Show simple item record

dc.contributor.authorCostanza, Mary E.
dc.contributor.authorBerry, D
dc.contributor.authorHenderson, I. C.
dc.contributor.authorRatain, M. J.
dc.contributor.authorWu, K
dc.contributor.authorShapiro, C
dc.contributor.authorDuggan, D
dc.contributor.authorKalra, J
dc.contributor.authorBerkowitz, I
dc.contributor.authorLyss, A. P.
dc.date2022-08-11T08:11:04.000
dc.date.accessioned2022-08-23T17:31:02Z
dc.date.available2022-08-23T17:31:02Z
dc.date.issued1995-07-01
dc.date.submitted2007-07-31
dc.identifier.citationClin Cancer Res. 1995 Jul;1(7):699-704.
dc.identifier.issn1078-0432 (Print)
dc.identifier.pmid9816035
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50639
dc.description.abstractAmonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9816035&dopt=Abstract">Link to article in PubMed</a>
dc.subjectAdult
dc.subjectAged
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjecteffects
dc.subjectBreast Neoplasms
dc.subjectCyclophosphamide
dc.subjectDoxorubicin
dc.subjectDrug Administration Schedule
dc.subjectFemale
dc.subjectFluorouracil
dc.subjectHumans
dc.subjectImides
dc.subjectIsoquinolines
dc.subjectMenopause
dc.subjectMiddle Aged
dc.subjectNaphthalimides
dc.subjectNeoplasm Metastasis
dc.subjectReceptors, Estrogen
dc.subjectHematology
dc.subjectOncology
dc.titleAmonafide: An active agent in the treatment of previously untreated advanced breast cancer--a cancer and leukemia group B study (CALGB 8642)
dc.typeArticle
dc.source.journaltitleClinical cancer research : an official journal of the American Association for Cancer Research
dc.source.volume1
dc.source.issue7
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1165&amp;context=wfc_pp&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/wfc_pp/166
dc.identifier.contextkey330789
refterms.dateFOA2022-08-23T17:31:02Z
html.description.abstract<p>Amonafide is a new imide derivative of naphthalic acid. The drug had demonstrated significant activity in preclinical studies and some activity in Phase I trials. The drug is extensively metabolized and detected in plasma and urine. Its toxicity has previously been correlated to the formation of an active metabolite, N-acetyl-amonafide. Amonafide was chosen for inclusion in the Cancer and Leukemia Group B (CALGB) master metastatic breast cancer protocol. CALGB 8642 randomizes previously untreated metastatic breast cancer patients either to one of several Phase II agents given for up to four cycles and then followed by standard cyclophosphamide-doxorubicin-5-fluorouracil, or to immediate treatment with standard cyclophosphamide-doxorubicin-5-fluorouracil. The end point of CALGB 8642 is to assess the difference in survival, toxicity, and overall response when limited exposure to Phase II agents precedes standard chemotherapy. This report deals only with amonafide as a Phase II agent. Comparisons with the cyclophosphamide-doxorubicin-5-fluorouracil arm will not be addressed. Patients had to have histologically documented measurable breast cancer and a performance status of 0-1. Patients could not have had prior chemotherapy for metastatic disease. Prior adjuvant chemotherapy was permitted. Patients could not have visceral crisis. Amonafide was given at 300 mg/m2/day i.v. for 5 days, and repeated at 21-day intervals for a maximum of four cycles. Escalation and reduction in dose was mandated dependent on hematotoxicity or lack thereof. Toxicity was primarily hematological and bimodal: 32% had grade 3 or 4 leukopenia and 24% had grade 3 or 4 thrombocytopenia; 22% had no leukopenia and 44% had no thrombocytopenia. The response rate was 18%, including one complete response. When response was analyzed by hematological toxicity, there was a 35.7% response if patients had leukopenia grade 3/4 (versus 8.3%, P = 0.08). There was a 50% response if patients had thrombocytopenia grade 3/4 (versus 7.1%, P = <0.01). We conclude that amonafide is somewhat active in previously untreated breast cancer patients. There may be a steep dose-response curve, based on the significant correlation between myelosuppression and response. Rates of responses in patients adequately dosed (i.e., with significant hematotoxicity) with amonafide ranged from 35 to 50%. Further studies will incorporate individualized dosing based on pretreatment acetylator phenotyping.</p>
dc.identifier.submissionpathwfc_pp/166
dc.contributor.departmentDepartment of Medicine, Division of Hematology/Oncology
dc.source.pages699-704


Files in this item

Thumbnail
Name:
699.pdf
Size:
1002.Kb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record