Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)

Blaney, Susan M.; Bernstein, Mark L.; Neville, Kathleen; Ginsberg, Jill P.; Kitchen, Brenda J.; Horton, Terzah M.; Berg, Stacey L.; Krailo, Mark; Adamson, Peter C.

doi:10.1200/jco.2004.12.185

Cited by 108 publications

(71 citation statements)

References 12 publications

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“…The role of bortezomib in the treatment of various pediatric solid malignancies has also been investigated by Blaney et al [87] . Thrombocytopenia was the only dose-limiting toxicity but no objective responses were found.…”

Section: Phase I Clinical Trialsmentioning

confidence: 99%

“…Thrombocytopenia was the dose-limiting toxicity and the maximum tolerated dose regimen was determined to be 1.0 mg/m 2 for bortezomib and 1000 mg/m 2 for gemcitabine. (2004) [87] Refractory solid tumors (pediatrics) [99] Advanced NSCLC In the study of Albanell et al [84] , bortezomib was administered with docetaxel to anthracycline-treated patients who had advanced breast carcinoma. The maximum tolerated dose had not been reached; however, dose-limiting toxicities of febrile neutropenia and neuropathy occurred in 14% of patients.…”

Section: Phase I Clinical Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

Russo

Fratto

Bazan

et al. 2007

Expert Opinion on Therapeutic Targets

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Section: Phase I Clinical Trialsmentioning

confidence: 99%

Section: Phase I Clinical Trialsmentioning

confidence: 99%

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

Russo

Fratto

Bazan

et al. 2007

Expert Opinion on Therapeutic Targets

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“…In this setting, bortezomib (Velcade) was demonstrated to be effective in the treatment of multiple myeloma and non-Hodgkin's lymphoma, when taken alone or in combination with traditional anticancer drugs [3][4][5][6][7]. Similarly, preliminary studies indicated that proteasome inhibitors induce clinical responses in patients with acute leukemia, prostate cancer, renal cell carcinoma, neuroendocrine tumors, and in children solid tumors [8][9][10][11][12]. How proteasome inhibition translates into a potent cytotoxic effect in tumor cells is not fully understood, even though inhibition of NF-jB and deregulated expression of p53, caspases, Bcl-2 family members, CDC25 family proteins and cyclins were all proposed to be relevant in this context [1,2].…”

Section: Introductionmentioning

confidence: 99%

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

et al. 2006

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Proteasome inhibitors possess potent antitumor activity against a broad spectrum of human malignancies. However, the effects of these compounds on the immune system still have to be clearly determined. In the present study, we have investigated the effects of proteasome inhibitors on dendritic cells (DC), antigen‐presenting cells playing a key role in the initiation of immune responses. Exposure to the proteasome inhibitors bortezomib, MG132 or epoxomicin was found to promote apoptosis of human monocyte‐derived DC and to reduce the yield of viable DC when given to monocytes early during differentiation to DC. DC apoptosis via proteasome inhibition was accompanied by mitochondria disruption and subsequent activation of the caspase cascade. Up‐regulation and intracellular redistribution of Bcl‐2‐associated X protein (Bax), a pro‐apoptotic Bcl‐2 family protein, were observed in DC treated with these compounds and represent a suitable mechanism leading to activation of the intrinsic apoptotic pathway. Finally, active protein synthesis was found to represent an upstream prerequisite for DC apoptosis induced by proteasome inhibitors, since the translation inhibitor cycloheximide blocked all of the steps of the observed apoptotic response. In conclusion, induction of apoptosis in DC may represent a novel mechanism by which proteasome inhibitors affect the immune response at the antigen‐presenting cell level.

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“…22 This has been exploited in the therapy of malignancies in which tumor cells have been shown to have preferential sensitivity to the proapoptotic effects of proteasome inhibition. [23][24][25][26][27] Studies in murine tumor models 28,29 and small clinical studies 30,31 have shown activity against a spectrum of malignancies. In addition, bortezomib has recently been approved for the treatment of patients with relapsed multiple myeloma in whom response rates of 40% have been observed after the failure of high-dose therapy followed by stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

NF-κB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145

Vodanovic-Jankovic

Hari

Jacobs

et al. 2006

Blood

104

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NF-B is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-B, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-B, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-B in the pathophysiology of GVHD and indicate that targeted inhibition of NF-B may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity. (Blood. 2006;107:827-834)

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Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)

Abstract: Bortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.

Cited by 108 publications

References 12 publications

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

Targeting apoptosis in solid tumors: the role of bortezomib from preclinical to clinical evidence

Proteasome inhibitor‐induced apoptosis in human monocyte‐derived dendritic cells

NF-κB as a target for the prevention of graft-versus-host disease: comparative efficacy of bortezomib and PS-1145

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