A phase I trial of combined ridaforolimus and MK-2206 in patients with advanced malignancies

Clinical Cancer Research

Volumn 21, Issue 23, 2015, Pages 5235-5244

  Gupta, Shilpa ^a   Argilés, Guillem ^b   Munster, Pamela N ^c   Hollebecque, Antoine ^d   Dajani, Olav ^e   Cheng, Jonathan D ^f   Wang, Ruixue ^f   Swift, Ann ^f   Tosolini, Alessandra ^f   Piha Paul, Sarina A ^g  

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

^b VALL D HEBRON UNIVERSITY HOSPITAL   (Spain)

^c UNIVERSITY OF CALIFORNIA   (United States)

^d DITEP   (France)

^e OSLO UNIVERSITY HOSPITAL   (Norway)

^f MERCK RESEARCH LABORATORIES   (United States)

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

Author keywords

[No Author keywords available]

Indexed keywords

8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; ALANINE AMINOTRANSFERASE; ASPARTATE AMINOTRANSFERASE; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; RIDAFOROLIMUS; ANTINEOPLASTIC AGENT; BIOLOGICAL MARKER; FUSED HETEROCYCLIC RINGS; MTOR PROTEIN, HUMAN; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE INHIBITOR; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE;

ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALOPECIA; ANTINEOPLASTIC ACTIVITY; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ASTHENIA; BREAST CANCER; CANCER COMBINATION CHEMOTHERAPY; CANCER PATIENT; COLLOID CARCINOMA; COLORECTAL CANCER; CONSTIPATION; DECREASED APPETITE; DIARRHEA; DRUG EFFICACY; DRUG RESPONSE; DRUG WITHDRAWAL; DRY SKIN; DYSGEUSIA; DYSPNEA; ENDOMETRIUM CANCER; FATIGUE; FEMALE; GLIOMA; GROWTH INHIBITION; HEADACHE; HUMAN; HYPERGLYCEMIA; HYPERTRIGLYCERIDEMIA; MALE; MAXIMUM TOLERATED DOSE; MELANOMA; NAUSEA; PHASE 1 CLINICAL TRIAL; PHASE 1 CLINICAL TRIAL (TOPIC); PNEUMONIA; PRIORITY JOURNAL; PROSTATE CANCER; PRURITUS; RASH; RECTUM HEMORRHAGE; SARCOMA; SIDE EFFECT; STOMATITIS; THROMBOCYTOPENIA; TREATMENT DURATION; TREATMENT OUTCOME; TUMOR GROWTH; VOMITING; WEIGHT REDUCTION; ADULT; AGED; ANALOGS AND DERIVATIVES; ANTAGONISTS AND INHIBITORS; CANCER STAGING; CLINICAL TRIAL; DRUG EFFECTS; MIDDLE AGED; MULTICENTER STUDY; NEOPLASMS; PATHOLOGY; RETREATMENT; SIGNAL TRANSDUCTION; VERY ELDERLY; YOUNG ADULT;

ADULT; AGED; AGED, 80 AND OVER; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; BIOMARKERS; FEMALE; HETEROCYCLIC COMPOUNDS, 3-RING; HUMANS; MALE; MIDDLE AGED; NEOPLASM STAGING; NEOPLASMS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; RETREATMENT; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84954143783     PISSN: 10780432     EISSN: 15573265     Source Type: Journal    
DOI: 10.1158/1078-0432.CCR-15-0180     Document Type: Article

References (50)

