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Investigational New Drugs Feb 2011Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with...
Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Glucosides; Humans; Male; Middle Aged; Neoplasms; Organoplatinum Compounds; Oxaliplatin
PubMed: 19774342
DOI: 10.1007/s10637-009-9322-9 -
Cancer Chemotherapy and Pharmacology Dec 2009Advanced cancers of the bile duct and gallbladder carry an ominous prognosis. Rebeccamycin analogue (RA) is a novel antitumor antibiotic where phase I trials suggested...
PURPOSE
Advanced cancers of the bile duct and gallbladder carry an ominous prognosis. Rebeccamycin analogue (RA) is a novel antitumor antibiotic where phase I trials suggested clinical efficacy in patients with biliary cancers.
METHODS
The primary objective was to determine the response rate to RA in patients with advanced gallbladder and bile duct tumors. Secondary endpoints were survival and pharmacokinetic characterization. RA was given at a dose 165 mg/(m(2) day) x 5 days every 3 weeks.
RESULTS
Forty-six patients were enrolled. Nine patients were removed from study before their first planned imaging study for response. Two patients had partial responses and 16 had stable disease. On an intent-to-treat analysis the median survival was 6.3 months. A >20% drop in CA19.9 was seen in 43% of patients with initial high levels. Grade 4 neutropenia and thrombocytopenia were seen in 35 and 5% of patients, respectively. Febrile neutropenia occurred in 16% of patients. The pharmacokinetic profile of this trial closely resembles those of prior phase I trials. Measured biliary concentrations of RA were as much as 100x greater than simultaneous plasma concentration.
CONCLUSION
Although RA has a response rate of 5% in advanced biliary cancers, it is associated with significant numbers of patients experiencing prolonged stable disease. Biliary concentrations of RA are significantly greater than plasma concentrations.
Topics: Aged; Antineoplastic Agents; Bile Duct Neoplasms; CA-19-9 Antigen; Carbazoles; Female; Fever; Gallbladder Neoplasms; Glucosides; Humans; Male; Middle Aged; Neutropenia; Survival Rate; Thrombocytopenia
PubMed: 19399502
DOI: 10.1007/s00280-009-1005-x -
Investigational New Drugs Feb 2003The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity.... (Clinical Trial)
Clinical Trial
The analog, rebeccamycin tartrate salt (NSC 655649, Cancer Therapy Evaluation Program, National Cancer Institute) has broad preclinical anti-neoplastic activity. Preliminary data from phase I study demonstrated antitumor activity in colorectal carcinoma. This phase II trial evaluates its efficacy in patients with minimally treated metastatic colorectal cancer. Eligibility included Karnofsky performance status > or = 70%, age > or = 18 years and bidimensionally measurable disease. Thirteen patients were treated with NSC 655649 at 500 mg/m2 by central venous catheter once every 3 weeks by bolus injection. Thirty-four cycles (median [range] 2 [1-6]) of therapy were administered. Twelve patients are eligible for response assessment. No major objective responses were seen using the RECIST criteria; however stable disease was observed in three patients with mean duration of 15 weeks. The median time to progression was 8 weeks. There was no toxic death. Four patients received only one cycle of treatment, and three had disease progression. Toxicities were tolerable and hematologic toxicity was the most common. The median (range) granulocyte and platelet nadir counts were 2043/microl (116-16,374/microl) and 276 x 10(3)/ microl (5-769), respectively. Non-hematologic toxicities were moderate, including generalized weakness/fatigue, nausea/vomiting, diarrhea and anorexia. One patient required dose reduction; three patients required dose delays. NSC 655649 at this dose and schedule is inactive against advanced previously minimally treated metastatic colorectal cancer and further study of this drug as a single agent in this disease using an every three-week schedule is not warranted.
Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Antineoplastic Agents; Carbazoles; Colorectal Neoplasms; Drug Administration Schedule; Female; Glucosides; Humans; Injections, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome
PubMed: 12795535
DOI: 10.1023/a:1022980613420 -
Journal of Clinical Oncology : Official... Jun 2001To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV)... (Clinical Trial)
Clinical Trial
PURPOSE
To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity.
