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Expert Opinion on Investigational Drugs Jan 2006The only approved camptothecins for use in patients to date (topotecan and irinotecan) are delivered intravenously. Thus, an oral camptothecin analogue that would... (Review)
Review
The only approved camptothecins for use in patients to date (topotecan and irinotecan) are delivered intravenously. Thus, an oral camptothecin analogue that would provide the convenience of oral delivery with the flexibility for a variety of prolonged treatment schedules would be advantageous. Rubitecan is an orally available camptothecin analogue that also has potential for delivery transdermally or by inhalation. Like all of the camptothecins, its antitumour activity is mediated through the inhibition of DNA topoisomerase I, which is involved in relaxing supercoiled DNA, which is important for the process of DNA replication and RNA transcription. Rubitecan exists in equilibrium as 9-nitro-camptothecin (9-NC) and 9-amino-camptothecin (9-AC), a metabolite that is thought to be active although it failed in clinical trials. Both 9-NC and 9-AC contain a lactone ring that is required for optimal activity with the carboxylic acid (open ring) forms being significantly less active or inactive. A more acidic environment favours the lactone ring structure, whereas neutral or basic conditions favour the conversion to the carboxylic acid form. In addition to issues of lactone ring stability at physiological pH (true for all of the camptothecin analogues), there is pharmacokinetic variability that has had to be dealt with during the development of rubitecan. Preclinically, rubitecan has shown activity against a broad spectrum of tumour types in in vitro and in vivo human tumour xenograft models. Frustratingly, the level of activity of an agent in preclinical models has not always translated into similar activity against human tumours in clinical trials. To date, with the exception of pancreatic and possibly ovarian cancer, rubitecan has had disappointing activity against a number of other solid tumours in relatively small Phase I/II trials; however, it has shown sufficient activity against pancreatic cancer, a malignancy that remains difficult to treat, to continue to be evaluated in clinical trials for this indication. Results of clinical trials in the next few years should determine whether rubitecan can find a role in cancer therapy.
Topics: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Drug Evaluation, Preclinical; Enzyme Inhibitors; Female; Humans; Male; Ovarian Neoplasms; Pancreatic Neoplasms; Randomized Controlled Trials as Topic; Topoisomerase I Inhibitors
PubMed: 16370935
DOI: 10.1517/13543784.15.1.71 -
Drugs in R&D 2004Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is...
Rubitecan [Orathecin, 9-nitrocamptothecin, 9NC, RFS 2000] is a topoisomerase I inhibitor extracted from the bark and leaves of the Camptotheca acuminata tree, which is native to China. Rubitecan is an oral compound being developed for the treatment of pancreatic cancer and other solid tumours by SuperGen. One of the major benefits of rubitecan is that it can be administered in an outpatient setting, so patients can be treated in their homes. Rubitecan was isolated by the Stehlin Foundation in the US. SuperGen is currently awaiting regulatory approval in the US and the EU for rubitecan in the treatment of pancreatic cancer. At the BIO-2004 conference, SuperGen announced it is seeking a partner for rubitecan for territories outside the US. SuperGen acquired exclusive worldwide rights to rubitecan from the Stehlin Foundation in 1997 except in Mexico, Canada, Spain, Japan, the UK, France, Italy and Germany. SuperGen has also received approval from the US FDA to use its own manufactured rubitecan in clinical trials. SuperGen and the Stehlin Foundation have an 8-year research agreement that secures global rights to other camptothecins and additional anticancer compounds for the former. In December 1999, SuperGen and Abbott signed a worldwide sales and marketing agreement for rubitecan. Under the terms of the agreement, Abbott had exclusive distribution and promotion rights for rubitecan outside the US, and co-promotion rights with SuperGen within the US. In return, Abbott made an initial equity investment in SuperGen. SuperGen and Abbott Laboratories ended their collaboration agreement in February 2002 by mutual consent with SuperGen stating that the dissolution of the agreement was based on commercial motivation rather than anything to do with rubitecan's safety or efficacy. Abbott no longer has rights or obligations to purchase shares of SuperGen stock or an option to purchase up to 49% of the company. For its part, SuperGen will no longer receive milestone payments worth up to $US57 million. SuperGen has formed a clinical and business alliance with US Oncology (created by the merger between American Oncology Resources and Physician Reliance Network in the US), and