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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 1/2008

01-12-2008 | Original Article

A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors

Authors: E. Claire Dees, Bert H. O’Neil, Celeste M. Lindley, Frances Collichio, Lisa A. Carey, Jason Collins, William J. Riordan, Anastasia Ivanova, Dixie Esseltine, Robert Z. Orlowski

Published in: Cancer Chemotherapy and Pharmacology | Issue 1/2008

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Abstract

Purpose

Pre-clinical studies combining the proteasome inhibitor bortezomib with anthracyclines have shown enhanced anti-tumor activity. We conducted a phase I trial of bortezomib and pegylated liposomal doxorubicin (PLD) in patients with refractory solid tumors.

Methods

Patients received bortezomib, 0.9–1.5 mg/m2, on days 1, 4, 8, and 11 of every 21-day cycle, along with PLD, 30 mg/m2, on day 4. The goals were to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD), and to investigate pharmacokinetic and pharmacodynamic interactions of the combination.

Results

A total of 37 patients with four median prior therapies were treated. Frequent grade 1–2 toxicities included fatigue, nausea, thrombocytopenia, anemia, neutropenia, constipation, myalgias, and peripheral neuropathy. DLTs included grade 3 nausea and vomiting in 1 of 6 patients receiving bortezomib at 1.2 mg/m2, and grade 3 nausea, vomiting, and diarrhea in 1 of 6 patients receiving bortezomib at 1.5 mg/m2. Grade 3 toxicities in later cycles included hand-foot syndrome, thrombocytopenia, anemia, neutropenia, nausea, diarrhea, and abdominal pain. Because of frequent dose-delays, dose-reductions, and gastrointestinal toxicity at the 1.4 and 1.5 mg/m2 levels, bortezomib at 1.3 mg/m2 and PLD at 30 mg/m2 are recommended for further testing. Among 19 patients with breast cancer, four had evidence of a clinical benefit. Pharmacokinetic and pharmacodynamic studies did not show any significant interactions between the two drugs.

