Erlotinib and Temsirolimus for Solid Tumors

Solid Tumors Clinical Trial

Official title:

Phase I Study of Erlotinib and Temsirolimus in Resistant Solid Malignancies

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00770263
• Other study ID #: 08-1092 / 201108327
• Status: Completed
• Phase: Phase 1
• First received: October 8, 2008
• Last updated: June 2, 2015
• Start date: May 2009
• Est. completion date: September 2014

Study information

• Verified date: December 2014
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

Define the maximum tolerated dose and dose limiting side-effects of temsirolimus in combination wtih erlotinib in patients with resistant solid tumors

Recruitment information / eligibility

• Status: Completed
• Enrollment: 46
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologic Diagnosis: Patients must have a histologically or cytologically proven solid malignancy which is resistant to conventional therapy or for which no effective therapy is known.

• Dose Expansion Phase ONLY: Patients must have archived tumor tissue available (paraffin blocks, unstained tissue sections, tissue cores).

• Tumor Mutational Status (Dose Expansion Phase ONLY): Patients must have tumor harboring PTEN loss, PIK3CA mutation, , and/or EGFR mutation. Patients cannot have KRAS or BRAF mutations. Patients must have mutational status determined by Genomic and Pathology Services at Washington University (GPS@WU) or other CLIA-certified laboratories.

• Dose Expansion Phase ONLY: Patients with squamous carcinoma histology, papillary thyroid carcinoma, and adenoid cystic carcinoma are eligible for the expansion cohort regardless of genetic alterations..

• Measurable or Non-Measurable Disease: Patients with measurable or non-measurable disease are eligible for entry to this study. In addition, patients without measurable or non-measurable disease are also eligible.

• Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as =20 mm with conventional techniques (PET, CT, MRI, x-ray) or as =10 mm with spiral CT scan. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).

• Tumor markers may be considered non-measurable disease.

• A positive bone scan, osteoblastic metastases, and pleural or peritoneal effusions are not considered measurable or non-measurable. Patients with only these lesions are eligible for entry to the study.

• Dose Expansion Phase ONLY: Patients must have a tumor that is easily accessible for biopsy determined by the treating physician or the study PI. Patients must agree to a mandatory biopsy at the end of cycle 1 treatment.

• Recovery from Prior Therapy: Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. No chemotherapy or radiotherapy may be given within 3 weeks prior to the start of protocol treatment. No prior therapy with erlotinib or temsirolimus allowed.

• Age: Patients must be =18 years old. Because no dosing or toxicity data are currently available on the use of temsirolimus in combination with erlotinib in patients <18 years of age, children are excluded from this study, but will be eligible for the pediatric phase I single-agent trials, when available.

• Performance Status: ECOG 0-1 at study entry.

• Life Expectancy: Patients must have a life expectancy of greater than 12 weeks.

• Required Laboratory Values:

• absolute neutrophil count =1,500/mm3

• platelets =100,000/mm3

• hemoglobin =9.0 g/dL

• total bilirubin =1.5 x ULN

• AST/ALT =3.0 x ULN

• alkaline phosphatase =2.5 x ULN

• creatinine =2.0 x ULN OR

• creatinine clearance =60 mL/min/1.732 for patients with creatinine levels above 2.0 mg/dl

• serum cholesterol =350 mg/dL /9.0 mmol/L (fasting)

• triglycerides =300 mg/dL (fasting)*

• PT/INR =1.5, unless the patient is on full dose warfarin or stable dose of LMW heparin with a therapeutic INR of >1.5 - =3

*Patients with triglyceride levels >400 mg/dL can be started on lipid lowering agents and reevaluated within 1 week. If levels go to =400 mg/dL, they can be considered for the trial and continue the lipid lowering agents.

