Trial Of Bortezomib Research Articles

Bortezomib induces G2-M arrest in human colon cancer cells through ROS-inducible phosphorylation of ATM-CHK1

Colorectal cancer (CRC) is one of the most common cancers; however, the development of drugs to treat the condition has reached a plateau. Bortezomib (PS-341, Velcade®) is a proteasome inhibitor approved for the treatment of hematological malignancies, including multiple myeloma. A few trials of bortezomib, alone or in combination chemotherapy, for CRC patients have been reported; however, the results were largely inconclusive. This may be related to a lack of understanding of the drug's mechanism of action. Although bortezomib is reported to induce apoptosis and cell cycle arrest in various human cancer cells, the inhibitory mechanism involved is not clear. In this study, the effect of bortezomib as a treatment for human CRC was examined in vitro using three CRC cell lines. Bortezomib induced G2-M arrest in CRC cells. Investigation of G2-M phase-related cell cycle proteins involved in the response to bortezomib revealed that the ataxia telangiectasia mutated (ATM)-cell cycle checkpoint kinase 1 (CHK1) pathway, but not ATM and Rad3-related (ATR), was activated, resulting in the inactivation of cdc2. Bortezomib caused an increase in intracellular reactive oxygen species (ROS) and treatment with the ROS scavenger NAC inhibited phosphorylation of ATM leading to a decrease in the number of cells in G2-M phase. Thus, increased ROS levels after exposure to bortezomib resulted in ATM phosphorylation. In addition, knockdown of endogenous ATM by RNA interference resulted in decreased sensitivity to bortezomib. These results suggest that bortezomib induces G2-M arrest through ROS-inducible ATM phosphorylation and demonstrate that bortezomib is a potential candidate for further investigations in the treatment for CRC patients.

A Phase 2 Trial of Bortezomib Followed by the Addition of Doxorubicin at Progression in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck: A trial of the Eastern Cooperative Oncology Group (E1303)

A Phase 2 Trial of Bortezomib Followed by the Addition of Doxorubicin at Progression in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma of the Head and Neck: A trial of the Eastern Cooperative Oncology Group (E1303)

Bortezomib Combined with Rituximab, Fludarabine, Mitoxantrone, and Dexamethasone (R-VFND) for the Treatment of Relapsed/Refractory Follicular Lymphoma

Background: Pre-clinical data suggests that bortezomib may have a suppressive effect on B-cell lymphoma 2 (bcl- 2), an anti-apoptotic protein over expressed in follicular lymphoma; therefore, the addition of bortezomib to standard chemotherapy may improve the treatment of follicular lymphoma. We conducted this prospective, single-arm, openlabel phase II trial of bortezomib combined with rituximab, fludarabine, mitoxantrone, and dexamethasone (R-VFND) to evaluate the efficacy and safety of this regimen in patients with relapsed/refractory advanced follicular lymphoma. Methods: Twelve patients with relapsed or refractory stage III or IV follicular lymphoma were treated with bortezomib 1.6 mg/m2 day 1 and day 8 in combination with R-FND (rituximab 375 mg/m2 day 1, fludarabine 25 mg/m2 iv days 1, 2, and 3; mitoxantrone 10 mg/m2 iv day 2; and dexamethasone 20 mg/m2 p.o. days 1, 2, 3, 4, and 5). Cycles were repeated every 28 days for a maximum of 8 cycles. Cycles were held for grade 3/4cytopenias and patients were withdrawn if drug was held for more than 2 weeks. Results: Of 11 evaluable patients, 7 had a response (64%) with 4 complete responses (CR) (36%). Two patients remain in CR after 43 months: on after four cycles with no further treatment, the other after three cycles followed by allogeneic hematopoietic stem-cell transplant. Cytopenias were significant: 55% of patients had grade 3-4 neutropenia and 55% had grade 3-4 thrombocytopenia. Four patients (36%) withdrew early due to hematologic adverse events and one patient (9%) due to neuropathy. Conclusion: The addition of bortezomib to R-FND for treatment of follicular lymphoma resulted in a high response rate, but it was not clearly higher than what is expected from R-FND and the cytopenias were severe. Therefore, while bortezomib’s role in the treatment of follicular lymphoma remains to be fully defined, we find it hard to justify further trials with the fludarabine based combination and suggest future studies focus on alternative combinations.