Conclusions

A regimen of bortezomib, 1.3 mg/m2 on days 1, 4, 8, and 11 with PLD, 30 mg/m2, on day 4 of a 21-day cycle, was safe in this study, and merits further investigation.
Literature
1.
Adams J, Palombella VJ, Sausville EA, Johnson J, Destree A, Lazarus DD et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–2622PubMed
2.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–2498PubMedCrossRef
3.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–2617PubMedCrossRef
4.
O’Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M et al (2005) Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol 23(4):676–684PubMedCrossRef
5.
Goy A, Younes A, McLaughlin P, Pro B, Romaguera JE, Hagemeister F et al (2005) Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23(4):667–675PubMedCrossRef
6.
Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S et al (2006) Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 24(30):4867–4874PubMedCrossRef
7.
Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X et al (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22(11):2108–2121PubMedCrossRef
8.
Fanucchi MP, Fossella FV, Belt R, Natale R, Fidias P, Carbone DP et al (2006) Randomized phase II study of bortezomib alone and bortezomib in combination with docetaxel in previously treated advanced non-small-cell lung cancer. J Clin Oncol 24(31):5025–5033PubMedCrossRef
9.
Kondagunta GV, Drucker B, Schwartz L, Bacik J, Marion S, Russo P et al (2004) Phase II trial of bortezomib for patients with advanced renal cell carcinoma. J Clin Oncol 22(18):3720–3725PubMedCrossRef
10.
Aghajanian C, Soignet S, Dizon DS, Pien CS, Adams J, Elliott PJ et al (2002) A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8(8):2505–2511PubMed
11.
Dy GK, Thomas JP, Wilding G, Bruzek L, Mandrekar S, Erlichman C et al (2005) A phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (bortezomib, velcade), in patients with advanced cancer. Clin Cancer Res 11(9):3410–3416PubMedCrossRef
12.
Voorhees PM, Orlowski RZ (2006) The proteasome and proteasome inhibitors in cancer therapy. Annu Rev Pharmacol Toxicol 46:189–213PubMedCrossRef
13.
Rajkumar SV, Richardson PG, Hideshima T, Anderson KC (2005) Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23(3):630–639PubMedCrossRef
14.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P et al (2003) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101(4):1530–1534PubMedCrossRef
15.
Ranson MR, Carmichael J, O’Byrne K, Stewart S, Smith D, Howell A (1997) Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol 15(10):3185–3191PubMed
16.
Rivera E, Valero V, Esteva FJ, Syrewicz L, Cristofanilli M, Rahman Z et al (2002) Lack of activity of stealth liposomal doxorubicin in the treatment of patients with anthracycline-resistant breast cancer. Cancer Chemother Pharmacol 49(4):299–302PubMedCrossRef
17.
Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M et al (2000) Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89(5):1037–1047PubMedCrossRef
18.
Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D et al (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101(6):2377–2380PubMedCrossRef
19.
Small GW, Shi YY, Edmund NA, Somasundaram S, Moore DT, Orlowski RZ (2004) Evidence that mitogen-activated protein kinase phosphatase-1 induction by proteasome inhibitors plays an antiapoptotic role. Mol Pharmacol 66(6):1478–1490PubMedCrossRef
20.
Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Kudrik FJ, Allred T et al (2005) Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood 105(8):3058–3065PubMedCrossRef
21.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216PubMedCrossRef
22.
Lightcap ES, McCormack TA, Pien CS, Chau V, Adams J, Elliott PJ (2000) Proteasome inhibition measurements: clinical application. Clin Chem 46(5):673–683PubMed
23.
Gabizon A, Chisin R, Amselem S, Druckmann S, Cohen R, Goren D et al (1991) Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin. Br J Cancer 64(6):1125–1132PubMed
24.
Gabizon A, Catane R, Uziely B, Kaufman B, Safra T, Cohen R et al (1994) Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 54(4):987–992PubMed
25.
Caravita T, de Fabritiis P, Palumbo A, Amadori S, Boccadoro M (2006) Bortezomib: efficacy comparisons in solid tumors and hematologic malignancies. Nat Clin Pract Oncol 3(7):374–387PubMedCrossRef
26.
Richardson PG, Briemberg H, Jagannath S, Wen PY, Barlogie B, Berenson J et al (2006) Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24(19):3113–3120PubMedCrossRef
27.
Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A et al (2007) Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol 25(25):3892–3901PubMedCrossRef
28.
Yang CH, Gonzalez-Angulo AM, Reuben JM, Booser DJ, Pusztai L, Krishnamurthy S et al (2006) Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Ann Oncol 17(5):813–817PubMedCrossRef
29.
Cardoso F, Ross JS, Picart MJ, Sotiriou C, Durbecq V (2004) Targeting the ubiquitin-proteasome pathway in breast cancer. Clin Breast Cancer 5(2):148–157PubMedCrossRef
30.
Messersmith WA, Baker SD, Lassiter L, Sullivan RA, Dinh K, Almuete VI et al (2006) Phase I trial of bortezomib in combination with docetaxel in patients with advanced solid tumors. Clin Cancer Res 12(4):1270–1275PubMedCrossRef
31.
Ma C, Mandrekar SJ, Alberts SR, Croghan GA, Jatoi A, Reid JM et al (2007) A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies. Cancer Chemother Pharmacol 59(2):207–215PubMedCrossRef
32.
Adjei AA (2005) Sequencing bortezomib with chemotherapy and targeted agents. Clin Lung Cancer 7(Suppl 2):S56–S58PubMedCrossRef
Metadata
Title
A phase I and pharmacologic study of the combination of bortezomib and pegylated liposomal doxorubicin in patients with refractory solid tumors
Authors
E. Claire Dees
Bert H. O’Neil
Celeste M. Lindley
Frances Collichio
Lisa A. Carey
Jason Collins
William J. Riordan
Anastasia Ivanova
Dixie Esseltine
Robert Z. Orlowski
Publication date
01-12-2008
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 1/2008
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-008-0716-8

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