1. Granville CA, Memmott RM, Gills JJ, Dennis PA. Handicapping the race to develop inhibitors of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway. Clin Cancer Res 2006;12:679-89.
2. Baselga J. Targeting the phosphoinositide-3 (PI3) kinase pathway in breast cancer. Oncologist 2011;16 Suppl 1:12-9.
3. Dancey JE, Monzon J. Ridaforolimus: a promising drug in the treatment of soft-tissue sarcoma and other malignancies. Future Oncol 2011;7:827-39.
4. Pal SK, Reckamp KL. Mammalian target of rapamycin, Akt, and phosphatidylinositol 3-kinase signaling. J Thorac Oncol 2010;5:S487-9.
5. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res 2007;13:3109-14.
6. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005;4:988-1004.
7. Brognard J, Clark AS, Ni Y, Dennis PA. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 2001;61:3986-97.
8. Lo Piccolo J, Blumenthal GM, Bernstein WB, Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 2008;11:32-50.
9. Pal SK, Reckamp K, Yu H, Figlin RA. Akt inhibitors in clinical development for the treatment of cancer. Expert Opin Investig Drugs 2010;19:1355-66.
10. Elit L. Drug evaluation: AP-23573-an mTOR inhibitor for the treatment of cancer. IDrugs 2006;9:636-44.
11. Ridaforolimus. Drugs R D 2010;10:165-78.
12. Rivera VM, Squillace RM, Miller D, Berk L, Wardwell SD, Ning Y, et al. Ridaforolimus (AP23573;MK-8669), a potent mTOR inhibitor, has broad antitumor activity and can be optimally administered using intermittent dosing regimens. Mol Cancer Ther 2011;10:1059-71.
13. Squillace RM, Miller D, Cookson M, Wardwell SD, Moran L, Clapham D, et al. Antitumor activity of ridaforolimus and potential cell cycle determinants of sensitivity in sarcoma and endometrial cancermodels. Mol Cancer Ther 2011;10:1959-68.
14. Berk L, Mita MM, Kreisberg J, Bedrosian CL, Tolcher AW, Clackson T, et al. Analysis of the pharmacodynamic activity of the mTOR inhibitor ridaforolimus (AP23573, MK-8669) in a phase 1 clinical trial. Cancer Chemother Pharmacol 2012;69:1369-77.
15. Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, et al. Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008;26:361-7.
16. Mita MM, Poplin E, Britten CD, Tap WD, Rubin EH, Scott BB, et al. Phase I/IIa trial of the mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) administered orally in patients with refractory or advanced malignancies and sarcoma. Ann Oncol 2013;24:1104-11.
17. Amato RJ, Wilding G, Bubley G, Loewy J, Haluska F, Gross ME. Safety and preliminary efficacy analysis of the mTOR inhibitor ridaforolimus in patients with taxane-treated, castration-resistant prostate cancer. Clin Genitourin Cancer 2012;10:232-8.
18. Chawla SP, Staddon AP, Baker LH, Schuetze SM, Tolcher AW, D'Amato GZ, et al. Phase II study of the mammalian target of rapamycin inhibitor ridaforolimus in patients with advanced bone and soft tissue sarcomas. J Clin Oncol 2012;30:78-84.
19. Colombo N, McMeekin DS, Schwartz PE, Sessa C, Gehrig PA, Holloway R, et al. Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, phase 2 trial. Br J Cancer 2013;108:1021-6.
20. Demetri GD, Chawla SP, Ray-Coquard I, Le Cesne A, Staddon AP, Milhem MM, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol 2013;31:2485-92.
21. Gore L, Trippett TM, Katzenstein HM, Boklan J, Narendran A, Smith A, et al. A multicenter, first-in-pediatrics, phase 1, pharmacokinetic and pharmacodynamic study of ridaforolimus in patients with refractory solid tumors. Clin Cancer Res 2013;19:3649-58.
22. Meulenbeld HJ, de Bono JS, Tagawa ST, Whang YE, Li X, Heath KH, et al. Tolerability, safety and pharmacokinetics of ridaforolimus in combination with bicalutamide in patients with asymptomatic, metastatic castrationresistant prostate cancer (CRPC). Cancer Chemother Pharmacol 2013;72: 909-16.
23. Perotti A, Locatelli A, Sessa C, Hess D, Vigano L, Capri G, et al. Phase IB study of the mTOR inhibitor ridaforolimus with capecitabine. J Clin Oncol 2010;28:4554-61.
24. Sessa C, Tosi D, Vigano L, Gabrail N, Stock W, Strair R, et al. Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel. Ann Oncol 2010;21:1315-22.
