Phase I trial of bortezomib and dacarbazine in melanoma and soft tissue sarcoma

Summary Purpose Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, a...

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Bibliographic Details
Published in:Investigational new drugs 2013-08, Vol.31 (4), p.937-942
Main Authors: Poklepovic, Andrew, Youseffian, Leena, Winning, Mary, Birdsell, Christine A., Crosby, Nancy A., Ramakrishnan, Viswanathan, Ernstoff, Marc S., Roberts, John D.
Format: Article
Language:English
Subjects:
Adult
Aged
Antiemetics
Antineoplastic agents
Antineoplastic Agents - adverse effects
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - adverse effects
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Biological and medical sciences
Boronic Acids - adverse effects
Boronic Acids - therapeutic use
Bortezomib
Cancer
Cancer therapies
Clinical trials
Cytotoxicity
Dacarbazine - adverse effects
Dacarbazine - therapeutic use
Dermatology
Dose-Response Relationship, Drug
Drug dosages
Drug therapy
Female
General aspects
Humans
Lung Neoplasms - diagnostic imaging
Lung Neoplasms - secondary
Male
Medical sciences
Medication Adherence
Medicine
Medicine & Public Health
Melanoma
Melanoma - diagnostic imaging
Melanoma - drug therapy
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Oncology
Patients
Peripheral neuropathy
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phase I Studies
Pyrazines - adverse effects
Pyrazines - therapeutic use
Radiography
Sarcoma
Sarcoma - drug therapy
Studies
Toxicity
Treatment Outcome
Tumors
Tumors of the skin and soft tissue. Premalignant lesions
Young Adult
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Summary:Summary Purpose Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. Experimental design Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. Results Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m 2 and dacarbazine 580 mg/m 2 are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. Conclusions Bortezomib 1.6 mg/m 2 and dacarbazine 580 mg/m 2 administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-012-9913-8