will collaborate on clinical trials of rubitecan. SuperGen believes that this relationship will increase the patient population available for trials and enable it to market the drug directly to Oncologists. SuperGen and Capital Research and Management Company have completed a $US16.6 million private placement transaction that will enable future funding for the rubitecan programme as well as other oncology programmes. In July 2004, SuperGen's European subsidiary, EuroGen Pharmaceuticals, submitted a Marketing Authorisation Application for rubitecan in the treatment of pancreatic cancer. The application will be reviewed under the EMEA Centralised Procedure. In June 2003, the EMEA granted SuperGen orphan drug status for rubitecan for the treatment of pancreatic cancer. The US FDA has also granted orphan drug status for rubitecan in the treatment of pancreatic cancer and fast-track status for rubitecan for the treatment of locally advanced or metastatic pancreatic cancer that is resistant or refractory to chemotherapy. SuperGen has conducted three phase III pivotal trials in patients with pancreatic cancer. A phase III randomised trial in chemotherapy-naive patients was conducted at 132 centres throughout the US. The trial enrolled approximately 994 patients who were randomised to receive rubitecan or gemcitabine. Enrollment was completed in October 2001. Another phase III trial has compared rubitecan with the most appropriate chemotherapy in chemotherapy-resistant patients. Enrollment of over 400 patients at 200 medical centres across the US was completed in June 2001. Results from the trial were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003) [Chicago, US; 31 May - 3 June 2003], after they had been compiled, analysed and submitted to the FDA. The results of the study showed that rubitecan could not help all chemotherapy-resistant patients, but could increase survival in those that do respond. The other phase III pivotal trial was conducted in patients with pancreatic cancer who had failed treatment with gemcitabine. This trial completed enrollment in October 2001, and had enrolled approximately 448 patients. SuperGen is conducting phase II trials of rubitecan in patients with solid tumours in the UK, Italy, France, Germany, the Netherlands and Denmark. Each trial will enroll 100-150 patients with various tumour types, including colorectal, lung, breast, gastric, prostate, cervical and head and neck cancers. Phase I/II trials are underway to investigate rubitecan as a radiosensitiser in patients with lung cancer, and phase II trials in patients with breast cancer are also being conducted. A phase II study in ovarian cancer patients is also being conducted. Results from an ongoing phase II study in cancer patients have shown that rubitecan was effective against chordomas, a rare type of bone cancer. Phase II studies are also underway in haematological malignancies including myelodysplastic syndrome (preleukaemia) and chronic myelomonocytic leukaemia. In February 2000, SuperGen announced that its IND submission for rubitecan had been approved by the Therapeutics Products Programme of Canada. The company stated that it intended to begin clinical trials in Canada in the near future. In February 2004, SuperGen announced an offering of shares of its common stock to finance the commercialisation of rubitecan capsules. In July 2003, SuperGen was granted a US patent covering combination therapies with chemotherapeutic anthracycline agents and structural modifications that may one day lead to next-generation rubitecan compounds. In December 2002, SuperGen was granted US patent No. 6,482,830, covering its polymorphic formulations of rubitecan. The patent also covers a class of polymorphs that are similar to the one at the centre of rubitecan. In addition, SuperGen was also issued US patent No. 6,485,514 in December 2002, covering the local delivery of rubitecan via stents and/or catheters to sites of proliferating cells. Stent- or catheter-delivered rubitecan may be beneficial in certain types of cardiac procedures, such as ablation or angioplasty, as well as for direct injection into a certain number of solid tumours. SuperGen is also developing an inhaled, liposomal formulation of rubitecan. It acquired the worldwide rights to this formulation from the Clayton Foundation in December 1999. Inhaled rubitecan is in clinical trials in the US for the treatment of lung cancer and pulmonary metastatic cancer.
Topics: Animals; Anti-HIV Agents; Antineoplastic Agents, Phytogenic; Antiviral Agents; Camptotheca; Camptothecin; Clinical Trials, Phase I as Topic; Enzyme Inhibitors; Humans; Neoplasms; Randomized Controlled Trials as Topic; Topoisomerase I Inhibitors
PubMed: 15357630
DOI: 10.2165/00126839-200405050-00007 -
International Journal of Oncology Jan 2002The purpose of this study is to establish the maximum tolerated dose of rubitecan in mice, dogs and men and to establish the anticancer activity of such dose against...