• Temsirolimus is primarily metabolized by CYP3A4. Patients cannot be receiving enzyme-inducing antiepileptic drugs (EIAEDs; e.g., phenytoin, carbamazepine, phenobarbital) nor any other CYP3A4 inducer such as rifampin or St. John's wort, as these may decrease temsirolimus levels. A partial list of agents which interact with cytochrome P450 (CYP3A) is found in Appendix AB. Use of agents that potently inhibit CYP3A (and hence may raise temsirolimus levels), such as ketoconazole, is discouraged, but not specifically prohibited. Temsirolimus can inhibit CYP2D6, and may decrease metabolism (and increase drug levels) of drugs that are substrates for CYP2D6, such as codeine. The appropriateness of use of such agents is left to physician discretion. A list of drugs that may have potential interactions with CYP2D6 is found in Appendix A. If there is any doubt about eligibility based on concomitant medication, the Principal Investigator, Dr. Andrea Wang-Gillam, should be contacted. All concomitant medications must be recorded.

• Known Allergies: Patients with known hypersensitivity reactions to macrolide antibiotics (such as erythromycin, clarithromycin, and azithromycin) are not eligible for this trial.

• Sexually Active Patients: For all sexually active patients, the use of adequate contraception (hormonal or barrier method of birth control) will be required prior to study entry and for the duration of study participation. Non-pregnant status will be determined in all women of childbearing potential. Pregnant and nursing women are not eligible.

• HIV-Positive Patients: Patients receiving anti-retroviral therapy (HAART) for HIV infection are excluded from the study because of possible pharmacokinetic interactions. Appropriate studies will be undertaken in patients receiving HAART therapy, when indicated.

• Neurologic Status: Patients must not have active CNS disease.

• Recovery from Intercurrent Illness: Patients must have recovered from uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or cardiac arrhythmia.

• Informed Consent: Patients must have signed a Washington University Human Research Protection Office (HRPO) approved informed consent. The patient should not have any serious medical or psychiatric illness that would prevent either the giving of informed consent or the receipt of treatment.

• Inclusion of Women and Minorities: Entry to this study is open to both men and women and to all racial and ethnic subgroups.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Solid Tumors

Intervention

Drug:
• Erlotinib

• Temsirolimus

Locations

Country	Name	City	State
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	Pfizer

Country where clinical trial is conducted

United States, 

References & Publications (67)

Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004 Mar 1;22(5):909-18. — View Citation

Azzariti A, Porcelli L, Gatti G, Nicolin A, Paradiso A. Synergic antiproliferative and antiangiogenic effects of EGFR and mTor inhibitors on pancreatic cancer cells. Biochem Pharmacol. 2008 Mar 1;75(5):1035-44. doi: 10.1016/j.bcp.2007.11.018. Epub 2007 Dec 3. — View Citation

Bianco R, Melisi D, Ciardiello F, Tortora G. Key cancer cell signal transduction pathways as therapeutic targets. Eur J Cancer. 2006 Feb;42(3):290-4. Epub 2006 Jan 11. Review. — View Citation

Blagosklonny MV, Darzynkiewicz Z. Four birds with one stone: RAPA as potential anticancer therapy. Cancer Biol Ther. 2002 Jul-Aug;1(4):359-61. — View Citation

Boffa DJ, Luan F, Thomas D, Yang H, Sharma VK, Lagman M, Suthanthiran M. Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer. Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):293-300. — View Citation

Brabender J, Danenberg KD, Metzger R, Schneider PM, Park J, Salonga D, Hölscher AH, Danenberg PV. Epidermal growth factor receptor and HER2-neu mRNA expression in non-small cell lung cancer Is correlated with survival. Clin Cancer Res. 2001 Jul;7(7):1850-5. — View Citation

Buck E, Eyzaguirre A, Brown E, Petti F, McCormack S, Haley JD, Iwata KK, Gibson NW, Griffin G. Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non-small-cell lung, pancreatic, colon, and breast tumors. Mol Cancer Ther. 2006 Nov;5(11):2676-84. — View Citation

Chan S, Scheulen ME, Johnston S, Mross K, Cardoso F, Dittrich C, Eiermann W, Hess D, Morant R, Semiglazov V, Borner M, Salzberg M, Ostapenko V, Illiger HJ, Behringer D, Bardy-Bouxin N, Boni J, Kong S, Cincotta M, Moore L. Phase II study of temsirolimus (CCI-779), a novel inhibitor of mTOR, in heavily pretreated patients with locally advanced or metastatic breast cancer. J Clin Oncol. 2005 Aug 10;23(23):5314-22. Epub 2005 Jun 13. — View Citation