25. Fouladi M, Perentesis JP, Phillips CL, Albanell J, Hess D, Maur M, et al. A phase I trial of MK-2206 in children with refractory malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 2014;61: 1246-51.
26. Yap TA, Yan L, Patnaik A, Fearen I, Olmos D, Papadopoulos K, et al. First-inman clinical trial of the oral pan-AKT inhibitor MK-2206 in patients with advanced solid tumors. J Clin Oncol 2011;29:4688-95.
27. Yap TA, Yan L, Patnaik A, Tunariu N, Biondo A, Fearen I, et al. Interrogating two schedules of the AKT inhibitor MK-2206 in patients with advanced solid tumors incorporating novel pharmacodynamic and functional imaging biomarkers. Clin Cancer Res 2014;20:5672-85.
28. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, et al. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 2010;9:1956-67.
29. Xu S, Li S, Guo Z, Luo J, Ellis MJ, Ma CX. Combined targeting of mTOR and AKT is an effective strategy for basal-like breast cancer in patient-derived xenograft models. Mol Cancer Ther 2013;12:1665-75.
30. Floc'h N, Kinkade CW, Kobayashi T, Aytes A, Lefebvre C, Mitrofanova A, et al. Dual targeting of the Akt/mTOR signaling pathway inhibits castration-resistant prostate cancer in a genetically engineered mouse model. Cancer Res 2012;72:4483-93.
31. Zhang W, Haines BB, Efferson C, Zhu J, Ware C, Kunii K, et al. Evidence of mTOR activation by an AKT-independent mechanism provides support for the combined treatment of PTEN-deficient prostate tumors with mTOR and AKT inhibitors. Translational Oncol 2012;5:422-9.
32. Loboda A, Nebozhyn M, Klinghoffer R, Frazier J, Chastain M, Arthur W, et al. A gene expression signature of RAS pathway dependence predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated tumors. BMC Med Genomics 2010;3:26.
33. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A 2001;98:10869-74.
34. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003;100:8418-23.
35. Cheang MC, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst 2009;101:736-50.
36. de Graffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3 kinase/Akt pathway. Ann Oncol 2004;15:1510-6.
37. Halvorsen OJ, Haukaas SA, Akslen LA. Combined loss of PTEN and p27 expression is associated with tumor cell proliferation by Ki-67 and increased risk of recurrent disease in localized prostate cancer. Clin Cancer Res 2003;9:1474-9.
38. Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, et al. Biomarkers of response to Akt inhibitor MK-2206 in breast cancer. Clin Cancer Res 2012;18:5816-28.
39. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci U S A 2001;98:10314-9.
40. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
41. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev 2014;28:126-33.
42. Martins F, de Oliveira MA, Wang Q, Sonis S, Gallottini M, George S, et al. A review of oral toxicity associated with mTOR inhibitor therapy in cancer patients. Oral Oncol 2013;49:293-8.
43. Pilotte AP, Hohos MB, Polson KM, Huftalen TM, Treister N. Managing stomatitis in patients treated with mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 2011;15:E83-E89.
44. Boers-Doets CB, Raber-Durlacher JE, Treister NS, Epstein JB, Arends AB, Wiersma DR, et al. Mammalian target of rapamycin inhibitor-associated stomatitis. Future Oncol 2013;9:1883-92.
45. Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, et al. Everolimus in postmenopausal hormone receptor-positive advanced breast cancer. N Engl J Med 2012;366:520-9.
46. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized phase II trial of everolimus in combinationwith tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 2012;30:2718-24.
47. Porta C, Ostanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011;47: 1287-98.
48. Boers-Doets CB, Epstein JB, Raber-Durlacher JE, Ouwerkerk J, Logan RM, Brakenhoff JA, et al. Oral adverse events associated with tyrosine kinase and mammalian target of rapamycin inhibitors in renal cell carcinoma: a structured literature review. Oncologist 2012;17:135-44.
49. Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E, Stockfleth E. mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transplant 2010;24:149-56.
50. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118:3065-74.