Phase II trial of peplomycin in non-Hodgkin's lymphoma

Seventeen patients with malignant lymphoma were entered into a phase II study of peplomycin (PEP) to determine the efficacy of the drug. There were 8 males and 9 females with a median age of 64 yrs (range 3-74 yrs) and a median PS 3 (range 2-4). Three of these were children. At first PEP was given intermittently and intramuscularly (8 cases) at a dose of 10 mg every one (3 cases) or two (5 cases) weeks, and then intravenously by 22-hr continuous infusion (9 cases) at a dose of 5 mg per day for 5 days. Mean cumulative dose was 78 mg. Objective responses were obtained in 6 patient (35%). CR lasting 4 weeks was obtained in one patient with diffuse mixed-type lymphoma. Five patients, one with diffuse medium-sized cell type and 3 with diffuse large cell type, had PR, lasting 6, 7, 7, 9, and 50+ weeks, respectively. Pulmonary fibrosis was found in two patients on autopsy and interstitial pneumonia in two patients clinically. Temporary high fever occurred in 7 patients, stomatitis in 3 patients and anorexia in 3 patients.     

Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin's lymphoma.

PURPOSE: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m2 over 30 to 60 minutes weekly for four treatments. RESULTS: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease (> or = 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m2 dose group and 27% in the 480 mg/m2 dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate. CONCLUSION: Epratuzumab was well tolerated at up to 1,000 mg/m2/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m2/wk indicates that this dose should be explored in additional studies.     

Phase I trial of fludarabine and paclitaxel in non-Hodgkin's lymphoma

Fludarabine is an active agent in low-grade non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Paclitaxel is also active in patients with refractory lymphoma, and preclinical data suggest an additive effect with fludarabine in vitro. We performed a phase I trial of fludarabine (25 mg/m² d 1–3) plus a 3-h infusion of paclitaxel (125, 150, or 175 mg/m²) on d 3 every 28 d in 13 patients with non-Hodgkin’s lymphoma. The paclitaxel dose was escalated in cohorts of 3–4 patients using standard phase I design schema. Dose-limiting toxicity was defined as febrile neutropenia, platelet nadir less than 50,000/μL, or grade 3–4 nonhematologic toxicity. Thirteen patients were accrued to the study, 8 of these 13 patients (62%) had received prior chemotherapy. At the 125-, 150-, and 175-mg/m² dose levels of paclitaxel, dose-limiting toxicity occurred in 1/4, 0/4, and 0/4 patients, respectively. The single patient with dose-limiting toxicity had febrile neutropenia. Partial response occurred in two of eight patients with low-grade lymphoma and none of five patients with other types of lymphoma. A paclitaxel dose of 175 mg/m² given as a 3-h infusion on d 3 in conjunction with fludarabine (25 mg/m² d 1–3 every 4 wk) is a well-tolerated regimen for non-Hodgkin’s lymphoma. Further study will be required in order to determine whether the fludarabine-paclitaxel is more active than fludarabine alone in patients with low-grade lymphoma and chronic lymphocytic leukemia.     

Phase II trial of temozolomide in low-grade non-Hodgkin's lymphoma.

Temozolomide, an imidazotetrazine derivative, was given to 18 patients with low-grade non-Hodgkin''s lymphoma (NHL) at a dose of 750 mg m-2 orally, divided over five consecutive days, escalated to 1000 mg m-2 over 5 days (i.e. 200 mg m-2 day-1) if no significant myelosuppression was noted at day 22 of the 28 day cycle. Fifty-six treatment cycles were given to 18 patients. The drug was well tolerated. Only one partial tumour response was documented. The patients were heavily pretreated but had chemoresponsive disease, as shown by a response rate of 69% among 13 patients who went on to receive alternative cytotoxic regimens. We conclude that temozolomide given in this schedule is inactive in previously treated low-grade NHL.     

Phase I/II trial of multiple dose 131Iodine-MAb LL2 (CD22) in patients with recurrent non-Hodgkin's lymphoma

The purpose of this to evaluate in a phase I/II study the efficacy and toxicity of a multi-dose administration of 131I labeled CD22 monoclonal antibody (131I-MAb-LL2) in escalating dose cohorts administered to relapsed non-Hodgkin's lymphoma (NHL) patients. Twenty-one patients with relapsed NHL received one of four dose levels of 131-MAb-LL2 administered in a twice weekly pattern. Starting with dose level 2, the patients also received 20 mg of unlabeled LL2 prior to each radiolabeled dose administered. Previously stored autologous peripheral blood progenitors were reinfused in case of prolonged cytopenias. Patients could repeat the same treatment if they had stable disease or a response to the first therapy at 8 weeks, and had not received their peripheral blood progenitors with the first cycle. Combining all of the dose cohorts, there were 5 complete responses or complete responses (undetermined) and 2 partial responses for a total response rate of 7/21 (33%). There was no dose response effect with responses documented at all dose levels. Expected toxicities were hematopoietic, requiring stem cell re-infusion in 5 patients. Other toxicities included hypothyroidism in 3 patients, and human anti-mouse antibody formation (HAMA) in 4 patients. In conclusion, 131I-MAb-LL2, when administered in a multi-dose fashion with 20 mg unlabeled antibody pre-dosing, resulted in a response rate of 33% in heavily pre-treated NHL patients. Non-hematologic toxicities were mild and few in number. Further evaluation of this treatment is warranted and further dose escalation will be possible.     