Chang SM, Wen P, Cloughesy T, Greenberg H, Schiff D, Conrad C, Fink K, Robins HI, De Angelis L, Raizer J, Hess K, Aldape K, Lamborn KR, Kuhn J, Dancey J, Prados MD; North American Brain Tumor Consortium and the National Cancer Institute. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005 Aug;23(4):357-61. — View Citation

DeGraffenried LA, Fulcher L, Friedrichs WE, Grünwald 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 Oct;15(10):1510-6. — View Citation

Di Nicolantonio F, Arena S, Tabernero J, Grosso S, Molinari F, Macarulla T, Russo M, Cancelliere C, Zecchin D, Mazzucchelli L, Sasazuki T, Shirasawa S, Geuna M, Frattini M, Baselga J, Gallicchio M, Biffo S, Bardelli A. Deregulation of the PI3K and KRAS signaling pathways in human cancer cells determines their response to everolimus. J Clin Invest. 2010 Aug;120(8):2858-66. doi: 10.1172/JCI37539. Epub 2010 Jul 26. — View Citation

Dragovich T, McCoy S, Fenoglio-Preiser CM, Wang J, Benedetti JK, Baker AF, Hackett CB, Urba SG, Zaner KS, Blanke CD, Abbruzzese JL. Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol. 2006 Oct 20;24(30):4922-7. Erratum in: J Clin Oncol. 2007 Jun 1;25(16):2334. — View Citation

Dudkin L, Dilling MB, Cheshire PJ, Harwood FC, Hollingshead M, Arbuck SG, Travis R, Sausville EA, Houghton PJ. Biochemical correlates of mTOR inhibition by the rapamycin ester CCI-779 and tumor growth inhibition. Clin Cancer Res. 2001 Jun;7(6):1758-64. — View Citation

Elit L. CCI-779 Wyeth. Curr Opin Investig Drugs. 2002 Aug;3(8):1249-53. Review. — View Citation

Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov. 2006 Aug;5(8):671-88. — View Citation

Fox SB, Smith K, Hollyer J, Greenall M, Hastrich D, Harris AL. The epidermal growth factor receptor as a prognostic marker: results of 370 patients and review of 3009 patients. Breast Cancer Res Treat. 1994 Jan;29(1):41-9. — View Citation

Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Pharmacol Ther. 1999 May-Jun;82(2-3):207-18. Review. — View Citation

Galanis E, Buckner JC, Maurer MJ, Kreisberg JI, Ballman K, Boni J, Peralba JM, Jenkins RB, Dakhil SR, Morton RF, Jaeckle KA, Scheithauer BW, Dancey J, Hidalgo M, Walsh DJ; North Central Cancer Treatment Group. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol. 2005 Aug 10;23(23):5294-304. Epub 2005 Jul 5. — View Citation

Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 2003 Feb;4(2):75-85. Review. — View Citation

Gatzemeier U. Targeting the HER1/EGFR receptor to improve outcomes in non-small-cell lung cancer. Oncology (Williston Park). 2003 Nov;17(11 Suppl 12):7-10. Review. — View Citation

Geoerger B, Kerr K, Tang CB, Fung KM, Powell B, Sutton LN, Phillips PC, Janss AJ. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy. Cancer Res. 2001 Feb 15;61(4):1527-32. — View Citation

Giralt J, Eraso A, Armengol M, Rosselló J, Majó J, Ares C, Espin E, Benavente S, de Torres I. Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys. 2002 Dec 1;54(5):1460-5. — View Citation

Gordon AN, Finkler N, Edwards RP, Garcia AA, Crozier M, Irwin DH, Barrett E. Efficacy and safety of erlotinib HCl, an epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor, in patients with advanced ovarian carcinoma: results from a phase II multicenter study. Int J Gynecol Cancer. 2005 Sep-Oct;15(5):785-92. — View Citation

Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA; TRIBUTE Investigator Group. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005 Sep 1;23(25):5892-9. Epub 2005 Jul 25. — View Citation

Hidalgo M, Rowinsky EK. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene. 2000 Dec 27;19(56):6680-6. Review. — View Citation

Hidalgo M, Siu LL, Nemunaitis J, Rizzo J, Hammond LA, Takimoto C, Eckhardt SG, Tolcher A, Britten CD, Denis L, Ferrante K, Von Hoff DD, Silberman S, Rowinsky EK. Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol. 2001 Jul 1;19(13):3267-79. — View Citation

Hidalgo, M., Rowinsky, E, Erlichman,C, Drengler, R, Marshall, B, Marks, R, Edwards, T, Boni, J, et al., Phase I and Pharmocologic Study of CCI-779, a Cell Cycle Inhibitor. 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy., 2000.