The purpose of this study is to establish the maximum tolerated dose of rubitecan in mice, dogs and men and to establish the anticancer activity of such dose against human tumors xenografted in nude mice. Nude mice received increasing doses of Rubitecan by intrastomach injection until the maximum tolerated dose (MTD) had been established for both the single dose and the multiple doses at the schedule of 5 days on, 2 days off. Extrapolating from the mouse data, MTD was determined for oral administration in dogs and man. Levels of the drug in plasma were determined by high pressure liquid chromatography (HPLC). Using maximum tolerated multiple doses, the sensitivity of human cancer xenografts in nude mice to Rubitecan was determined. MTD of Rubitecan in mice for multiple doses intrastomach at the schedule of 5+,2- was 1 mg/kg/day. MTD in dogs was also 1 mg/kg/day, administered orally but at the schedule of 4+,3-. In man, it was 1 mg/m2/day at the schedule of 5+,2-. Treatment of human cancer xenografts in nude mice with MTD of Rubitecan resulted in 100% growth inhibition of 30/30 tumors tested and in 24/30 in their total disappearance. These 30 tumors comprised all the most common human cancers: lung, colorectal, breast, pancreatic, ovarian, prostate, stomach, melanoma and a leukemia. From the data collected, it appears that rubitecan is a very promising anticancer drug with high potency against a wide spectrum of human cancers. These cancers growing as xenografts in nude mice are always growth inhibited (30/30) and frequently (24/30) totally destroyed by the administration of non-toxic doses of Rubitecan.
Topics: Animals; Antineoplastic Agents; Camptothecin; Chromatography, High Pressure Liquid; Dogs; Drug Administration Routes; Drug Evaluation, Preclinical; Drug Screening Assays, Antitumor; Female; Half-Life; Humans; Male; Maximum Tolerated Dose; Mice; Mice, Nude; Neoplasms, Experimental
PubMed: 11743646
DOI: No ID Found -
Investigational New Drugs Jul 2006Rubitecan (RFS-2000, 9NC, Orathecin) is an orally bioavailable camptothecin analogue, with evidence of preclinical activity in colon cancer cell lines. We evaluated oral...
BACKGROUND
Rubitecan (RFS-2000, 9NC, Orathecin) is an orally bioavailable camptothecin analogue, with evidence of preclinical activity in colon cancer cell lines. We evaluated oral rubitecan (5 days on, 2 days rest per week) on a continuous schedule, in patients with advanced colorectal cancer (CRC), who progressed after 5-fluorouracil based chemotherapy.
PATIENTS AND RESULTS
Fourteen eligible patients were treated with rubitecan at 1.5 mg/m2/day on a 5 day/week continuous schedule. Therapy was well tolerated with most adverse events in the mild to moderate category. Grade 3/4 toxicity consisting of anemia, diarrhea and elevated bilirubin was seen in 4 patients. No responses were seen in 13 evaluable patients. Overall median survival (95% confidence interval) was 10.1 (range 3.1-12.6) months, and median time to progression was 2.1 months.
CONCLUSIONS
Administration of rubitecan was well tolerated, but this schedule does not appear to have clinical activity in patients with advanced previously treated CRC.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Camptothecin; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Fluorouracil; Humans; Male; Middle Aged; Survival Analysis; Treatment Failure; Treatment Outcome
PubMed: 16525767
DOI: 10.1007/s10637-006-6451-2 -
The Oncologist Mar 2005Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits.... (Clinical Trial)
Clinical Trial
BACKGROUND
Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy.
METHODS
Fifty-eight patients with failed or relapsed advanced pancreatic cancer after receiving at least one prior chemotherapy regimen were enrolled to receive eight consecutive weeks of treatment with rubitecan at a dose of 1.5 mg/m2 orally on five consecutive days per week, followed by 2 days off therapy, repeatedly. The primary end point was response rate. Time to progression, overall survival, changes in CA19-9 levels, and the composite measure of clinical benefit response were evaluated as secondary end points.