PATIENTS AND METHODS
Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649.
RESULTS
Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin.
CONCLUSION
Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.
Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antineoplastic Agents; Carbazoles; Dose-Response Relationship, Drug; Female; Glucosides; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia
PubMed: 11387367
DOI: 10.1200/JCO.2001.19.11.2937 -
Journal of Clinical Oncology : Official... Apr 2001Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated... (Clinical Trial)
Clinical Trial
PURPOSE
Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily x 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions.
PATIENTS AND METHODS
Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m(2)/d x 5 days.
RESULTS
Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m(2)/d x 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 +/- 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve infinity. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression.
CONCLUSION
The recommended phase II dose for NSC 665649 on a daily x 5 every 3 weeks schedule is 141 and 165 mg/m(2)/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.
Topics: Adult; Aged; Aminoglycosides; Anti-Bacterial Agents; Antineoplastic Agents; Carbazoles; Cholangiocarcinoma; Disease Progression; Dose-Response Relationship, Drug; Female; Gallbladder Neoplasms; Glucosides; Humans; Infusions, Intravenous; Liver Neoplasms; Male; Middle Aged; Neoplasms; Neutropenia
PubMed: 11304785
DOI: 10.1200/JCO.2001.19.8.2309 -
Pediatric Blood & Cancer Mar 2008Rebeccamycin Analogue (NSC #655649), a chemically synthesized glycosyl-dichloro-indolocarbazole derivative of rebeccamycin with topoisomerase inhibiting activity, has in...
BACKGROUND
Rebeccamycin Analogue (NSC #655649), a chemically synthesized glycosyl-dichloro-indolocarbazole derivative of rebeccamycin with topoisomerase inhibiting activity, has in vitro activity against pediatric tumor cell lines and tumor specimens including rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma and medulloblastoma.
PROCEDURE
The primary objective of this trial was to determine the response rate to Rebeccamycin analogue NSC #655649 in children with refractory solid and CNS tumors. Secondary objectives included further evaluation of the toxicity and pharmacokinetic profile of Rebeccamycin analogue in children with relapsed and refractory cancer. A two-stage design was used for this Phase II trial. Rebeccamycin analogue, 650 mg/m(2), was administered every 21 days, and could be escalated to 780 mg/m(2) in subsequent cycles to achieve a maximum plasma drug concentration >5 microg/ml.
RESULTS
From July 2000 to October 2004, 72 male and 61 female eligible patients were enrolled. Of 126 evaluable patients for response, only 4 patients had an objective response: 3 patients with rhabdomyosarcoma (1 CR and 2 PR) and 1 patient with neuroblastoma (1 PR). Grade 3 or 4 myelosuppression occurred in 81% (215/265) of patient courses and hepatotoxicity in 14% (37/265) of patient courses. Transient pancreatitis and/or elevation of amylase and lipase occurred in 6 patients.
CONCLUSIONS
The 15% response rate to Rebeccamycin analogue observed in patients with rhabdomyosarcoma, while of interest, is associated with significant myelosuppression. With a global response rate of 3% observed in children with relapsed CNS and non-CNS solid tumors, further development of Rebeccamycin analogue in pediatric solid tumors is not recommended.
Topics: Adolescent; Adult; Aminoglycosides; Antibiotics, Antineoplastic; Bone Marrow Diseases; Carbazoles; Central Nervous System Neoplasms; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Female; Glucosides; Humans; Infant; Infant, Newborn; Infusions, Intravenous; Male; Neoplasm Proteins; Neoplasms; Pancreatitis; Rhabdomyosarcoma; Salvage Therapy; Topoisomerase II Inhibitors
PubMed: 17610262
DOI: 10.1002/pbc.21274 -
Investigational New Drugs Nov 2003Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate... (Clinical Trial)
Clinical Trial
OBJECTIVE
Rebeccamycin analog (NSC-655649) is an antibiotic with antitumor properties demonstrated in preclinical and phase I studies. We conducted a phase II trial to evaluate the efficacy and toxicity of this agent in patients with advanced renal cell cancer (RCC).
METHODS
Eligible patients had histologically or cytologically confirmed diagnosis of RCC that was either locally advanced unresectable, locally recurrent, or metastatic. Patients had to have measurable disease, no prior chemotherapy, life expectancy of greater than 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, adequate-organ function, and be >/=18 years old. Patients were treated with NSC-655649 at a dose of 165 mg/m(2) daily i.v. over 30-60 min for 5 days. Treatment was repeated every 21 days. Response was assessed every two courses.
RESULTS
Twenty-four patients were enrolled. There were sixteen males and eight females with a median age of 60.5 years (range 42-76). Nineteen were Caucasians, seventeen had prior nephrectomy, and thirteen had prior immunotherapy. The major toxicity was myelosuppression with grade 3 and 4 neutropenia in 38% of patients and anemia in 33% of patients. There were two partial responses (2/24, 8%) and 11 patients (46%) achieved stable disease (SD). The 6-month progression-free rate for patients with SD was 30%. Of the seventeen patients with progressive disease at registration, one had a PR and eight had SD. The overall median survival time for all 24 patients was 10.0 months (90% CI=5.2, 17.4 months). The 12-month survival rate was 39%, with 90% CI=(0.21, 0.58). Nine patients are still alive with survival times ranging from 3.8 to 24.2 months, at a median follow-up time of 11.9 months.
CONCLUSION
Rebeccamycin analog (NSC-655649) is well tolerated and has modest antitumor activity in patients with advanced RCC.
Topics: Adult; Aged; Aminoglycosides; Carbazoles; Carcinoma, Renal Cell; Confidence Intervals; Female; Glucosides; Humans; Indoles; Kidney Neoplasms; Male; Middle Aged; Survival Rate
PubMed: 14586215
DOI: 10.1023/a:1026259503954 -
Journal of Pediatric Hematology/oncology 1998This study determined the in vitro antitumor activity of a rebeccamycin analog (NSC# 655649) using tetrazolium/formazan (MTT) and clonogenic assays against established...
PURPOSE
This study determined the in vitro antitumor activity of a rebeccamycin analog (NSC# 655649) using tetrazolium/formazan (MTT) and clonogenic assays against established pediatric cell lines and solid tumor specimens obtained from children.
MATERIALS AND METHODS
Tumor cells from 14 established cell lines and 20 patient specimens were exposed in vitro for 1 hour to NSC# 655649 at concentrations ranging from 0.015 to 15.0 microM. The cytotoxicity (IC50) of this agent against established cell lines was determined using both the MTT (cytotoxic) and clonogenic/soft agar cloning (cytostatic) assays. Tumor specimens from children undergoing biopsy or surgical resection were also evaluated in vitro against NSC# 655649 using the clonogenic assay. For studies using patient specimens, antitumor activity was measured by comparing the number of tumor colonies from NSC# 655649-treated cells with those from solvent-treated controls.
RESULTS
These studies showed that the mean IC50S using the MTT and clonogenic assays using established solid tumor cell lines were 0.94 and 0.51 microM, respectively. In general, for cell lines tested using both types of assays, the clonogenic assay resulted in a smaller IC50. The overall in vitro responses (< or = 50% survival compared to controls) using patient tumor specimens and the clonogenic assay were 35% (1.5 microM), 60% (7.5 microM), and 80% (15.0 microM). Of the 9 patients with neuroblastoma, responses to NSC# 655649 were seen in 33% (1.5 microM), 58% (7.5 microM), and 92% (15.0 microM) of the specimens. Prior chemotherapy did not appear to adversely affect in vitro responses.
CONCLUSIONS
NSC# 655649 appears to have broad antitumor activity in vitro against pediatric malignancies at drug concentrations achieved during adult phase I clinical trials. These studies support the further development of NSC# 655649 for solid tumors in children.
Topics: Aminoglycosides; Anti-Bacterial Agents; Antineoplastic Agents; Carbazoles; Child; Drug Screening Assays, Antitumor; Glucosides; Humans; Medulloblastoma; Neoplasms; Neuroblastoma; Rhabdomyosarcoma; Sarcoma, Ewing; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured
PubMed: 9544164
DOI: 10.1097/00043426-199803000-00009 -
Clinical Cancer Research : An Official... Dec 2005To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin...
PURPOSE
To evaluate the feasibility of administering NSC 655649, a water-soluble rebeccamycin analogue that inhibits both topoisomerases I and II, in combination with cisplatin (CDDP) in adults with solid malignancies. Major toxicologic and pharmacologic differences between the two sequences of drug administration were also assessed.
EXPERIMENTAL DESIGN
NSC 655649 was administered as a 60-minute i.v. infusion; CDDP was given i.v. before or after NSC 655649 on day 1. Each patient was treated with alternating drug sequences every 3 weeks; doses of each drug were escalated in separate cohorts of new patients. Sequential dose escalation of NSC 655649 or CDDP resulted in three dosage permutations of NSC 655649/CDDP: 440/50, 550/50, and 440/75 mg/m2. After the maximum tolerated dose level was determined, the feasibility of using granulocyte colony-stimulating factor to permit further dose escalation was explored.
RESULTS
Twenty patients were treated with 70 courses of NSC 655649/CDDP. Myelosuppression was the principal toxicity. The incidence of severe neutropenia, often associated with severe thrombocytopenia, was unacceptably high in minimally pretreated patients at the NSC 655649/CDDP dose level of 550/50 mg/m2 without and with granulocyte colony-stimulating factor. Major pharmacokinetic interactions between NSC 655649 and CDDP were not apparent. No relevant sequence-dependent differences in toxicity or pharmacokinetic variables occurred. Three patients had partial responses.
CONCLUSIONS
NSC 655649 and CDDP were well tolerated by minimally pretreated subjects at 440 and 50 mg/m2, respectively. Neither pharmacokinetic interactions between the agents nor sequence-dependent toxicologic or pharmacokinetic effects were apparent. The tolerance and preliminary activity observed with this combination suggest that disease-directed evaluations of the regimen are warranted.
Topics: Adult; Aged; Aged, 80 and over; Aminoglycosides; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Cisplatin; Drug Interactions; Female; Glucosides; Humans; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia; Tomography, X-Ray Computed
PubMed: 16361560
DOI: 10.1158/1078-0432.CCR-05-1572 -
Bioorganic & Medicinal Chemistry Aug 2003In the course of structure-activity relationship studies on rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized...
In the course of structure-activity relationship studies on rebeccamycin analogues, a series of compounds bearing an amino function on the sugar moiety were synthesized with the aim of improving the solubility and interaction with the macromolecular target(s). The syntheses of amino derivatives and the corresponding chloro, iodo and azido intermediates are described. Their interaction with DNA and effects on human DNA topoisomerases I and II were investigated. Their antimicrobial activities against two Gram-positive bacteria, Bacillus cereus and Streptomyces chartreusis, a Gram-negative bacterium Escherichia coli and a yeast Candida albicans were also determined. 6'-Amino compound 7 and 6'-N-methylamino 14 very efficiently inhibit the growth of E. coli. The introduction of an amino group at the 6'-position strongly enhances the capacity of the drugs to interact with DNA but almost abolishes their poisoning effect on topoisomerase I. Unlike the vast majority of rebeccamycin analogues previously studied, the newly designed compounds do not stimulate DNA cleavage by topoisomerase I. The enhanced capacity of the 6'-amino glycosyl rebeccamycin derivatives to bind to DNA likely account for the improved biological profiles. DNA and topoisomerase I represent two independent targets which can both be used for the development of antitumor rebeccamycin derivatives.
Topics: Amines; Aminoglycosides; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Carbazoles; Deoxyribonucleases; Glucose; Glucosides; Glycosylation; Humans; Indoles; Structure-Activity Relationship; Topoisomerase II Inhibitors
PubMed: 12901916
DOI: 10.1016/s0968-0896(03)00343-2