Hidalgo, M., Rowinsky, E, Erlichman,C, et al., CCI-779, a Rapamycin Analog and Multifaceted Inhibitor of Signal Transduction: a Phase I Study. Proc Am Soc Clin Oncol, 2000. 19.

Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002 Feb;3(2):295-304. Review. — View Citation

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, McDermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007 May 31;356(22):2271-81. — View Citation

Janus A, Robak T, Smolewski P. The mammalian target of the rapamycin (mTOR) kinase pathway: its role in tumourigenesis and targeted antitumour therapy. Cell Mol Biol Lett. 2005;10(3):479-98. Review. — View Citation

Jimeno A, Kulesza P, Wheelhouse J, Chan A, Zhang X, Kincaid E, Chen R, Clark DP, Forastiere A, Hidalgo M. Dual EGFR and mTOR targeting in squamous cell carcinoma models, and development of early markers of efficacy. Br J Cancer. 2007 Mar 26;96(6):952-9. Epub 2007 Mar 6. — View Citation

Lorenz MC, Heitman J. TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin. J Biol Chem. 1995 Nov 17;270(46):27531-7. — View Citation

Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004 May 20;350(21):2129-39. Epub 2004 Apr 29. — View Citation

Mancuso A, Sternberg CN. New treatments for metastatic kidney cancer. Can J Urol. 2005 Feb;12 Suppl 1:66-70; discussion 105. Review. — View Citation

Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell. 2002 Jul;10(1):151-62. — View Citation

Margolin K, Longmate J, Baratta T, Synold T, Christensen S, Weber J, Gajewski T, Quirt I, Doroshow JH. CCI-779 in metastatic melanoma: a phase II trial of the California Cancer Consortium. Cancer. 2005 Sep 1;104(5):1045-8. — View Citation

Mendelsohn J, Baselga J. Epidermal growth factor receptor targeting in cancer. Semin Oncol. 2006 Aug;33(4):369-85. Review. — View Citation

Meyers MB, Shen WP, Spengler BA, Ciccarone V, O'Brien JP, Donner DB, Furth ME, Biedler JL. Increased epidermal growth factor receptor in multidrug-resistant human neuroblastoma cells. J Cell Biochem. 1988 Oct;38(2):87-97. — View Citation

Miller VA, Hirsch FR, Johnson DH. Systemic therapy of advanced bronchioloalveolar cell carcinoma: challenges and opportunities. J Clin Oncol. 2005 May 10;23(14):3288-93. Review. — View Citation

Neal DE, Mellon K. Epidermal growth factor receptor and bladder cancer: a review. Urol Int. 1992;48(4):365-71. Review. — View Citation

O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006 Feb 1;66(3):1500-8. — View Citation

Oldham S, Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 2003 Feb;13(2):79-85. Review. — View Citation

Oza, A., Elit, L, Biagi, J, Gotlieb, W, Tonkin, K, Tsao, MN, et al., A Phase II Study of Temsirolimus (CCI-779) in Patients with Metastatic and/or Recurrent Endometrial Cancer - NCI-CTG IND.160. Clin Cancer Res, 2005. 11(24): p. 9099s.

Pandya KJ, Dahlberg S, Hidalgo M, Cohen RB, Lee MW, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group (E1500). A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500). J Thorac Oncol. 2007 Nov;2(11):1036-41. — View Citation

Parra HS, Cavina R, Latteri F, Zucali PA, Campagnoli E, Morenghi E, Grimaldi GC, Roncalli M, Santoro A. Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. Br J Cancer. 2004 Jul 19;91(2):208-12. — View Citation

Peralba JM, DeGraffenried L, Friedrichs W, Fulcher L, Grünwald V, Weiss G, Hidalgo M. Pharmacodynamic Evaluation of CCI-779, an Inhibitor of mTOR, in Cancer Patients. Clin Cancer Res. 2003 Aug 1;9(8):2887-92. — View Citation