The clinical effectiveness and cost-effectiveness of bortezomib and thalidomide in combination regimens with an alkylating agent and a corticosteroid for the first-line treatment of multiple myeloma: a systematic review and economic evaluation.

Multiple myeloma (MM) is the second most common haematological cancer in the UK. MM is not curable but can be treated with a combination of supportive measures and chemotherapy that aim to extend the duration and quality of survival. The majority of patients are not able to withstand intensive treatment, such as high-dose chemotherapy with autologous stem cell transplantation (SCT), and so they are offered single-agent or combination chemotherapy. Combination therapies typically include chemotherapy with an alkylating agent and a corticosteroid. More recently, combination therapies have incorporated drugs such as thalidomide (Thalidomide Celgene®, Celgene) and bortezomib (Velcade®, Janssen-Cilag). To assess the clinical effectiveness and cost-effectiveness of bortezomib or thalidomide in combination chemotherapy regimens with an alkylating agent and a corticosteroid for the first-line treatment of MM. Electronic bibliographic databases, including MEDLINE, EMBASE and The Cochrane Library, were searched from 1999 to 2009 for English-language articles. Bibliographies of articles, grey literature sources and manufacturers' submissions were also searched. Experts in the field were asked to identify additional published and unpublished references. Titles and abstracts were screened for eligibility by two reviewers independently. The inclusion criteria specified in the protocol were applied to the full text of retrieved papers by one reviewer and checked independently by a second reviewer. Data extraction and quality assessment were undertaken by one reviewer and checked by a second reviewer. Differences in opinion were resolved through discussion at each stage. A cost-utility decision-analytic model was used to compare the cost-effectiveness estimates of bortezomib in combination with melphalan and prednisolone/prednisone (VMP), thalidomide in combination with cyclophosphamide and attenuated dexamethasone (CTDa), and thalidomide in combination with melphalan and prednisolone/prednisone (MPT) versus melphalan and prednisolone/prednisone (MP). A total of 1436 records were screened and 40 references were retrieved for the systematic review of clinical effectiveness. Five randomised controlled trials (RCTs) met the inclusion criteria for the review: one RCT evaluated VMP, three evaluated MPT and one evaluated CTDa. The comparator in all of the included trials was MP. The review found that VMP and MPT can both be considered more clinically effective than MP for the first-line treatment of MM in people for whom high-dose therapy and SCT would not be appropriate. CTDa was more effective than MP in terms of complete response but data on survival outcomes did not meet the inclusion criteria. Cost-effectiveness analysis indicated that MPT has a greater probability of being cost-effective than either VMP or CTDa. For most RCTs, details needed to judge study quality were incompletely reported. All studies stated that the analyses followed intention-to-treat principles but none adequately reported data censoring. Only one RCT contributed data on VMP and the published peer-reviewed follow-up data were immature. For MPT, overall survival data from two trials were eligible for inclusion but the doses of thalidomide differed between the trials and the treatment period was not reflective of current UK practice so the generalisability of the findings was uncertain. Two RCTs had a maintenance phase with thalidomide that did not meet the inclusion criteria so some of these results were not eligible for the review. Limited evidence on health-related quality of life (HRQoL) was provided by the single trial of VMP versus MP. Service provision is unlikely to change greatly. As uncertainties remain, further research is needed regarding the use of bortezomib- and thalidomide-containing combination regimens. Head-to-head trials of bortezomib- and thalidomide-containing combination regimes are required, including assessments of patient HRQoL in response to treatment. The National Institute for Health Research Health Technology Assessment programme.

Therapeutic inhibition of proteasomes in systemic lupus erythematosus

When activated, B cells can differentiate either into memory B cells, or into plasma cells, which secrete the B cells antibody at high rates. Plasma cells can be short-lived or long-lived. Long-lived plasma cells are maintained mostly in the bone marrow, in privileged survival niches, which are organised by dedicated stroma cells [1]. Long-lived plasma cells constitute a discrete type of immunological memory cells, providing humoral protection to recurrent pathogens. In immune-mediated diseases, like allergy or inflammatory rheumatic diseases, however, memory plasma cells can turn detrimental, constantly providing pathogenic antibodies. In systemic lupus erythematosus (SLE), autoreactive memory plasma cells, secreting antibodies against self antigens such as DNA, are readily detectable. These cells represent a therapeutic challenge. While short-lived plasma cells, respectable their precursors and their generation, are targeted by conventional immunosuppression with drugs such as cyclophosphamide, memory plasma cells do not respond, continue to secrete antibodies, and thus sustain persistence of disease [2,3]. New therapies, targeting memory plasma cells, have to be developed, to meet this challenge. Several different therapeutic strategies have been proposed so far.One of the more promising strategies aims at the inhibition of proteasomes, since this strategy has been shown to be effective to eliminate multiple myeloma cells, i.e. transformed plasma cells. In a first study, Neubert and collegues could show in 2008 that in the NZB/W mouse model of SLE, memory plasma cells are depleted from spleen and bone marrow by the proteasome inhibitor bortezomib (Velcade) [4]. Clinically, treated mice showed reduced nephritis and prolonged survival. Consequently, the groups of ReinhardVoll and our group initiated a clinical trial of bortezomib for the treatment of patients with SLE. Those patients had not responded to other treatments earlier and showed persistent autoantibody titers, indicating the presence of autoreactive memory plasma cells. Four patients with active SLE, previously treated with cyclophosphamide, received bortezomib (Velcade®) at doses of 1.3mg/m2 on days +1, 4, 8, 11 followed by a 10 days treatment-free interval for four cycles along with 20mg dexamethasone according to the approved myeloma protocol. Under proteasome inhibition, a significant clinical improvement was achieved in all patients associated with a reduction in lupus-specific autoantibodies. In addition, protective, vaccine-specific antibodies and total immunoglobulin levels dropped significantly, suggesting a depletion of bone marrow memory plasma cells secreting these antibodies.In all patients, like in the NZB/W mice, repeated treatment was needed for sustained efficacy, indicating that autoreactive memory plasma cells are continuously generated in chronic disease. Thus, a therapeutic regimen combining B cell depletion with memory plasma cells depletion might be preferable. First experiments in NZB/W mice showed a sustained effect of combination therapies depleting plasma cell precursors as well as fully differentiated plasma cells. In conclusion proteasome inhibition in SLE has demonstrated the therapeutic relevance of autoreactive memory plasma cells as such, and it constitutes a new therapeutic option, which has to be developed with respect to sustained effectivity, minimization of side effects and reduction of risk of infection.

A Phase II Trial of Bortezomib and Vorinostat in Mantle Cell Lymphoma and Diffuse Large B-Cell Lymphoma

Abstract 779▪FN2▪This icon denotes a clinically relevant abstractNumerous preclinical studies have demonstrated synergistic interactions between proteasome and histone deacetylase (HDAC) inhibitors which interact to induce cell death in various human tumors, particularly indolent B-cell malignancies such as multiple myeloma. Furthermore, recent phase I studies have shown promising results for proteasome/HDAC inhibitor regimens in myeloma. The primary objective of this phase II study was to estimate the response rates of patients with mantle cell lymphoma (MCL), or relapsed or refractory diffuse large B-cell lymphoma (DLBCL) to the proteasome inhibitor bortezomib administered in conjunction with the pan-HDAC inhibitor vorinostat.Patients were assigned to 1 of 3 cohorts: (A) bortezomib - naïve MCL; (B) bortezomib - exposed MCL; and (C) relapsed or refractory DLBCL. The schedule of administration was vorinostat 400 mg administered orally on days 1–5 and 8–12, and bortezomib 1.3 mg/m2 administered intravenously on days 1, 4, 8, and 11; on a 21 day cycle.Fifty-one patients have been enrolled and 47 treated, 17 in cohort A, 4 in cohort B, and 26 in cohort C. Cohort B was closed due to inadequate accrual. Patient characteristics included male/female n = 33 (70%)/14 (30%), median age = 62 years [range 33–83]. ECOG performance scores ranged from 0–2. The median number of prior therapies was 2 [range 0–8].Common treatment-related adverse events included fatigue, dizziness, leukopenia, neutropenia, lymphopenia, peripheral sensory neuropathy, nausea, vomiting, anorexia, elevated creatinine, thrombocytopenia, diarrhea, and chills. Common grade 3 and 4 toxicities (CTCAE v4) included anemia, diarrhea, fatigue, thrombocytopenia, lymphopenia, dehydration, hyponatremia, and hypotension. Two deaths have occurred: 1 associated with neutropenic sepsis and felt possibly related to study treatment, and 1 due to disease progression after discontinuation of study treatment.Patients were accrued according to a 2-stage Simon minimax design. Investigator-reported responses (CR + PR) have been achieved in cohort A (8 out of 17, 47%) and cohort C (3 out of 26, 12%). Both of these response rates met the thresholds to proceed from the 1st to the 2nd stage of enrollment.CohortTotalABCResponseComplete Response (CR)2–13Partial Response (PR)6–28Stable Disease (SD)32510Progressive Disease (PD)521522Too Early To Evaluate1––1Not Assessed––33Total1742647Correlative studies are ongoing and are designed to determine whether the combination of bortezomib and vorinostat is more active in lymphomas in which baseline activation of NF-kappa B can be detected. Sample analysis and results are pending.These findings indicate that combined treatment with vorinostat and bortezomib is active in patients with MCL, or relapsed or refractory DLBCL, particularly for MCL where the 47% response rate greatly exceeds the 29% (8 of 28) needed to proceed to stage 2. Disclosures:Sokol:Medimmune: Honoraria; Celgene: Consultancy, Speakers Bureau; Eisai: Consultancy, Speakers Bureau; Allos: Consultancy. Richards:Celgene: Research Funding; Merck: Consultancy; Millennium: Consultancy.

Bone effects of cancer therapies

Agents used for systemic chemotherapy can alter normal bone homeostasis through mechanisms that affect both osteoblast and osteoclast function. The identification of those agents that influence maintenance of the bone-remodeling compartment is an important component of the drug development and testing process. This brief review focuses on preclinical and clinical data illustrating the effect of several classes of chemotherapeutic agents on skeletal development and bone remodeling. New preclinical data demonstrate that several classes of chemotherapeutic agents, including histone deacetylase inhibitors and proteasome inhibitors, alter osteoblast and osteoclast function. Preclinical data on retinoic acid analogues demonstrate that these agents inhibit osteoclastogenesis. In addition, a dose-dependent effect of methotrexate treatment on growth plate thickness and primary spongiosa height in rats has been demonstrated. Two recently published analyses of clinical data from trials of bortezomib in myeloma patients found increased biochemical markers of bone formation and evidence of increased bone deposition after bortezomib treatment. Several classes of chemotherapeutic agents alter bone metabolism and negatively impact bone homeostasis. Bone mineral density (BMD) monitoring guidelines for patients receiving systemic chemotherapy are not established. Limited guidelines exist for BMD monitoring in patients receiving long-term hormonal modulation; however, the negative effect of other chemotherapeutic agents on the skeleton is underappreciated.

An Integrated In Vitro and In Vivo High-Throughput Screen Identifies Treatment Leads for Ependymoma

Using a mouse model of ependymoma-a chemoresistant brain tumor-we combined multicell high-throughput screening (HTS), kinome-wide binding assays, and invivo efficacy studies, to identify potential treatments with predicted toxicity against neural stem cells (NSC). We identified kinases within the insulin signaling pathway and centrosome cycle as regulators of ependymoma cell proliferation, and their corresponding inhibitors as potential therapies. FDA approved drugs not currently used to treat ependymoma were also identified that posses selective toxicity against ependymoma cells relative to normal NSCs both invitro and invivo, e.g., 5-fluorouracil. Our comprehensive approach advances understanding of the biology and treatment of ependymoma including the discovery of several treatment leads for immediate clinical translation.

Phase II clinical trial of bortezomib and bevacizumab combination in recurrent glioblastoma.

2056 Background: The only approved 2nd-line treatment for glioblastoma is Bevacizumab (Avastin), with estimated 6-month progression-free survival (PFS) rate of 42.6% and overall survival (OS) of 9.2 months. Laboratory data show Bortezomib (Velcade) is an effective agent in glioma models. We evaluated the combination of Avastin and Velcade in patients with recurrent GBM in a phase II, 2 center, open-label trial. Methods: Eligible patients were over 18 years of age, with WHO grade 4 glioma, Karnofsky score 70%. Bevacizumab was given 15 mg/kg IV every 3 weeks, and Bortezomib was given on days 1, 4, 8, 11, 22, 25, 29, and 32 of a 42 day cycle, at 1.7 mg/m2 for patients on non-enzyme-inducing antiepileptic drugs (EIAED) and 2.5 mg/m2 for patients on EIAED. Primary end points were 6-month PFS; secondary endpoints were toxicity, PFS, OS and radiographic response. Results: There were a total of 61 patients enrolled, 32 patients on non-EIAEDs, and 29 patients on EIADs. Median age was 55.2. Six-month PFS was 40.6% for patients on non-EIAEDs, and 24.1% for patients on EIAEDs (p=0.17). Eleven patients are still alive; median OS was 9.1 months, with 8.8 months for non-EIAED patients, and 9.6 months for EIAED patients (p = 0.9). Of the patients on non-EIAEDs, best radiographic response included 11 patients (34.4%) with partial response, 13 with stable disease (40.6%), and 8 with progressive disease. Of patients on EIAEDs, 3 patients (10.3%) had a partial response, 18 (62.1%) with stable disease, and 6 with progression. On comparison of partial response rates between the 2 groups, p=0.03 was obtained. Most frequent grade 3 non-hematologic toxicities included fatigue (15.9%), sensory neuropathy (10.2%), diarrhea (9%), and thrombosis (8%). There were 2 episodes of grade 4 hyponatremia and 1 episode of epistaxis from a nasal septal ulcer. 14 patients eventually had to be taken off of Velcade and continued Avastin alone, due to sensory neuropathy. Conclusions: Bevacizumab and Bortezomib appear to be an effective treatment for recurrent malignant gliomas with a moderate toxicity profile. However, this phase II clinical study suggests that the combination is not superior to single-agent Bevacizumab and that the response may be blunted in the presence of EIAEDs.

Low Venous Thromboembolic Risk With Bortezomib in Multiple Myeloma and Potential Protective Effect With Thalidomide/Lenalidomide-based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens

Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE risk in MM is increased by various patient- and disease-related factors. The type of anti-MM therapy represents a key factor, with a substantially elevated VTE risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide or lenalidomide in combination with dexamethasone and/or chemotherapy; VTE risk with lenalidomide-dexamethasone is further increased with concomitant erythropoietin. By contrast, treatment with the proteasome inhibitor bortezomib, alone or in combination, does not increase VTE risk; rates of DVT/PE do not appear affected by the use of erythropoiesis-stimulating agents. Bortezomib has shown antihemostatic effects in patients with relapsed or refractory MM, which supports that it exerts antithrombotic actions and thus potentially provides a protective effect in combination with regimens with an elevated VTE risk. Herein, we review data from phase 3 trials of bortezomib- and/or IMiD-based therapy in frontline MM, together with other studies of novel combination regimens. Despite the confounding effect of variable VTE prophylaxis, bortezomib-based regimens were typically associated with DVT/PE rates of ≤5%, similar to those seen with melphalan-prednisone and dexamethasone, whereas IMiD-based bortezomib-free regimens were generally associated with higher rates. Direct comparisons of regimens of thrombogenic potential with or without bortezomib demonstrated lower VTE risk with bortezomib. Between-study comparisons of VTE risk support these findings. Taken together, these data confirm the low VTE risk associated with bortezomib and support a potential protective effect of bortezomib in combination with IMiD-based regimens associated with elevated VTE risk.

Fewer bone disease events, improvement in bone remodeling, and evidence of bone healing with bortezomib plus melphalan–prednisone vs. melphalan–prednisone in the phase III VISTA trial in multiple myeloma

Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment. Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338). Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease. These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck

Bortezomib, an inhibitor of the 26S proteasome and NF-κB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin. Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and ejection fraction within normal limits. Patients with stable disease for ≥9 months were excluded. Patients received bortezomib 1.3 mg/m(2) by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m(2) IV on Days 1 and 8 was added at the time of progression. Twenty-five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single-agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression-free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3-4 neutropenia (n = 3) and grade 3 anorexia (n = 2). Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC.

Phase 1 trial of bortezomib plus R‐CHOP in previously untreated patients with aggressive non‐Hodgkin lymphoma

Bortezomib has preclinical and clinical in B-cell lymphomas, both alone and in combination with other agents. A phase 1 evaluation was conducted of bortezomib with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or mantle cell lymphoma (MCL). Twenty patients (16 with DLBCL and 4 with MCL) with a median age of 66 years (range, 29-84 years) were enrolled. Eleven subjects (55%) had an elevated lactate dehydrogenase level, and 10 patients (50%) had International Prognostic Index scores of 3 to 5. Standard R-CHOP was administered on a 21-day cycle for 6 cycles, with 1 of 3 dose levels of bortezomib (0.7 mg/m2 [n=4 patients], 1.0 mg/m2 [n=9 patients], or 1.3 mg/m2 [n=7 patients]) administered on Days 1 and 4 of each cycle. The maximum tolerated dose of bortezomib with R-CHOP was not reached, and the 1.3-mg/m2 dose level had acceptable tolerability. A dose-limiting toxicity (pulmonary) was only observed in 1 patient receiving 1.0 mg/m2 of bortezomib. Neuropathy occurred in 13 patients (65%), but was mostly grade 1 (45%) and reached grade 3 in only 1 patient (all toxicities were graded using the Common Terminology Criteria for Adverse Events, version 3.0). Grade 4 hematologic toxicity occurred in 7 patients (35%). Of 19 evaluable patients, all responded, with 18 (95%) cases of complete response/complete response unconfirmed achieved and 1 (5%) partial response reported. At a median follow-up of 56 months, overall survival at 4 years was 75% and progression-free survival was 58%. Bortezomib at a dose of 1.3 mg/m2 twice per cycle can be added to R-CHOP chemotherapy with acceptable toxicity. Multi-institutional and cooperative group follow-up studies of this regimen are currently ongoing.

A phase II open-label trial of bortezomib in patients with multiple myeloma who have undergone an autologous peripheral blood stem cell transplant and failed to achieve a complete response

A majority of multiple myeloma (MM) patients fail to achieve complete response (CR) to peripheral blood stem cell transplantation (PBSCT); effective options following autologous transplantation are needed. Bortezomib (B) is active against MM. This study was conducted to determine the feasibility, safety, tolerability, and efficacy of B following high-dose melphalan therapy and PBSCT. Methods Fifty patients enrolled (48 evaluable) and 49 were treated (safety population). 4 cycles B 1.3 mg/m(2) Days 1, 4, 8, and 11/21-days; 4 additional cycles were permitted for stable or responding patients. Results Median age was 55 years (range, 38-73), 68% male, 64% ECOG PS = 0, 44% Durie-Salmon Stage IIIA prior to induction, 42% had symptomatic IgG MM; 74% had prior single transplant (26% tandem). Responses post-transplant: 70% PRs, 18% MRs. A median of 4 cycles (range, 2-8) of B were administered. Responses: CR 8%, uCR 2%, PR 23%, uPR 19%, MR 10%, and no change 35%; median time-to-treatment failure (TTF) was 6.2 months (range, 1.0-19.4). Three deaths occurred (n = 1 sepsis, n = 2 disease progression). Grade 3-4 treatment-related toxicities included: thrombocytopenia, neuropathy (14%, each); asthenia, neutropenia (10%, each); and nausea (4%). Twelve patients (24%) discontinued treatment due to toxicity and 30 patients (60%) completed the study; 20 patients started new treatment (median 5.8 months [range, 1.5-20.3]). The study closed early due to widespread availability of B, and the lack of B-naïve patients. Bortezomib monotherapy after melphalan and autologous PBSCT was feasible, safe and well-tolerated (toxicities were manageable), but failed to produce the hypothesized response rates.

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma

Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

Phase I trial of bortezomib in combination with rituximab‐HyperCVAD alternating with rituximab, methotrexate and cytarabine for untreated aggressive mantle cell lymphoma

Mantle cell lymphoma (MCL) outcomes have improved over the last two decades; however, late relapses occur. Bortezomib has shown single agent activity of 33% in relapsed MCL and has an additive/synergistic effect in vitro when combined with drugs currently used to treat MCL. We hypothesized that a combination of bortezomib with current intense non-transplant chemoimmunotherapy might prevent late relapses. The toxicity of bortezomib when combined with methotrexate and cytarabine is unknown. Patients aged 18-79 years with untreated aggressive MCL were treated with R-HyperCVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with rituximab-methotrexate/cytarabine (R-M/A). Bortezomib was added to the R-Hyper-CVAD combination as a fixed dose of 1·3 mg/m(2) IV on days 2 and 5 and was added to the R-M/A regimen after rituximab, in increasing doses of 0·7, 1, and 1·3 mg/m(2) in cohorts of three patients. Twenty patients were assessed for toxicity of the regimen. The principal toxicity was haematological and did not differ from that observed with a similar regimen without the bortezomib. In particular, there was no pulmonary or neurological dose-limiting toxicity, showing that bortezomib can be safely combined with R-HyperCVAD and R-M/A.

A multicenter, phase II study of Bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma

The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma. We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1. We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0-22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB. Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.

Mature results of a phase I trial of bortezomib, cisplatin, and radiotherapy for advanced or recurrent head and neck cancer.

5560 Background: Proteasome inhibitor bortezomib (VELCADE) has radiosensitzing properties and preclinical activity against head and neck cancer (HNC). A phase I trial of bortezomib, cisplatin, and radiotherapy (XRT) for advanced or recurrent HNC was conducted. Methods: Eligible patients had locoregionally advanced or recurrent HNC, with disease states for which no standard chemo-XRT regimen exists (e.g. reirradiation or salivary gland cancer). Patients had performance status 0 or 1, good hematologic and renal reserve, and no pre-existing grade >2 peripheral neuropathy. XRT was given once daily for at least 2 weeks. Cisplatin was given once weekly at 30 mg/m2/wk. Bortezomib was given on days 1, 4, 8, and 11 of a 21-day cycle, starting day 1 of XRT. The initial starting dose of bortezomib was 0.7 mg/m2, with planned escalation levels of 1.0 mg/m2 and 1.3 mg/m2. Dose escalation was performed after patients at the previous dose level were assessed > 30 days to rule out any dose limiting toxicity (DLTs), defined as grade 4-5 toxicity or grade 3 toxicity attributable to bortezomib that required hospitalization. Results: 27 patients with previously untreated local-regionally advanced (10 patients) or recurrent/previously irradiated (17 patients) HNC were enrolled. All patients completed XRT as planned (median 60.8 Gy); the median number of doses of bortezomib received was 7. There were no grade 5 toxicities. There were no DLTs in 7 patients enrolled in dose level I (0.7 mg/m2), and one DLT of grade 4 neutropenia in 10 patients enrolled in dose level II (1.0 mg/m2; re-irradiation). In dose level III (1.3 mg/m2), 2 DLT's occurred in 10 patients (asymptomatic grade 4 thrombocytopenia, both re-irradiation). grade 3 toxicities were common at all dose levels (17 of 27 evaluable patients), with most attributable to XRT/cisplatin (e.g. mucositis) and not considered DLTs. There was no clinically significant peripheral neuropathy (grade >2). At a median 7.3 month follow-up, 8 patients (30%) are without progression. Conclusions: Bortezomib in combination with XRT and weekly cisplatin is feasible and active. MTD was reached at 1.3 mg/m2 for radiation-naive patients and 1.0 mg/m2for re-irradiation patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium

Nuclear factor-kappa B pathway and response in a phase II trial of bortezomib and docetaxel in patients with recurrent and/or metastatic head and neck squamous cell carcinoma

BackgroundOur previous study has shown that nuclear factor-kappa B (NF-κB)-signaling pathway was associated with a higher rate of recurrence in head and neck squamous cell carcinoma (HNSCC). The combination of bortezomib, an NF-κB inhibitor by inhibition of proteasomes, plus docetaxel was assessed for efficacy and toxicity. Materials and methodsPatients with recurrent and/or metastatic HNSCC were enrolled on a phase II bortezomib/docetaxel trial (bortezomib 1.6 mg/m2 and docetaxel 40 mg/m2 on days 1 and 8 of a 21-day cycle). Response was assessed using RECIST. Tissue specimens were evaluated for the presence of human papillomavirus (HPV) and expression of NF-κB-associated genes. ResultsTwenty-one of 25 enrolled patients were assessable for response; one partial response (PR, 5%), 10 stable disease (SD, 48%) and 10 progressive disease (PD, 48%). Patients with PR/SD had significantly longer survival compared with patients with PD and the regimen was well tolerated. Only one of 20 tumors was positive for HPV. Patients with PD had higher expression of NF-κB and epidermal growth factor receptor-associated genes in their tumors by gene expression analysis. ConclusionFurther understanding of treatment resistance and interactions between bortezomib and docetaxel may provide novel approaches in managing HNSCC.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients With Advanced Solid Malignancies

To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy. An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0 mg/m(2), 1.3 mg/m(2), and 1.6 mg/m(2)/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks. A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6 mg/m(2). One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients). The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6 mg/m(2) is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6 mg/m(2).