RESULTS
Among 43 patients with measurable disease, 7% (3/43) achieved partial responses and 16% (7/43) had disease stabilization for an overall response and disease stabilization rate of 23%. All responses were confirmed by independent radiology review. Median survival was longer in responding patients than in the overall study cohort (10 months versus 3 months). Gastrointestinal and hematologic toxicities were the most commonly reported adverse events.
CONCLUSION
Oral rubitecan produced responses and was well tolerated by heavily pretreated patients with refractory pancreatic cancer. The overall risk-benefit profile of oral rubitecan appears promising, supporting further evaluation in phase III trials in patients with refractory and chemotherapy-naive pancreatic cancer.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Camptothecin; Disease Progression; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis
PubMed: 15793221
DOI: 10.1634/theoncologist.10-3-183 -
Expert Opinion on Drug Delivery Mar 2005In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan,... (Review)
Review
In order to improve the therapeutic index of camptothecin (CPT) analogues, alternative administration of CPT analogues is being evaluated. Topotecan, irinotecan, rubitecan, lurtotecan and 9-aminocamptothecin have been administered orally with response rates equivalent to that seen after intravenous administration, where applicable. Oral availability and administration of some of the newer CPT analogues, including diflomotecan (BN80915) and grimatecan (ST1481), have also shown promising results. Aerosolisation of liposomal 9-nitrocamptothecin has been studied in patients with advanced malignancies involving the lung, demonstrating systemic antitumour activity. Intrathecal administration of topotecan has been studied in children with refractory neoplastic meningitis. It is well tolerated and associated with some antitumour activity. Intraperitoneal administration of topotecan as consolidation therapy in patients with ovarian cancer has shown promising results. Transdermal administration of rubitecan has been studied in mice. So far, no CPT has been approved for an alternative route of administration.
Topics: Administration, Cutaneous; Administration, Inhalation; Administration, Oral; Aerosols; Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Injections, Spinal; Liposomes
PubMed: 16296757
DOI: 10.1517/17425247.2.2.323 -
Cancer Chemotherapy and Pharmacology Jul 2008Rubitecan is an oral camptothecin analogue that has shown activity against a broad spectrum of human tumor xenografts and has been tested in several diseases.
PURPOSE
Rubitecan is an oral camptothecin analogue that has shown activity against a broad spectrum of human tumor xenografts and has been tested in several diseases.
PATIENTS AND METHODS
In the present study, 19 patients with incurable, recurrent or metastatic head and neck cancer were treated with rubitecan at the initial dose of 1.5 mg/m(2) x 5 days per week. An appropriate dose modification program was set up according to the observed toxicities.
RESULTS
Thirteen out of the 19 treated patients were formally evaluable for tumor response. Ten patients had a disease progression and three patients had a stabilization of disease as their best response. The mean duration of stable disease was 141 days. Median survival was 16 weeks (range 2-22 weeks). Three patients died during the study or less than a month after their last dose of study medication. Hematologic toxicity was serious in this study since four patients discontinued their participation because of severe anemia. The drug was also associated with grade 1-4 neutropenia, and with 1-3 thrombocytopenia.
CONCLUSION
We conclude that rubitecan is not effective as a single-agent in recurrent or metastatic head and neck cancer with the doses and schedule used in this study.
Topics: Adult; Aged; Antineoplastic Agents; Camptothecin; Carcinoma, Squamous Cell; Disease-Free Survival; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local
PubMed: 17882418
DOI: 10.1007/s00280-007-0592-7 -
European Journal of Cancer (Oxford,... Apr 2002A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Clinical phase II study and pharmacological evaluation of rubitecan in non-pretreated patients with metastatic colorectal cancer-significant effect of food intake on the bioavailability of the oral camptothecin analogue.