Perez-Soler R. The role of erlotinib (Tarceva, OSI 774) in the treatment of non-small cell lung cancer. Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4238s-4240s. Review. — View Citation

Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A, Xie D, Kelley SK. Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro Oncol. 2006 Jan;8(1):67-78. — View Citation

Raizer JJ. HER1/EGFR tyrosine kinase inhibitors for the treatment of glioblastoma multiforme. J Neurooncol. 2005 Aug;74(1):77-86. Review. — View Citation

Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol. 2004 Jun 15;22(12):2336-47. Epub 2004 May 10. — View Citation

Raymond, E., Alexandre, J, Depenbrock, H et al., CCI-779, a Rapamycin Analog with Antitumor Activity: A Phase I Study utilizing a Weekly Schedule. Proc Am Soc Clin Oncol, 2000.

Robins, H.I., Wen, P.Y, Chang, S.M, Kuhn, K, et al., Phase I study of erlotinib and CCI-779 (temsirolimus) for patients, with recurrent malignant gliomas (MG) (NABTC 04-02). J Clin Oncol, 2007. 25(18s): p. 2057.

Rowinsky EK. Targeting the molecular target of rapamycin (mTOR). Curr Opin Oncol. 2004 Nov;16(6):564-75. Review. — View Citation

Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, Abraham RT. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem. 1995 Jan 13;270(2):815-22. — View Citation

Saif MW. Erlotinib: the first biologic in the management of pancreatic cancer. Expert Opin Pharmacother. 2008 Jun;9(9):1595-607. doi: 10.1517/14656566.9.9.1595 . — View Citation

Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. Review. — View Citation

Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol. 2004 Jul 15;22(14):2954-63. Review. — View Citation

Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, Campos D, Maoleekoonpiroj S, Smylie M, Martins R, van Kooten M, Dediu M, Findlay B, Tu D, Johnston D, Bezjak A, Clark G, Santabárbara P, Seymour L; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005 Jul 14;353(2):123-32. — View Citation

Soulieres D, Senzer NN, Vokes EE, Hidalgo M, Agarwala SS, Siu LL. Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck. J Clin Oncol. 2004 Jan 1;22(1):77-85. — View Citation

Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR. Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005 Aug 15;65(16):7052-8. — View Citation

Teachey DT, Obzut DA, Cooperman J, Fang J, Carroll M, Choi JK, Houghton PJ, Brown VI, Grupp SA. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Blood. 2006 Feb 1;107(3):1149-55. Epub 2005 Sep 29. — View Citation

Vignot S, Faivre S, Aguirre D, Raymond E. mTOR-targeted therapy of cancer with rapamycin derivatives. Ann Oncol. 2005 Apr;16(4):525-37. Epub 2005 Feb 22. Review. — View Citation

Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. Epub 2005 Jun 27. — View Citation

Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy. Pharmacol Ther. 1999 May-Jun;82(2-3):241-50. Review. — View Citation

Wosikowski K, Schuurhuis D, Johnson K, Paull KD, Myers TG, Weinstein JN, Bates SE. Identification of epidermal growth factor receptor and c-erbB2 pathway inhibitors by correlation with gene expression patterns. J Natl Cancer Inst. 1997 Oct 15;89(20):1505-15. — View Citation

Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, Gibbons JJ. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer. 2001 Sep;8(3):249-58. — View Citation

* Note: There are 67 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To define the maximum tolerated dose and dose-limiting toxicities of temsirolimus in combination with erlotinib in patients with resistant solid malignancies.		3 years for MTD to be determined, DLT occurs in 1st cycle only	Yes
Primary	To determine the incidence and severity of other toxicities of temsirolimus in combination with erlotinib in patients with resistant solid malignancies.		30 days after end of treatment	Yes
Secondary	To assess the pharmacodynamic profile of temsirolimus in combination with erlotinib.		Prior to each cycle	No
Secondary	To determine any anti-tumor activity and response to the combination of temsirolimus and erlotinib in treatment of patients with resistant solid malignancies.		End of treatment	Yes
Secondary	To evaluate the relation between pS6K1 and p-Akt to clinical response to temsirolimus.		End of treatment	Yes

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine