAF inhibition with PX-866 and vemurafenib in patients with advanced BRAF V600-mutant solid tumors

Clinical Cancer Research

Volumn 24, Issue 1, 2018, Pages 22-32

  Yam, Clinton ^a,b   Xu, Xiaowei ^a   Davies, Michael A ^b   Gimotty, Phyllis A ^c   Morrissette, Jennifer J D ^c   Tetzlaff, Michael T ^b   Wani, Khalida M ^b   Liu, Shujing ^a   Deng, Wanleng ^b   Buckley, Meghan ^c   Zhao, Jianhua ^c   Amaravadi, Ravi K ^a   Haas, Naomi B ^a   Kudchadkar, Ragini R ^d   Pavlick, Anna C ^e   Sosman, Jeffrey A ^f   Tawbi, Hussein ^b,g   Walker, Luke ^h   Schuchter, Lynn M ^a   Karakousis, Giorgos C ^a   Gangadhar, Tara C ^a   more..

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

^d H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

^e NEW YORK UNIVERSITY MEDICAL CENTER   (United States)

^f VANDERBILT INGRAM CANCER CENTER   (United States)

^g UNIVERSITY OF PITTSBURGH   (United States)

^h Cascadian Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; B RAF KINASE; B RAF KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; PROGRAMMED DEATH 1 LIGAND 1; PROTEIN KINASE B; SONOLISIB; TRIACYLGLYCEROL LIPASE; VEMURAFENIB; ANTINEOPLASTIC AGENT; GONANE DERIVATIVE; PHOSPHATIDYLINOSITOL 3 KINASE; PX-866;

ADULT; AGED; AKT SIGNALING; ALOPECIA; ARTHRALGIA; ARTICLE; CD8+ T LYMPHOCYTE; CHILL; CLINICAL ARTICLE; DECREASED APPETITE; DIARRHEA; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG SAFETY; DRY EYE; DRY SKIN; DYSGEUSIA; FATIGUE; FEMALE; FEVER; GASTROINTESTINAL STROMAL TUMOR; GENE DELETION; GENE MUTATION; HAND FOOT SYNDROME; HUMAN; HUMAN TISSUE; HYPERTRANSAMINASEMIA; IMMUNOHISTOCHEMISTRY; LIVER CELL DAMAGE; LYMPHOCYTIC INFILTRATION; MACULOPAPULAR RASH; MALE; MAXIMUM TOLERATED DOSE; MELANOMA; MULTICENTER STUDY; MULTIPLE CYCLE TREATMENT; MYALGIA; NAUSEA; OPEN STUDY; PANCREATITIS; PERIPHERAL EDEMA; PHARMACODYNAMICS; PHASE 1 CLINICAL TRIAL; PHOTOSENSITIVITY; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; PRURITUS; RASH; SIDE EFFECT; SOLID MALIGNANT NEOPLASM; TUMOR BIOPSY; UVEITIS; VOMITING; ALLELE; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CLINICAL TRIAL; GENETICS; METASTASIS; MIDDLE AGED; MORTALITY; MUTATION; NEOPLASM; SIGNAL TRANSDUCTION; TREATMENT OUTCOME;

ADULT; AGED; ALLELES; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; FEMALE; GONANES; HUMANS; MALE; MIDDLE AGED; MUTATION; NEOPLASM METASTASIS; NEOPLASM STAGING; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTO-ONCOGENE PROTEINS B-RAF; SIGNAL TRANSDUCTION; TREATMENT OUTCOME; VEMURAFENIB;

EID: 85040044571     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-17-1807     Document Type: Article

References (34)

