Study Of Topotecan Research Articles

2‐Hydroxyethyl Methacrylate Hydrogels for Local Drug Delivery: Study of Topotecan and Vincristine Sorption/Desorption Kinetics and Polymer‐Drug Interaction by ATR‐FTIR Spectroscopy

AbstractPoly(2‐hydroxyethyl methacrylate) (pHEMA) hydrogels are well known in ophthalmological applications and recently investigated as drug delivery systems. The study represents a theoretical approach where the sorption/desorption experiments and spectroscopic study is used to describe the influence of the pHEMA network structure on the sorption capacity and mechanism of the release of topotecan (TPT) and vincristine (VCR). The hydrogels are synthesized by free‐radical crosslinking polymerization of HEMA monomer with ethylene glycol dimethacrylate as a crosslinker in the concentration range from 0.3 to 1 wt%. Experimental data from sorption kinetics are evaluated using sorption kinetic models and sorption isotherms, drug release mechanism is assessed by two different models and attenuated total reflectance Fourier transform infrared (ATR‐FTIR) spectroscopy is employed to describe the polymer‐drug interaction. pHEMA hydrogels exhibit higher affinity for TPT than for VCR and hydrogels prepared with 0.5 wt% of crosslinker show the maximum sorption capacity for both drugs. Physisorption is proved to be the sorption mechanism. Analyzing the FTIR spectra, it is concluded that the hydrophobic crosslinks play an important role in the interaction of the hydrogel backbone with molecules of both drugs.

Neurocognitive functioning and quality of life in patients with recurrent malignant gliomas treated on a phase Ib trial evaluating topotecan by convection-enhanced delivery.

Malignant gliomas are highly proliferative, invasive tumors that are resistant to conventional treatment, and disease progression is often accompanied by physical and mental debilitation. Neurocognitive functioning (NCF) and quality of life (QoL) were evaluated as part of a prospective phase Ib dose-escalation study of topotecan by convection-enhanced delivery (CED) for adult patients with recurrent malignant gliomas. Sixteen patients were enrolled, and NCF and QoL were evaluated using the Cognitive Stability Index and SF-36 at baseline and monthly for 4 months post treatment. Descriptive analyses included the reliable change index for serial evaluations and correlations for associations between outcome variables and age, tumor volume, total topotecan dose, and treatment effect. Individual classifications of response to treatment indicated that a majority of patients reported stable scores over the follow-up period. Demographic and treatment-related variables were not associated with outcomes. Baseline processing speed scores were invalid for 6 subjects. Higher rates of valid scores were observed on subsequent administrations. As the first study to use CED of any kind to evaluate the impact of CED on NCF or QoL, there was no evidence of severe detriment to either outcome. Long-term evaluation is necessary to track changes in NCF and QoL related to disease progression. Invalid scores suggest that computer-based assessments may not be suitable for all patients with malignant gliomas, especially those with cognitive deficits secondary to their disease. Future trials should include a wider range of sensitive measures to assess the impact of CED on patient NCF and QoL.

Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC): A randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR).

5031 Background: We present the efficacy data from a phase III study of topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1-3/q21d) + C (AUC 5/d1/q21d) or to standard therapy with CP or GC or PLDC based on patient preference. Progression free survival at 1 year was defined as primary endpoint. Results: Median number of cycles was 6 (range 0-9) in both arms. Most patients preferred GC (78%) in the standard therapy arm.. Best Response (CR+PR) was 73.1% (95%CI) and 75.1% (95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 (0-48) months for standard therapy. TC failed to show any advantage regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan plus carboplatin failed to improve PFS or OAS in platinum sensitive relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities compared to paclitaxel-carboplatin. [Table: see text]

Phase I Study of Topotecan, Ifosfamide, and Etoposide (TIME) with Autologous Stem Cell Transplant in Refractory Cancer: Pharmacokinetic and Pharmacodynamic Correlates

To determine the maximum tolerated dose (MTD) of topotecan in combination with ifosfamide, mesna, and etoposide (TIME), followed by autologous hematopoietic cell transplant (HCT), in patients with chemotherapy-refractory malignancies. Patients were treated with (in mg/m(2)/d) ifosfamide 3,333, mesna 3,333, and topotecan 3.3 to 28.3 during days -8 through -6 and etoposide 500 (days -5 through -3) followed by HCT on day 0. Once MTD was defined, we expanded this dosing cohort to include patients with high-risk lymphoma due to activity seen during dose escalation. Topotecan pharmacokinetic analyses were carried out, and topoisomerase I levels and activity were measured. The topotecan MTD in this regimen was 64 mg/m(2) (21.3 mg/m(2)/d). Mucositis was dose limiting and correlated with topotecan dose level and area under the curve (AUC). Dose level was also correlated with length of hospitalization, number of days of parenteral nutrition, and neutrophil and platelet engraftment. Topotecan AUC was significantly correlated with time to platelet recovery. The baseline peripheral blood mononuclear cell topoisomerase I level was found to be a significant positive predictor for overall and progression-free survival. Topotecan AUC was positively correlated with dose level, with a trend toward decreasing clearance with increasing dose. Topotecan can be a useful drug in the high-dose setting given its activity in some malignancies when given in standard dose. Pharmacokinetic monitoring may be a valuable tool for optimizing the use of topotecan and to avoid toxicity seen with high-systemic exposures. Baseline topoisomerase I levels may have an important role in predicting topotecan efficacy.

Phase I Study of Topotecan and Cisplatin in Patients with Small Cell Lung Cancer

A single-agent topotecan has an indication for the treatment of small cell lung cancer in Japan. Previous studies demonstrated that topotecan combined with a platinum agent could provide additional antitumor efficacy. This study was to find the recommended dose of topotecan in combination with cisplatin and preferred administration sequence in untreated patients with extensive disease small cell lung cancer for Phase II study. Patients received topotecan as a 30 min infusion for 5 days in escalating doses (starting at 0.5 mg/m(2)/day), and cisplatin at a fixed dose of 60 mg/m(2), 3 weeks cycle. This study employed the following stages: cisplatin was given before topotecan on day 1 to previously treated patients (Stage 1). After the maximum-tolerated dose level was achieved, the same schedule was applied for untreated patients (Stage 2). Subsequently, cisplatin was given after topotecan on day 5 to untreated patients (Stage 3). The recommended doses of cisplatin on day 1 and 5 schedules were estimated by considering results obtained from Stages 2 and 3, respectively. A total of 34 patients were enrolled. The maximum-tolerated doses in Stages 1-3 were estimated at 0.65, 0.65, and 1.4 mg/m(2), respectively. The recommended doses of cisplatin on day 1 and 5 schedules in untreated patients were determined at 0.65 and 1.0 mg/m(2), respectively. The major toxicity in this combination was hematological events. For treatment-naive patients, the combined use of 0.65/60 mg/m(2) topotecan/cisplatin with cisplatin on day 1 schedule or 1.0/60 mg/m(2) topotecan/cisplatin with cisplatin on day 5 schedule is recommended for Phase II study.

A phase I study of topotecan and gemcitabine in advanced solid tumors

Gemcitabine and topotecan are commonly used anti-tumor agents with a wide spectrum of activity in vitro and in vivo. A phase I trial of a combination of these two agents was initiated based on the premise that both gemcitabine and topotecan cause DNA damage and interfere with DNA repair by different mechanisms. Synergism has been demonstrated in vitro when gemcitabine and other topoisomerase I inhibitors have been combined. Seventeen patients with advanced solid tumors signed consent and were treated on this study with at least one cycle. Treatment consisted of gemcitabine at doses of 400 to 625 mg/m(2) days 1 and 5 in combination with topotecan at doses of 0.8 to 1 mg/m(2) given on days 2 through 5 every 21 days. The dose limiting toxicities of granulocytopenia and thrombocytopenia were reached at the highest dose level of gemcitabine 625 mg/m(2) and topotecan 1 mg/m(2). A diffuse skin rash was also seen in four treated patients and responded well to treatment with steroids. One partial response and seven stable disease were seen as best response in 16 evaluable patients. The combination of gemcitabine and topotecan was found to be tolerable with interesting preliminary activity. The recommended phase II dose for this combination is gemcitabine at 500 mg/m(2) on days 1 and 5 with topotecan at 0.8 mg/m(2) on days 2 to 5.

A phase I/II study of topotecan and sorafenib in recurrent, platinum-resistant ovarian cancer: HOG GYN-111.

5108 Background: Recent data showed that the multikinase inhibitor sorafenib (S) is active in ovarian cancer (OC). The scope of this trial was to determine efficacy and tolerability of S in combination with topotecan (T), an FDA-approved agent for platinum resistant OC. Methods: This multi-institutional phase I/II study was designed to determine the maximum-tolerated dose (phase I) and the response rate (phase II) to the regimen S+T in platinum resistant OC. Secondary endpoints were to measure PFS, toxicities, and rate of clinical benefit. Eligible patients had measurable or detectable recurrent OC, up to three prior cytotoxic treatments, ECOG PS of 0-1 and normal end-organ function. S was administered orally daily and T was given IV weekly at a fixed dose of 4 mg/m2, 3 weeks on and 1 week off during a 28 day cycle. For the phase I trial a 3 + 3 dose escalation design was used, testing two S dose levels: 400 mg daily (level 1) and 800 mg daily (level 2). The T dose was reduced to 3.5 mg/m2 weekly. The regimen tested during phase II was S at 400 mg daily and T at 3.5 mg/m2 weekly. Results: 16 pts were enrolled in phase I and 14 pts in phase II; all 30 were evaluable. Median age was 52.5 years (range 35-79), 27 pts had OC, and 3 pts had PPC. Nine pts were platinum refractory, 18 platinum-resistant, and 3 had platinum allergy. Median number of cycles administered was 2.5 (0-15). There were 5 PRs (16.7%), and 12 pts (40%) with stable disease (SD). Four PRs were recorded during phase I and 1 PR during phase II. Of these, 2 PRs occurred in pts receiving T at 4 mg/m2 and 1 PR in a pt receiving S at 800 mg/day. Median SD duration was 4.2 months (95% CI, 3.7-4.9). The most common treatment related all grade toxicities were nausea (53%), anemia (53%), thrombocytopenia (40%), neutropenia (50%), fatigue (37%), vomiting (23%), hand-foot syndrome (HFSR), and anorexia (20% each). Grade 3/4 toxicities included neutropenia (23%), thrombocytopenia (17%), anemia (10%), and fatigue, nausea, vomiting (6.7% each). One case of grade 3 HFSR was recorded. Conclusions: S can be safely combined with T in OC patients, but requires reduction of T to 3.5 mg/m2 weekly. The combination has clinical activity, however most responses were registered in pts receiving the higher doses of S or T. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer

A phase II study of topotecan and bevacizumab in advanced refractory non-small cell lung cancer: Interim analysis.

e18040 Background: Previous studies have suggested improved outcomes with a single topoisomerase I inhibitor for chemotherapy naive advanced non-squamous non-small cell lung (NSCLC). Bevacizumab is...

9134 Phase II study of topotecan and bevacizumab in patients with metastatic non-small cell lung cancer who have failed prior systemic chemotherapy – interim analysis

9134 Phase II study of topotecan and bevacizumab in patients with metastatic non-small cell lung cancer who have failed prior systemic chemotherapy – interim analysis

P1-228: A combination phase I study of topotecan with carboplatin for relapsed small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTOG0202)

P1-228: A combination phase I study of topotecan with carboplatin for relapsed small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTOG0202)

A combination phase I study of topotecan with carboplatin for relapsed small cell lung cancer: Results of West Japan Thoracic Oncology Group trial (WJTOG0202)

18126 Background: Topotecan is an active agent for relapsed or recurrent SCLC. Combination chemotherapy of topotecan and carboplatin for relapsed SCLC has not been fully evaluated. To determine the maximum-tolerated dose (MTD), a phase I study was conducted. Method: Patients with measurable disease and one prior chemotherapy regimen excluding topotecan were enrolled in this study. Topotecan was administered through days 1 to 5, whereas carboplatin was administered on day 5. Courses were repeated every 3 weeks. The starting doses of topotecan and carboplatin were 0.50 mg/m2/day and AUC=5, respectively. The dose levels examined are shown in the table below. Results: A total of 32 patients with relapsed SCLC have been enrolled. Patient characteristics are as follows: median age, 64 yrs (range 43–74); male/female, 23/9; ECOG PS 0/1, 15/17 patients. Dose-limiting toxicities (DLTs) were observed in 1 patient at dose level 1 (infection), level 3 (diarrhea), and level 5 (thrombocytopenia), respectively. Three of 6 patients have experienced DLTs at dose level 6 (thrombocytopenia). MTD of topotecan and carboplatin were determined to be 0.85 mg/m2 and AUC=5, respectively. Five of 29 (17 %) assessable patients have responded to treatment with a partial response (PR), and 13 (45 %) patients have had stable disease (SD) at best response. Conclusions: The recommended doses are 0.75 mg/m2 of topotecan and AUC=5 of carboplatin. The combination of topotecan and carboplatin shows an acceptable activity and toxicity profile in relapsed SCLC patients. Further study in the phase III setting is warranted. [Table: see text] No significant financial relationships to disclose.

Phase I study of topotecan (T) with weekly 5-fluorouracil (5FU)/leucorin (LV) in patients with advanced malignancies

13018 Background: Topotecan (T) is a semi-synthetic camptothecin analog with a broad spectrum of activity targeting the nuclear enzyme topoisomerase I. Daily iv schedules (up to 5) can result in dose limiting neutropenia. Reported synergy in vitro between topoisomerase I inhibitor and 5 FU/LV led us to explore a weekly schedule of 5FU, LV, and T in refractory tumors. Methods: Entry criteria: metastatic or locally advanced solid tumors; up to two prior chemotherapy regimens; prior adjuvant regimen admissible; no chemotherapy or radiation therapy within 4 weeks; adequate hepatic, hematologic, renal function. Exclusion: active second malignancy; CNS metastases; prior topotecan; allergy to related agents; active uncontrolled infection or conditions that would interfere with the study. Treatment was administered days 1, 8, 15, 22 of a 42 day cycle as LV 20 mg/meter (m)2 over 15 minutes intravenously (iv), 5 FU 400mg/m2 bolus, iv, and T at the specified dose (1.5mg/m2, 1.75, 2.0, up to 4 mg) over 30 minutes iv. Cohorts were advanced after at least three pts had completed 42 d. Study is reported through cohort 9: 5 FU 400/m2, LV 20/m2, topotecan 4 mg/m2. Results: Pt characteristics: 19 F, 25 M; ages 29–80, median 62. Tumor types: Pancreas (9), colorectal (6), lung (6), liver (3), salivary gland (5), sinus (2), nasopharynx (2) esophagus (2), and tongue, larynx, ovary granulosa cell tumor (gct), endometrium, mixed mullerian, mesothelioma, sarcoma, gastric (1 each). Related toxicities: gr 3/4 neutropenia 9%/2%, Hb 11%/0, platelets 4.5%/0, fatigue 4.5%/0. Stable disease of ≥ 4 cycles was observed in 18%: pancreas (2), ovarian (1), endometrium (1), salivary gland (3) (2 adenoid cystic, 1 adenocarcinoma). Conclusions: 5 FU, LV and T is well tolerated as a weekly out patient schedule (4 of 6 wks). It achieved minor response in one patient with gct for 8+ cycles and stable disease for ≥ 4 cycles in 6 pts. It is worthy of further exploration for gynecologic, salivary gland and pancreatic cancers. No significant financial relationships to disclose.

Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.

Phase II study of topotecan and carboplatin in the treatment of platinum-sensitive recurrent ovarian and peritoneal cancer

15001 Background: The aim of this trial was to investigate the efficacy and toxicity of the combination of Topotecan (T) and Carboplatinum (C) in the management of recurrent platinum sensitive ovarian and peritoneal cancer. Methods: T (1 mg/m2) was given as a 30-minute infusion daily × 3 days and C (AUC 5) was given as a 30-minute infusion following T on day 3 on a 21-day cycle. Results: Thirty patients (pts) were enrolled and all pts were evaluable for response and toxicity. Mean age was 63.2 (range = 44–84). One hundred eighty five cycles (mean/pt = 6, range 2–10) were evaluable for toxicity. Dose escalation (T = 1.25 mg/m2) was possible in 25 (83.3%) pts. Hematologic toxicity grade 3 and 4 neutropenia was seen in 60 (32.4%) and 10 (5.4%) cycles, respectively. Grade 3 thrombocytopenia was encountered in 24 (13%) cycles. Grade 3 Hgb was observed in 4 (2.2%) cycles. No grade 4 thrombocytopenia/Hgb or neutropenic fever was encountered. Blood transfusions were required in 9 (4.9%) cycles. Bone marrow support with erythropoiten (40% pts), and filgrastim (43.3% pts) were utilized. No neuropathy > grade 1 was encountered. Fourteen pts (46.6%) pts had a hypersensitivity reaction to C and successful desensitization was carried out in 8 (57.1%). Mean follow-up interval was 16.9 months (mos) (Range 1.7–43). To date, 6 (20%) pts are alive without disease, 16 (53.3%) are alive with disease, and 8 (26.7) have died of disease. The overall response rate was 83.3% (5 CR and 20 PR). Five (16.6%) pts had SD. Median progression-free interval was 8.2 mos. Overall mean survival for the cohort was 31.2 mos (95% CI: 24.47–37.71). Conclusions: Given the ICON-4 data, supporting combination therapy in recurrent platinum-sensitive patients, this regimen provides an effective and tolerable alternative to Taxane-platinum combination with no significant neuropathy. This regimen is especially attractive in patients who have significant residual neuropathy after initial treatment. Carboplatinum desensitization was feasible in previously pre-treated patients. No significant financial relationships to disclose.

P-798 Phase I study of topotecan and bortezomib (Vc) withpharmacokinetic and pharmacodynamic correlates

P-798 Phase I study of topotecan and bortezomib (Vc) withpharmacokinetic and pharmacodynamic correlates

P-766 Phase II study of topotecan (T) and paclitaxel (P) as first-line treatment in patients (pts) with extensive disease small cell lung cancer (ED-SCLC)

P-766 Phase II study of topotecan (T) and paclitaxel (P) as first-line treatment in patients (pts) with extensive disease small cell lung cancer (ED-SCLC)

P-764 Phase II study of topotecan plus gemcitabine in previously treated small cell lung cancer (SCLC) patients: An Alpe-Adria Thoracic Oncology Multidisciplinary Group study (ATOM 012)

P-764 Phase II study of topotecan plus gemcitabine in previously treated small cell lung cancer (SCLC) patients: An Alpe-Adria Thoracic Oncology Multidisciplinary Group study (ATOM 012)

Pharmacokinetically guided phase I trial of topotecan and etoposide phosphate in recurrent ovarian cancer

A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0–2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m−2 day−1 days 1–5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 μg ml−1. The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIα levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.

