epothilone-a and Diarrhea

To review the role of combination therapy in the treatment of metastatic breast cancer and to describe strategies to help manage adverse events associated with combination therapy.. Although the median survival of patients with metastatic breast cancer has increased over the last several decades, new treatment options are needed to further improve survival and quality of life for these patients. Novel cytotoxic and noncytotoxic agents have recently been evaluated in combination regimens for patients with metastatic breast cancer. Combinations for metastatic breast cancer that appear in recently approved labeling include ixabepilone with capecitabine, and the targeted biological agent lapatinib in combination with capecitabine. Ixabepilone is the first of a new family of cytotoxic agents--the epothilones--to enter clinical practice. Similar to the taxanes, ixabepilone binds to and stabilizes intracellular microtubules, resulting in decreased DNA replication and cell proliferation. Ixabepilone possesses antitumor activity in taxane-resistant tumor cells and has been shown to significantly improve progression-free survival when used in combination with capecitabine in patients with taxane-resistant tumors. Lapatinib, an oral small-molecule inhibitor of human epidermal growth factor receptors-1 and -2, has been shown, when combined with capecitabine, to improve progression-free survival in patients with advanced metastatic breast cancer who had progressed on prior therapy. The combination of paclitaxel and bevacizumab carries approved labeling for treatment of metastatic breast cancer, although there are concerns about bevacizumab and the risk of toxicity.. Ongoing clinical trials continue to define the role of novel antitumor agents in combination regimens for patients with metastatic breast cancer. Targeted agents are less likely to produce adverse events that are typical of cytotoxic chemotherapy but, because of their effects on specific molecular targets, may cause toxicities that were previously uncommon in cancer therapy.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Capecitabine; Cytotoxins; Deoxycytidine; Diarrhea; Drug Delivery Systems; Epothilones; Female; Fluorouracil; Humans; Lapatinib; Quinazolines; Signal Transduction; Skin Diseases; Trastuzumab

Only a limited number of cytotoxic drugs have shown activity in metastatic colorectal carcinoma. Patupilone is a novel agent with promising activity in this common cancer. Diarrhea represents the dose-limiting toxicity of patupilone. Measurement of intestinal permeability is one of the potential methods of non-invasive laboratory assessment of gastrointestinal toxicity.. We have assessed intestinal permeability by measuring absorption of lactulose, mannitol and xylose in 27 previously treated patients with metastatic colorectal cancer enrolled in a phase I trial of patupilone.. Lactulose/mannitol and lactulose/xylose ratios increased after the treatment. Significantly higher lactulose/mannitol ratio was observed in patients who had severe diarrhea. Moreover, patients who subsequently had an adverse event of grade 3 or higher had significantly higher baseline lactulose/mannitol or lactulose/xylose ratios.. Measurement of intestinal permeability using the lactulose/mannitol test may represent a biomarker for the monitoring, or even prediction of toxicity of cytotoxic drugs, including patupilone.

Topics: Aged; Antineoplastic Agents; Colonic Neoplasms; Diarrhea; Epothilones; Female; Humans; Intestinal Mucosa; Intestines; Lactulose; Liver Neoplasms; Male; Mannitol; Middle Aged; Permeability; Xylose

Phase I trials of the microtubule stabilising agent patupilone showed encouraging tumour control and response rates in patients with metastatic colorectal cancer.. Patients with metastatic or locally recurrent colorectal cancer who had progressed following treatment with oxaliplatin, irinotecan and fluoropyrimidines were treated with patupilone (8 mg/m(2) IV every 3 weeks) in combination with dexamethasone or prednisolone.. The trial was closed early after 29 patients had been enrolled due to concerns about toxicity. 20 patients (71.4 %) experienced at least one grade 3-5 toxicity, most commonly diarrhoea (14 patients), dehydration (7 patients) and lethargy (6 patients). The 12 week progression-free survival rate was 16.7 % (95 % CI 6.1 %-36.5 %) in the 24 patients with a 12 week scan available or who had died prior to the 12 week scan. No complete or partial responses were seen by 12 weeks. The median progression-free survival was 2.6 months (95 % CI 2.3-2.9) and median overall survival was 6.1 months (95 % CI 3.7-8.4).. Patupilone given at a dose of 8 mg/m(2) IV over 20 min every 3 weeks was associated with high levels of toxicity and no significant evidence of efficacy in patients with pre-treated colorectal cancer.

