Treatment with PF-04449913, an oral smoothened antagonist, in patients with myeloid malignancies: A phase 1 safety and pharmacokinetics study

The Lancet Haematology

Volumn 2, Issue 8, 2015, Pages e339-e346

  Martinelli, Giovanni ^a   Oehler, Vivian G ^b   Papayannidis, Cristina ^a   Courtney, Rachel ^c   Shaik, M Naveed ^c   Zhang, Xiaoxi ^c   O'Connell, Ashleigh ^d   McLachlan, Karen R ^c   Zheng, Xianxian ^c   Radich, Jerald ^b   Baccarani, Michele ^a   Kantarjian, Hagop M ^e   Levin, Wendy J ^c   Cortes, Jorge E ^e   Jamieson, Catriona ^f  

^a UNIVERSITY OF BOLOGNA   (Italy)

^b Fred Hutchinson Cancer Research Center   (United States)

^c PFIZER INC   (United States)

^d Pfizer Ltd   (United States)

^e UNIVERSITY OF TEXAS   (United States)

^f UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

GLASDEGIB; 1-(2-(1H-BENZO(D)IMIDAZOL-2-YL)-1-METHYLPIPERIDIN-4-YL)-3-(4-CYANOPHENYL)UREA; BENZIMIDAZOLE DERIVATIVE; CARBANILAMIDE DERIVATIVE;

ADULT; AGED; ALOPECIA; ARTICLE; CLINICAL ARTICLE; DECREASED APPETITE; DIARRHEA; DISEASE COURSE; DRUG DOSE ESCALATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; DYSGEUSIA; FATIGUE; FEMALE; HEMORRHAGIC GASTRITIS; HUMAN; HUMAN TISSUE; HYPOXIA; MALE; MAXIMUM TOLERATED DOSE; MUCOSAL DISEASE; MUCOSAL INFLAMMATION; MULTIPLE CYCLE TREATMENT; MUSCLE CRAMP; MYELOID LEUKEMIA; NAUSEA; NEUTROPHIL COUNT; PERIPHERAL EDEMA; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; PLEURA EFFUSION; PRIORITY JOURNAL; RECOMMENDED DRUG DOSE; SINGLE DRUG DOSE; SPLENOMEGALY; THROMBOCYTE COUNT; THROMBOCYTOPENIA; TREATMENT WITHDRAWAL; VOMITING; WEIGHT REDUCTION; CLINICAL TRIAL; HALF LIFE TIME; ITALY; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; LEUKEMIA, MYELOID, ACUTE; MULTICENTER STUDY; MYELODYSPLASTIC SYNDROMES; ORAL DRUG ADMINISTRATION; PRIMARY MYELOFIBROSIS; TREATMENT OUTCOME; UNITED STATES;

ADMINISTRATION, ORAL; BENZIMIDAZOLES; HALF-LIFE; HUMANS; ITALY; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; LEUKEMIA, MYELOID, ACUTE; MAXIMUM TOLERATED DOSE; MYELODYSPLASTIC SYNDROMES; PHENYLUREA COMPOUNDS; PRIMARY MYELOFIBROSIS; TREATMENT OUTCOME; UNITED STATES;

EID: 84955178161     PISSN: None     EISSN: 23523026     Source Type: Journal    
DOI: 10.1016/S2352-3026(15)00096-4     Document Type: Article

References (28)

1. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev 2001; 15: 3059-87.
2. McMillan R, Matsui W. Molecular pathways: the hedgehog signaling pathway in cancer. Clin Cancer Res 2012; 18: 4883-88.
3. Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood 2012; 119: 2196-204.
4. Katoh Y, Katoh M. Hedgehog target genes: mechanisms of carcinogenesis induced by aberrant hedgehog signaling activation. Curr Mol Med 2009; 9: 873-78.
5. Dierks C, Grbic J, Zirlik K, et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 2007; 13: 944-51.
6. Peacock CD, Wang Q, Gesell GG, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 2007; 104: 4048-53.
7. Zhao C, Chen A, Jamieson CH, et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukemia. Nature 2009; 458: 776-79.
8. Dierks C, Beigi R, Guo GR, et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 2008; 14: 238-49.
9. Queiroz KCS, Ruela-de-Sousa RR, Fuhler GM, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. Oncogene 2010; 29: 6314-22.
10. Singh RR, Kunkalla K, Qu C, et al. ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma. Oncogene 2011; 30: 4874-86.
11. Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res 2008; 68: 190-97.
12. Zahreddine HA, Culjkovic-Kraljacic B, Assouline S, et al. The Sonic Hedgehog factor GLI1 imparts drug resistance through inducible glucuronidation. Nature 2014; 511: 90-93.
13. Munchhof MJ, Li Q, Shavnya A, et al. Discovery of PF-04449913, a potent and orally bioavailable inhibitor of smoothened. ACS Med Chem Lett 2012; 3: 106-11.
14. Jackson-Fisher AJ, McMahon MJ, Lam J, et al. PF-04449913, a small molecule inhibitor of the hedgehog signaling pathway, is effective in inhibiting tumor growth in preclinical models. Clin Cancer Res 2011; 71 (suppl 8): 4504 (abstr).
15. Sadarangani A, Pineda G, Lennon KM, et al. GLI2 inhibition abrogates human leukemia stem cell dormancy. J Transl Med 2015; 13: 98.
16. Jackson-Fisher AJ, Whalen P, Elliott M, et al. Interrogating hedgehog pathway and smoothened inhibition by PF-04449913 in patient derived acute myeloid leukemia models. Cancer Res 2014; 74: 1958 (abstr).
17. Minami Y, Fukushima N, Sadarangani A, Minami H, Jamieson C, Naoe T. Treatment with hedgehog inhibitor PF-913 attenuates leukemia-initiation potential in acute myeloid leukemia cells. Cancer Res 2014; 74: 1884 (abstr).
18. Cheson BD, Bennett JM, Kopecky KJ, et al, for the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: 4642-49.
19. Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419-25.
20. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia 2008; 22: 14-22.
21. Baccarani M, Saglio G, Goldman J, et al. European LeukemiaNet. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809-20.
22. Baccarani M, Cortez J, Pane F, et al, for European LeukemiaNet. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009; 27: 6041-51.
23. Rudin CM, Hann CL, Laterra J, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med 2009; 361: 1173-78.
24. Axelson M, Liu K, Jiang X, et al. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res. 2013; 19: 2289-93.
25. Lin TL, Matsui W. Hedgehog pathway as a drug target: smoothened inhibitors in development. Onco Targets Ther 2012; 5: 47-58.
26. Ruch JM, Kim EJ. Hedgehog signaling pathway and cancer therapeutics: progress to date. Drugs 2013; 73: 613-23.
27. Cortes JE, O'Connell A, Shaik MN, et al. Phase IB study of PF-04449913, a hedgehog (Hh) inhibitor, in combination with low-dose cytarabine or intensive chemotherapy, in acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). The 19th Congress of the European Hematology Association (EHA); Milan, Italy; June 12-15, 2014. Abstract P179.
28. Wagner AJ, Messersmith WA, Shaik MN, et al. A phase I study of PF-04449913, an oral hedgehog inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 1044-51.