1. Samuels Y, Ericson K. Oncogenic PI3K and its role in cancer. Curr Opin Oncol 2006;18:77-82.
2. Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011;333:1157-60.
3. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 2005;11:2875-8.
4. Carracedo A, Pandolfi PP. The PTEN-PI3K pathway: of feedbacks and cross-talks. Oncogene 2008;27:5527-41.
5. Jiang CC, Lai F, Thorne RF, Yang F, Liu H, Hersey P, et al. MEKindependent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res 2011;17:721-30.
6. Zhang Y, Moerkens M, Ramaiahgari S, de Bont H, Price L, Meerman J, et al. Elevated insulin-like growth factor 1 receptor signaling induces antiestrogen resistance through the MAPK/ERK and PI3K/Akt signaling routes. Breast Cancer Res 2011;13:R52.
7. Engelman JA. targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 2009;9:550-62.
8. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 2010;18:683-95.
9. Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 2011;11:289-301.
10. Shull AY, Latham-Schwark A, Ramasamy P, Leskoske K, Oroian D, Birtwistle MR, et al. Novel somatic mutations to PI3K pathway genes in metastatic melanoma. PLoS One 2012;7:e43369.
11. Ihle NT, Williams R, Chow S, Chew W, Berggren MI, Paine-Murrieta G, et al. Molecular pharmacology and antitumor activity of PX-866, a novel inhibitor of phosphoinositide-3-kinase signaling. Mol Cancer Ther 2004;3: 763-72.
12. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O'Bryant CL, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2012;18:4173-82.
13. Bowles DW, Ma WW, Senzer N, Brahmer JR, Adjei AA, Davies M, et al. A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours. Br J Cancer 2013; 109:1085-92.
14. Bowles DW, Senzer N, Hausman D, Peterson S, Vo A, Walker L, et al. A multicenter phase 1 study of PX-866 and cetuximab in patients with metastatic colorectal carcinoma or recurrent/metastatic squamous cell carcinoma of the head and neck. Invest New Drugs 2014;32:1197-203.
15. Shannan B, Chen Q, Watters A, Perego M, Krepler C, Thombre R, et al. Enhancing the evaluation of PI3K inhibitors through 3D melanoma models. Pigment Cell Melanoma Res 2016 May;29(3):317-28. doi: 10.1111/pcmr.12465. Epub 2016 Mar 21.
16. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res 2012;25:248-58.
17. Maira SM, Stauffer F, Schnell C, Garcia-Echeverria C. PI3K inhibitors for cancer treatment: where do we stand? Biochem Soc Trans 2009;37:265-72.
18. McCarty KS Jr, Miller LS, Cox EB, Konrath J, McCarty KS Sr. Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 1985;109:716-21.
19. Daber R, Sukhadia S, Morrissette JJ. Understanding the limitations of next generation sequencing informatics, an approach to clinical pipeline validation using artificial data sets. Cancer Genet 2013;206:441-8.
20. Smigielski EM, Sirotkin K, Ward M, Sherry ST. dbSNP: a database of single nucleotide polymorphisms. Nucleic Acids Res 2000;28:352-5.
21. Forbes S, Clements J, Dawson E, Bamford S, Webb T, Dogan A, et al. Cosmic 2005. Br J Cancer 2006;94:318-22.
22. Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM, et al. A map of human genome variation from populationscale sequencing. Nature 2010;467:1061-73.
23. Davies MA, Stemke-Hale K, Lin E, Tellez C, Deng W, Gopal YN, et al. Integrated molecular and clinical analysis of AKT activation in metastatic melanoma. Clin Cancer Res 2009;15:7538-46.
24. Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, et al. Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res 2010;70:8736-47.
25. E/K mutant advanced melanoma. J Clin Oncol 32:9101.
26. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19.
27. Das Thakur M, Salangsang F, Landman AS, Sellers WR, Pryer NK, Levesque MP, et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013;494:251-5.
28. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16.
29. Valpione S, Carlino MS, Mangana J, Mooradian M, McArthur GA, Schadendorf DH, et al. Re-challenge with BRAF-directed treatment: a multi-institutional retrospective study. J Clin Oncol 2017;35: 9512.
30. Schreuer M, Jansen Y, Planken S, Chevolet I, Seremet T, Kruse V, et al. Combination of dabrafenib plus trametinib for BRAF and MEK inhibitor pretreated patients with advanced BRAFV600-mutant melanoma: an openlabel, single arm, dual-centre, phase 2 clinical trial. Lancet Oncol 2017; 18:464-72.
31. Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010;141:69-80.
32. Peng W, Chen JQ, Liu C, Malu S, Creasy C, Tetzlaff MT, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 2016;6:202-16.
33. Dong Y, Richards JA, Gupta R, Aung PP, Emley A, Kluger Y, et al. PTEN functions as a melanoma tumor suppressor by promoting host immune response. Oncogene 2014;33:4632-42.
34. Noh KH, Kang TH, Kim JH, Pai SI, Lin KY, Hung CF, et al. Activation of Akt as a mechanism for tumor immune evasion. Mol Ther 2009;17:439-47.