Topics: Adult; Aged; Antineoplastic Agents; Colorectal Neoplasms; Diarrhea; Epothilones; Female; Humans; Lethargy; Male; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome; Tubulin Modulators

First-in-man study of KOS-1584, a second generation epothilone.. Patients with advanced solid malignancies received KOS-1584 every 3 weeks until disease progression. Using a modified Fibonacci dose escalation scheme, one patient was enrolled at each dose level until the first instance of grade 2 toxicity. Thereafter, a standard 3 + 3 design was utilized.. Sixty-six patients in 14 cohorts were dosed from 0.8 to 48 mg/m(2). Diarrhea, arthralgias, and encephalopathy were dose-limiting toxicities (DLTs) at doses ≥36 mg/m(2). At the recommended phase II dose (RP2D), the most common adverse effects were peripheral neuropathy (low grade), fatigue, arthralgias/myalgias, and diarrhea (31, 6%). The incidence of neutropenia was low. The overall clearance, volume of distribution, and half-life of KOS-1584 were 11 ± 6.17 L/h/m(2), 327 ± 161 L/m(2), and 21.9 ± 8.75 h, respectively. The half-life for the seco-metabolite (KOS-1891) was 29.6 ± 13.8 h. KOS-1584 exhibited linear pharmacokinetics. A dose-dependent increase in microtubulin bundle formation was observed at doses ≥27 mg/m(2). Two patients achieved partial responses and 24 patients had stable disease (SD).. The RP2D of KOS-1584 is 36 mg/m(2). The lack of severe neurologic toxicity, diarrhea, neutropenia, or hypersensitivity reactions; favorable pharmacokinetic profile; and early evidence of activity support further evaluation.

Topics: Adult; Aged; Aged, 80 and over; Area Under Curve; Arthralgia; Diarrhea; Dose-Response Relationship, Drug; Epothilones; Fatigue; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Molecular Structure; Neoplasms; Peripheral Nervous System Diseases; Treatment Outcome; Tubulin Modulators

Epothilones are active tubulin-interacting agents that warrant combinations in clinical studies. This phase I combination study explored ixabepilone administered as a 3-h infusion followed by a 90-minute infusion irinotecan, on days 1 and 14 of every 28-day cycle. Forty-one patients received doses of ixabepilone and irinotecan ranging from 15-30 mg/m(2) and 120-180 mg/m(2) every 2 weeks for a total of 173 cycles, respectively. Dose limiting toxicities reported at doses 25 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan consisted of acute grade 3 diarrhoea and asthenia, eventually associated with neutropenia and sepsis, and/or delayed grade 3 peripheral neuropathy. Therefore, the recommended doses were 20 mg/m(2) ixabepilone and 180 mg/m(2) irinotecan. At this dose level, acute side effects were neutropenia, anaemia, nausea-vomiting, diarrhoea, asthenia, and alopecia. Delayed neuropathy was mostly restricted to reversible grade I-II. Pharmacokinetic data suggested no drug-drug interaction. Five objective responses were observed in four patients with lung cancer and one unknown primary epidermoid carcinoma patient. In conclusion, toxicity including peripheral neuropathy was manageable at the recommended doses of 20 mg/m(2) ixabepilone combined with 180 mg/m(2) irinotecan on days 1 and 14 every 28 days. Promising antitumour activity was observed in patients with platinum-pretreated lung cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asthenia; Camptothecin; Diarrhea; Dose-Response Relationship, Drug; Epothilones; Female; Hematologic Diseases; Humans; Infusions, Intravenous; Irinotecan; Male; Middle Aged; Nausea; Neoplasms; Paresthesia; Vomiting

BMS-310705, a water-soluble semi-synthetic analogue of epothilone B, was selected for clinical development because of its in vivo anti-tumour activity and toxicity profile similar to that of ixabepilone, currently the most extensively evaluated and promising epothilone B analogue. The improved solubility of BMS-310705 allowed a cremophore-free formulation that avoided the need for pre-medication.. Two schedules were tested, one with drug administrations on days (D) 1, 8 and 15 followed by 1-week's rest, the other with administrations on D1 and 8 (D1&8 schedule) followed by 1-week's rest. Treatment was given as a 15-min infusion without pre-medication against hypersensitivity. The plasma pharmacokinetics of BMS-310705 was studied in 30 patients. An accelerated titration design 2B was applied for dose escalations. Twenty-seven patients were accrued in the D1, 8, 15 and 32 in the D1&8 schedule.. The dose was escalated from 5-30 mg/m(2)/week with diarrhoea as dose-limiting toxicity; 15 and 20 mg/m(2) were the recommended doses in the D1, 8, 15 and D1&8 schedule, respectively. Other frequent non-haematological toxicities were neurotoxicity, mainly paraesthesia, asthenia and myalgia. Preliminary results showed linear pharmacokinetics along the range of doses tested with a short half-life. Five objective responses were reported.. Further clinical development of BMS-310705 might be worthwhile in solid tumours where ixabepilone or other epothilones are not indicated.

Topics: Adult; Aged; Antineoplastic Agents; Diarrhea; Drug Administration Schedule; Epothilones; Female; Humans; Male; Middle Aged; Neoplasms; Nervous System Diseases; Neutropenia; Tubulin Modulators