Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies

Orłowski, Robert Z.; Stinchcombe, Thomas E.; Mitchell, Beverly S.; Shea, Thomas C.; Baldwin, Albert S.; Stahl, Stephanie; Adams, Julian; Esseltine, Dixie Lee; Elliott, Peter J.; Pien, Christine; Guerciolini, Roberto; Anderson, Jessica; Depcik‐Smith, Natalie D.; Bhagat, Rita; Lehman, Mary Jo; Novick, Steven; O’Connor, Owen A.; Soignet, Steven L.

doi:10.1200/jco.2002.01.133

Cited by 699 publications

(460 citation statements)

References 18 publications

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“…Inhibition levels were also equivalent in patients with MM receiving 20 mg/m 2 carfilzomib as a 2‐ to 10‐min or 30‐min infusion, which is consistent with results reported in animals (Yang et al , 2011). It is noteworthy that the overall level of CT‐L inhibition seen with carfilzomib is higher than the 65–70% inhibition rate reported in bortezomib‐treated patients (Orlowski et al , 2002; Papandreou et al , 2004; Moreau et al , 2008). Using ProCISE, we also demonstrated that the administration of carfilzomib inhibits proteasome subunit occupancy in bone marrow–derived tumour cells.…”

Section: Discussionmentioning

confidence: 79%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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SummaryWhile proteasome inhibition is a validated therapeutic approach for multiple myeloma (MM), inhibition of individual constitutive proteasome (c20S) and immunoproteasome (i20S) subunits has not been fully explored owing to a lack of effective tools. We utilized the novel proteasome constitutive/immunoproteasome subunit enzyme‐linked immunosorbent (ProCISE) assay to quantify proteasome subunit occupancy in samples from five phase I/II and II trials before and after treatment with the proteasome inhibitor carfilzomib. Following the first carfilzomib dose (15–56 mg/m2), dose‐dependent inhibition of c20S and i20S chymotrypsin‐like active sites was observed [whole blood: ≥67%; peripheral blood mononuclear cells (PBMCs): ≥75%]. A similar inhibition profile was observed in bone marrow–derived CD138+ tumour cells. Carfilzomib‐induced proteasome inhibition was durable, with minimal recovery in PBMCs after 24 h but near‐complete recovery between cycles. Importantly, the ProCISE assay can be used to quantify occupancy of individual c20S and i20S subunits. We observed a relationship between MM patient response (n = 29), carfilzomib dose and occupancy of multiple i20S subunits, where greater occupancy was associated with an increased likelihood of achieving a clinical response at higher doses. ProCISE represents a new tool for measuring proteasome inhibitor activity in clinical trials and relating drug action to patient outcomes.

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Section: Discussionmentioning

confidence: 79%

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

et al. 2016

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“…Another example of this type of approach may prove to be the use of the proteasome inhibitor bortezomib (VELCADE ® ), or a bortezomib-based regimen, in patients with deletions of chromosome 13. Originally, this agent was found to have activity against relapsed/refractory multiple myeloma in the phase I-III settings [18][19][20] and, interestingly, subset analysis of the phase II study 19 showed that patients with deletion (del) of 13 had the same response rate as controls. When results of the phase III trial 20 were analyzed in this regard, it was found that patients with del 13 who received dexamethasone had an inferior survival compared with matched controls, as would be expected.…”

Section: Risk Stratificationmentioning

confidence: 99%

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

Orłowski¹

2006

Hematology

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Multiple myeloma patients deemed to not be candidates for high-dose therapy followed by stem cell rescue who nonetheless need chemotherapy have traditionally received an oral regimen combining melphalan and prednisone. With the advent of novel agents, however, such as immunomodulatory drugs and proteasome inhibitors that are active in the relapsed/refractory setting, there has been an impetus to incorporate these new options into front-line therapy. Several phase II studies have recently revealed that addition of either thalidomide, lenalidomide, or bortezomib to melphalan and prednisone increased the overall and complete response rates, albeit at the cost of some increased toxicity. Randomized phase III studies of melphalan and prednisone with thalidomide have already shown that, compared to melphalan and prednisone alone, the three-drug regimen prolonged time to progression and overall survival in this population, thereby defining a new standard of care. Moreover, our increasing knowledge of the molecular role that cytogenetic abnormalities play in the biology of multiple myeloma and our growing chemotherapeutic armamentarium are beginning to allow us to rationally select therapies based on these characteristics of each patient's disease. Such a risk-and molecular-adapted strategy to the therapy of multiple myeloma promises to revolutionize and personalize our care of these patients and bring us closer to a cure for this disease.Using the diagnostic criteria recommended by the International Working Group, patients with multiple myeloma are classified as having either asymptomatic or symptomatic (Table 1) disease. 1 The latter population, generally considered candidates for a chemotherapy-based intervention, are then further divided into those who either are or are not eligible for high-dose chemotherapy followed by stem cell rescue. 2 Criteria that are weighed to help make this second distinction have generally included age, performance status, and co-morbid medical conditions. 2 There is some variability in these parameters and how they are applied, since studies examining stem cell transplantation have used different criteria. In regard to age, for example, which is the most objective of these measures, initial studies tended to enroll patients younger than 65 years of age, 3 while more recent studies suggest that transplant is safe in at least some who are over the age of 70 (for example 4,5 ). On the other hand, data suggesting that patients with poor-risk chromosomal features have a short time to progression after autologous transplantation have led to suggestions that even younger patients with these abnormalities may not be candidates for standard approaches. Nonetheless, as little as two years ago, there was general agreement that the standard of care for patients who were not eligible for transplantation and yet needed chemotherapy was melphalan

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“…Following encouraging preliminary phase I clinical trial results [5], 202 patients (193 evaluable for response) with relapsed or refractory MM were treated in the pivotal phase II SUMMIT trial [6] with bortezomib (1.3 mg/m 2 i.v.) on days 1, 4, 8, and 11 of a 21-day cycle for a maximum of eight cycles.…”

Section: Efficacy and Safety Of Bortezomibmentioning

confidence: 99%

A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma

et al. 2006

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Learning ObjectivesAfter completing this course, the reader will be able to:1. Discuss clinical trial data for treatment with bortezomib monotherapy and bortezomib-based combination therapy in patients with multiple myeloma who have received at least one prior therapy.2. Discuss the management of the most common adverse events associated with bortezomib, including peripheral neuropathy and thrombocytopenia.3. Describe prognostic factors in patients with multiple myeloma who have received at least one prior therapy. Access and take the CME test online and receive 1 AMA PRA category 1 credit at CME.TheOncologist.com CME CME This material is protected by U.S.

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Phase I Trial of the Proteasome Inhibitor PS-341 in Patients With Refractory Hematologic Malignancies

Cited by 699 publications

References 18 publications

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Clinical activity of carfilzomib correlates with inhibition of multiple proteasome subunits: application of a novel pharmacodynamic assay

Initial Therapy of Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation

A Practical Update on the Use of Bortezomib in the Management of Multiple Myeloma

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