Phase I study of topotecan and amrubicin in patients with chemo-naive extensive disease (ED) or relapsed small-cell lung cancer (SCLC)

7340 Background: Combination chemotherapy of topotecan and amrubicin for ED or relapsed SCLC has not been fully evaluated. To determine the maximum-tolerated dose (MTD), a Phase I study in patients with ED or relapsed SCLC was conducted. Methods: Both relapsed patients with prior chemotherapy and chemo-naïve ED patients were enrolled in this study. Topotecan was administered through days 1 to 5, whereas amrubicin was administered on days 3 to 5. Courses were repeated every 3 weeks. The starting doses of topotecan and amrubicin were 0.75 and 30 mg/m2/day, respectively. Blood samples were obtained during the second and third days of the first cycle. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria (Ver2.0). Results: Patients with ED or relapsed SCLC (n = 9) were enrolled between April and November 2003, including 3 sensitive-relapsed cases. A total of 24 courses were assessable for safety. The principle toxicity was myelosuppression. In the first course of dose level 3, DLT was observed in all 3 patients (persistence of grade 4 neutropenia in 1 patient, grade 3 thrombocytopenia with platelet transfusion in 1 patient, plus persistence of grade 4 neutropenia and leukopenia and grade 3 febrile neutropenia in 1 patient). Thus, MTDs of topotecan and amrubicin were determined to be 0.75 and 40 mg/m2, respectively. Objective response was obtained in 7 patients (78%), including 4 relapsed patients. Cmax and AUC of amrubicinol were correlated to duration of grade 4 neutropenia (Spearman’s test, p=0.0239 and 0.0211). Additionally, the mean Cmax of topotecan on day 2 in 7 responders was significantly higher than that in 2 non-responders (22.9±3.6 and 10.9±0.4, respectively, Mann-Whitney U test, p=0.0404). Conclusions: This combination was well tolerated and produced a promising antitumor effect for ED or relapsed SCLC. Several pharmacokinetic factors may be predictive of toxicity and response. No significant financial relationships to disclose.

A Phase II Study of Topotecan and Cyclophosphamide with G-CSF in Patients with Small Cell Lung Cancer with Poor Prognostic Factors

Purpose: We conducted a multicenter phase II study to evaluate the efficacy and safety of the combination of topotecan and cyclophosphamide for patients with small cell lung cancer (SCLC) with poor prognostic factors. Patients and Methods: Patients were eligible if they had newly diagnosed extensive stage SCLC or if they had SCLC that progressed more than three months after completion of the first chemotherapy regimen. Patients were treated every 21 days with cyclophosphamide 600mg/m2 IV on day 1 and topotecan 1.0 mg/m2 on days 1 to 5. Filgrastim was administered for 10 days starting on day 6. Patients were evaluated for objective tumor response, time to tumor progression, overall survival and toxicity. Results: Forty–two eligible patients were treated. Seventeen patients (40.5%) had an objective response including 4 (9.5%) complete remissions (CR). Fifteen patients (35.7 %) had stable disease. There are 2 patients known to be alive at the time of this report: one with stable disease at 26 months and another with a CR at 37 months. The median number of cycles completed was 6 (range 1-12). The major toxicities were grades 3 and 4 neutropenia (73.8%), grades 3 and 4 anemia (35.7%) and grades 3 and 4 thrombocytopenia (50%). Five patients died during the first cycle of chemotherapy. The median time to progression was 3 months (range 5 days-36 months) )[95% confidence interval (CI),2 months to 4.5 months] for all patients. The median overall survival was 9 months (range 5 days – 37 months) [95% CI, 7 months to 11 months]. The two-year survival rate was 21%. Conclusions: The combination of topotecan and cyclophosphamide is highly active in small cell lung cancer. Myelosuppression is the major toxicity and is rapidly reversible in most patients. The incidence of treatment-related mortality was comparable to other intensive chemotherapy regimens. This incidence is unacceptably high and indicates better selection criteria are needed in order to exclude patients at excessive risk of morbidity.