A randomised, open label phase II study was performed in patients with advanced colorectal cancer to evaluate the safety, toxicity and antineoplastic activity of the topoisomerase I-inhibitor rubitecan. A cross-over design was chosen to determine the intrapatient variation of the bioavailability and pharmacokinetics of the anticancer agent depending on the timing of food intake in relation to the oral drug administration. Patients with previously untreated metastatic disease received two single oral doses of rubitecan 1.5 mg/m2 for assessment of the pharmacokinetics. They were randomised to have the first administration either after an overnight fasting period or immediately after a high calorie breakfast, and crossed over to the alternative schedule after a one-week washout period. After completion of the pharmacokinetic sampling, treatment continued with rubitecan given orally at a dose of 1.5 mg/m2/day, to be increased up to 2.0 mg/m2/day, under fasting conditions for 5 consecutive days per week until disease progression. 19 patients entered the trial after informed consent was obtained. A total number of 35 treatment cycles (median 2, range 1-4) were administered. All patients were evaluable for safety. The toxicity profile of rubitecan was generally mild to moderate, with sporadic cases of grade 4 toxicities (Common Toxicity Criteria (CTC) version 2.0) diarrhoea, leucopenia and neutropenia. None of 15 evaluable patients achieved an objective response. The majority had early disease progression. 14 patients were evaluable for pharmacokinetic analysis. The bioavailability of rubitecan was found to be strongly dependent on the timing of food intake with a fasted-to-fed ratio for C(max) of 1.98 (two-tailed P<0.001; ANOVA), T(max) 0.49 (P<0.001), AUC(0-8 h) 2.52 (P<0.001) and AUC(0-24 h) 1.64 (P=0.003). Rubitecan is well tolerated, but clinically inactive in colorectal cancer at the currently recommended dose and schedule. The bioavailability is strongly dependent on the timing of food intake in relation to the oral administration of the drug. The topoisomerase I-inhibitor should be administered under fasting conditions to achieve adequate drug exposure in future prospective trials in other tumour types.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Biological Availability; Camptothecin; Colorectal Neoplasms; Cross-Over Studies; Eating; Female; Humans; Male; Middle Aged; Neoplasm Metastasis
PubMed: 11937315
DOI: 10.1016/s0959-8049(02)00022-9 -
Annals of Oncology : Official Journal... Nov 2002Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate... (Clinical Trial)
Clinical Trial Comparative Study
BACKGROUND
Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies.
PATIENTS AND METHODS
Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle.
RESULTS
The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients.
CONCLUSIONS
The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Camptothecin; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms; Risk Assessment; Survival Analysis; Treatment Outcome; Gemcitabine
PubMed: 12419757
DOI: 10.1093/annonc/mdf342 -
Annals of the New York Academy of... 2000The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on... (Review)
Review
The binding of camptothecin (CPT) to the DNA-topoisomerase complex is reversible, but it needs to be maintained for maximal inhibitory activity. It is also dependent on the chemical structure of CPT. The lactone form is thought to be necessary for the activity. In human serum, the equilibrium between lactone and carboxylate is in favor of the latter. For these reasons, alternative administration of CPT analogues is being evaluated. The ideal compound would remain in lactone form and would expose the host for long periods of time to its effects. Oral administration of irinotecan (CPT-11) and topotecan (TPT) is discussed by other investigators. We studied oral rubitecan and reported a low lactone to total drug area under the plasma concentration-time curve (AUCP) ratio (14.7%), with low plasma concentration over time despite repeated administrations and the presence of an enterohepatic cycle. Aerosolization of a liposomal formulation of rubitecan is currently under study. Six patients have been treated once a day for 5 days every 3 weeks. The dose was 6.7 micrograms/kg/day. Plasma levels are dose for dose higher than those after oral administration, but the ratio of lactone versus total drug is low. No toxicity was observed. The study will continue with increasing doses and lengths of administration. Intrathecal administration of topotecan has been studied in a phase I trial in children. Doses of 0.4 mg are tolerated without toxicity, and clinical responses have been seen in patients with refractory meningial carcinomatosis. Phase II studies are planned. Intraperitoneal (i.p.) administration of topotecan has been studied in a phase I trial as a 24-hour infusion in 5% dextrose at pH 3.5 every 21 days. Dose-limiting toxicity is 4 mg/m2. Toxic effects are neutropenia, anemia, emesis, fever, and pain. Five of 10 patients with ascites had symptomatic relief. Pharmacokinetic analysis demonstrates a second-order kinetics with elimination half-lives of 0.49 and 2.7 hours. The peritoneal to plasma AUC ratio was 31.2. Intramuscular, transdermal, and subcutaneous administrations have been extensively studied in the mouse.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Drug Administration Routes; Enzyme Inhibitors; Humans; Irinotecan
PubMed: 11193899
DOI: 10.1111/j.1749-6632.2000.tb07042.x