Reference

Phase I study of sequential deoxyazacytidine/depsipeptide infusion in patients with malignancies involving lungs or pleura

Phase I study of sequential deoxyazacytidine/depsipeptide infusion in patients with malignancies involving lungs or pleura. Schrump, David S.; Nguyen, Dao M.Several substances are used for example 2353-33-5 and 128517-07-7 which are their cas registry numbers.; Kunst, Tricia F.; Hancox, Ana; Figg, William D.; Steinberg, Seth M.; Pishchik, Vitaliy; Becerra, Yvonne (Thoracic Oncology Section, Surgery Branch, National Institutes of Health, Bethesda, MD, USA). Clinical Lung Cancer, 4(3), 186-192 (English) 2002 Cancer Information Group. CODEN: CLCLCA. ISSN: 1525-7304. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) In light of our preclin. data, and the results of our single-agent deoxyazacytidine (DAC) and depsipeptide (DP) trials, we have initiated a new trial (NCI-02-C-0205) examg. gene induction mediated by sequential DAC/DP infusion in patients with malignancies involving the lungs and pleura. The overall goal of this study is to recapitulate in patients the conditions that facilitate target gene induction and apoptosis in cultured cancer cells following sequential DAC/DP treatment. The primary endpoints include feasibility, toxicity, definition of max. tolerated dose (MTD), and pharmacokinetics of sequential DAC/DP infusion in patients with lung cancer or pleural mesothelioma. Secondary endpoints include anal. of NY-ESO-1 expression in biopsy specimens and evaluation of immune response to this cancer testis antigen (CTA). Addnl. secondary endpoints include anal. of apoptosis as well as evaluation of p16 and p21 expression in biopsy specimens to det. if sequential drug treatment enhances expression of these genes which are known to be modulated by chromatin structure. Patients with histol. or cytol. proven primary small-cell lung cancer (SCLC), non-small-cell lung cancer (NSCLC) , or pleural mesothelioma (MPM) are eligible for evaluation, including those with intracranial metastases that have been treated by surgery or radiation therapy provided there is no evidence of active disease and no ongoing requirement for anticonvulsant therapy or steroids. Patients will undergo biopsy of their tumors via endoscopic procedures or percutaneous techniques. NY-ESO-1 expression will be evaluated. In addn., samples will be evaluated for p16 and p21 expression. Peripheral blood samples will be obtained to analyze serol. reactivity to NY-ESO-1 using std. enzyme-linked immunosorbent assays and recombinant in vitro translated protein; lymphocytes will be frozen for possible addnl. correlative studies of immune response to NY-ESO-1. Once tumor biopsies have been obtained, patients will be admitted to the Thoracic Surgery Service, Clin. Center, NIH, and receive 2 cycles of 72-h DAC/4-h DP infusion. Because this study is designed to evaluate the toxicity of DAC/DP infusion without cytokine support, each treatment cycle will last approx. 5 wk to allow full bone marrow recovery. Due to potential cardiac toxicity related to DP, all patients will be monitored by telemetry for 24 h following commencement of the initial DP infusion as well as the DP infusion on day 10, and will undergo standardized cardiac assessment utilizing serial EKGs, serum troponin levels, and MUGA scans. Blood will be obtained at designated time points to assess DAC and DP levels. Approx. 34 days following initiation of the first treatment cycle, tumor biopsies will be obtained, and a second treatment cycle will commence. At the end of the second cycle (approx. 68 days following the initiation of the first treatment cycle), patients will return to the Thoracic Surgery Clinic for repeat x-rays and blood work to det. treatment response. Dose escalation will continue until dose-limiting toxicity (DLT) (assessed during the first treatment cycle) is obsd. Following completion of the second cycle of therapy, patients will undergo evaluation consisting of phys. exam, blood work, and x-rays to define response to treatment. Those individuals who exhibit disease progression will be taken off study. Patients who exhibit stabilization or regression of their disease will be eligible for 2 addnl. DAC/DP infusions at the same dose level at which they were originally treated. Patients will continue therapy in this manner until off-study criteria have been met. Although not a primary endpoint, a major component of this study will be evaluation of mol. endpoints (NY-ESO-1, p16 and p21 expression) and apoptosis in tumor tissues. An attempt will be made to correlate target gene induction and apoptosis with plasma DAC and DP levels and clin. response to therapy. .

A phase I trial of Depsipeptide (FR901228) in patients with advanced cancer

A phase I trial of Depsipeptide (FR901228) in patients with advanced cancer. Marshall, John L.; Rizvi, Naiyer; Kauh, John; Dahut, William; Figuera, Manuela; Kang, Min H.; Figg, William D.; Wainer, Irving; Chaissang, Christoff; Li, Megan Zhaoyang; Hawkins, Michael J. (Georgetown University, Washington, DC, USA). Journal of Experimental Therapeutics and Oncology, 2(6), 325-332 (English) 2002 Blackwell Publishing, Inc. CODEN: JETOFX. ISSN: 1359-4117. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Depsipeptide (FR901228) is a bicyclic peptide isolated from Chromobacterium violaceum that has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. The primary mechanism of action is through inhibition of histone deacetylase. Initial development was halted due to significant cardiac toxicity. Subsequent studies performed at the National Cancer Institute demonstrated administration without cardiotoxicity was possible by varying the schedule of administration. A phase I trial was designed to det. the max. tolerated dose and toxicity profile when administered as a 4-h infusion weekly ′ 3 with one week rest. 33 Patients with advanced, incurable cancers were enrolled into this trial and treated with doses of Depsipeptide ranging from 1 mg/m2 to 17.7 mg/m2. At doses above 5 mg/m2, we obsd. common symptoms of nausea, vomiting, fatigue, and anorexia. Subtle changes in ECGs were seen in several patients. However, no cardiac enzyme abnormalities or redn. in ejection fraction were obsd. The MTD was defined as 13.In this experiment, several chemicals are used like 9076-57-7 and 128517-07-7 3 mg/m2 with dose limiting toxicities being grade 3 thrombocytopenia and fatigue. Depsipeptide can be safely administered when given as a 4-h infusion and further clin. trials are warranted. .