Evaluation of merbarone (NSC 336628) in disseminated malignant melanoma

Merbarone, NSC 336628, is an investigational anticancer drug with activity against experimental animal tumors including melanoma. This paper presents results of a Phase II clinical study of merbarone in patients with biopsy proven stage IV malignant melanoma without prior chemotherapy and with no evidence of CNS involvement. Thirty-five patients with median age 58 (range 27–81), with performance status 0–2 were treated with merbarone 1000 mg/m 2 /day for five days by intravenous continuous infusion repeated every 3 weeks. All patients (21 males and 14 females) were evaluable for toxicity. Two patients were not evaluable for response having been removed from protocol treatment due to toxicity and received other treatment during the first course of chemotherapy. Among the evaluable patients there was one complete response in a supraclavicular lymph node lasting four months and one partial liver response lasting three months. The remaining thirty-one patients were non-reponders. Of these one had a stable disease lasting 21 months. The overall objective response rate was 6% (2/35) with a 95% confidence interval of 1%–19%. Twenty-six of the 35 patients have died. The estimated median survival of the entire group was 9 months with a 95% confidence interval of six to eleven months. Renal toxicity was dose-limiting and manifested as increasing serum creatinine (54% of patients), proteinuria (51%) and hematuria (9%). One patient experienced grade 4 creatinine increase, proteinuria and acute renal failure. Other toxicities included nausea (71%), vomiting (51%), malaise (23%), weakness (20%), alopecia (17%), diarrhea (17%), anorexia (14%), transaminase (SGOT, SGPT) increase (14%), constipation (14%), alkaline phosphatase or 5′nucleotidase increase (9%), and fever (9%). Hematologictoxicity (granulocytopenia, leukopenia, and anemia) was generally mild and infrequent (29%, only one patient had grade 4 granulocytopenia). Overall 9 patients (26%) had at least one grade 3 toxicity. We conclude that merbarone at this dose and schedule has detectable but minimal activity in the treatment of metastatic malignant melanoma and given the significant renal toxicity this schedule does not merit further evaluation in this disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45186/1/10637_2004_Article_BF00872863.pd

A phase I trial of Flavopiridol in relapsed multiple myeloma

PURPOSE: Flavopiridol is primarily a cyclin-dependent kinase-9 inhibitor, and we performed a dose escalation trial to determine the maximum tolerated dose and safety and generate a pharmacokinetic (PK) profile. METHODS: Patients with a diagnosis of relapsed myeloma after at least two prior treatments were included. Flavopiridol was administered as a bolus and then continuous infusion weekly for 4 weeks in a 6-week cycle. RESULTS: Fifteen patients were treated at three dose levels (30 mg/m(2) bolus, 30 mg/m(2) CIV to 50 mg/m(2) bolus, and 50 mg/m(2) CIV). Cytopenias were significant, and elevated transaminases (grade 4 in 3 patients, grade 3 in 4 patients, and grade 2 in 3 patients) were noted but were transient. Diarrhea (grade 3 in 6 patients and grade 2 in 5 patients) did not lead to hospital admission. There were no confirmed partial responses although one patient with t(4;14) had a decrease in his monoclonal protein >50 % that did not persist. PK properties were similar to prior publications, and immunohistochemical staining for cyclin D1 and phospho-retinoblastoma did not predict response. CONCLUSIONS: Flavopiridol as a single agent given by bolus and then infusion caused significant diarrhea, cytopenias, and transaminase elevation but only achieved marginal responses in relapsed myelom

A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC)

Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer. Experimental design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m 2 over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression. Results: A total of seventeen patients were enrolled on this study. 94% of all patients enrolled had prior treatment. Sixteen patients were evaluable for response with fifteen patients showing evidence of disease progression and one patient with prolonged stable disease. One patient had non-evaluable disease. Following this interim analysis, the drug was considered ineffective and the study was terminated early. The most frequent adverse event was anemia. No patients discontinued the treatment because of toxicity. Conclusion: CQS, when given at a dose of 2000 mg/m 2 weekly for 4 weeks every 42 days to patients with metastatic colorectal cancer, does not result in significant tumor regression.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43416/1/10637_2005_Article_4827.pd

A Phase II Trial of Pyrazine Diazohydroxide in Patients with Disseminated Malignant Melanoma and no Prior Chemotherapy – Southwest Oncology Group Study

Malignant melanoma is rapidly increasing inthe United States. Metastatic diseaseresponds poorly to currently availablechemotherapy. Pyrazine diazohydroxide(PZDH) is a new agent inhibiting DNAsynthesis that is active in mouse tumormodels and human xenografts and lackscross resistance withmultiple standard agents. In this phase IItrial, patients with no prior chemotherapyor immunotherapyfor metastatic disease and performancestatus (SWOG) of 0–1, were treated withpyrazine diazohydroxide at a dose of 100 mg/m 2 /day by IV bolus injectionover 5–15 minutes for 5 consecutive daysevery 6 weeks. There were 23 eligiblepatients entered on this trial with 74%having PS of 0 and 91% having visceralmetastases. There were no confirmed anti-tumor responses. Theoverall response rate is 0% (95% CI 0%–15%). Median overall survival is sixmonths (95% CI 5-8months). The most common toxicities were hematologic and consisted of lymphopenia,thrombocytopenia, anemia, and leukopenia. Fatigue, and nausea and vomiting were thenext mostcommon toxicities. Pyrazine diazohydroxideby this dose and schedule has insufficientactivity in thetreatment of disseminated malignantmelanoma to warrant further investigation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45216/1/10637_2004_Article_390690.pd

Cancer- and Chemotherapy-Induced Anemia

Anemia is prevalent in 30% to 90% of patients with cancer. Anemia can be corrected through either treating the underlying cause or providing supportive care through transfusion with packed red blood cells or administration of erythropoiesis-stimulating agents (ESAs), with or without iron supplementation. Recent studies showing detrimental health effects of ESAs sparked a series of FDA label revisions and a sea change in the perception of these once commonly used agents. In light of this, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer- and Chemotherapy-Induced Anemia underwent substantial revisions this year. The purpose of these NCCN Guidelines is twofold: 1) to operationalize the evaluation and treatment of anemia in adult cancer patients, with an emphasis on those who are receiving concomitant chemotherapy, and 2) to enable patients and clinicians to individualize anemia treatment options based on patient condition. (JNCCN 2012;10:628-653