Secondary prophylactic G-CSF (filgrastim) administration in chemotherapy of stage I and II Hodgkin's lymphoma with ABVD

The purpose of this study was to determine the effect of granulocyte colony-stimulating factor (filgrastim, G-CSF) for maintenance of chemotherapy dose-intensity in patients with stage I or II Hodgkin's lymphoma treated with six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Fifty-six patients with stage I or II Hodgkin's lymphoma treated with ABVD were eligible for secondary prophylactic G-CSF administration because of neutropenia (absolute neutrophil count < 1 x 10(9) /L) causing treatment delay or febrile neutropenia. Patients received 300 microg (total dose) of G-CSF (filgrastim) subcutaneously on days 3 to 7 and 17 to 21 of each cycle in order to prevent dose reduction or delay in subsequent cycles of treatment continuing the G-CSF until completion of chemotherapy. Results showed that 30 (54%) of the patients required the use of G-CSF, 26 (47%) during the first or second cycle. After G-CSF administration delay in chemotherapy did not occur in 25 patients, whereas delays in the fifth or sixth cycle occurred in four patients. Despite treatment with G-CSF, one patient had febrile neutropenia. Dose intensity greater than 90% of that planned was delivered to more the 85% of patients. IN CONCLUSION: Secondary prophylactic G-CSF administration was necessary in more than half of patients with stage I or II Hodgkin's lymphoma during chemotherapy with ABVD. The use of G-CSF allowed maintenance of chemotherapy schedule and dose intensity in the majority of patients.     

Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin's lymphoma.

PURPOSE: To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. RESULTS: The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. CONCLUSION: There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.     

Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin's lymphoma and advanced solid tumors

Background: To define a maximum tolerated dose (MTD) for the combination of epirubicin and cyclophosphamide with filgrastim (r-met-HuG-CSF) in patients with advanced solid tumors and non-Hodgkin's lymphoma (NHL).Patients and methods: Thirty-five patients with advanced solid tumors were enrolled in stages I and II. Twenty-one patients were treated in stage I in sequential cohorts of at least three patients at increasing dosage levels of cyclophosphamide and epirubicin, for up to six cycles every 21 days. At the completion of stage I, a MTD for epirubicin was established. Fourteen patients were treated in stage II, in cohorts of three or more. The epirubicin dose remained constant at the MTD dosage from stage I. Cyclophosphamide was further dose-escalated to establish its MTD. Twenty-one patients with previously untreated non-Hodgkin's lymphoma were treated in stage III with the MTD established in the prior stages.Results: The MTD in stage I was epirubicin 150 mg/m² and cyclophosphamide 1500 mg/m² with cumulative neutropenia as the dose-limiting toxicity (DLT). Cumulative thrombocytopenia prevented further dose-escalation of cyclophosphamide in stage II. The stage III regimen consisted of six, 21-day cycles of epirubicin 150 mg/m², cyclophosphamide 1500 mg/m², vincristine 2 mg, and prednisolone 100 mg for five days with filgrastim support. Nineteen of twenty-one patients (90%) completed six cycles of treatment, eight (38%) without dose reduction. Common toxicity criteria (CTC) grade 4 neutropenia (neutrophil nadir <0.5 × 10⁹/l) was documented in 85 of 118 cycles (72%). Neutropenic fever was documented in 17 of 21 patients (81%) on at least one occasion. Severe thrombocytopenia (<25 × 10⁹/l) was seen in fourteen of 118 cycles (12%) and increased with cycle number. There was no significant non-hematological toxicity.Conclusion: Significant dose-escalation of epirubicin and cyclophosphamide was possible with filgrastim support. The MTD achieved was approximately double that of standard-dose therapy. This study forms the basis of an ongoing randomized study evaluating dose-intensification in intermediate grade NHL.     

A phase I/II trial of pixantrone (BBR2778), methylprednisolone, cisplatin, and cytosine arabinoside (PSHAP) in relapsed/refractory aggressive non-Hodgkin's lymphoma

The purpose of the study was to evaluate the safety, efficacy, and pharmacokinetics of pixantrone (BBR2778) when substituted for etoposide in the ESHAP regimen in patients with aggressive relapsed or refractory non-Hodgkin's lymphoma. Nineteen patients received protocol therapy, consisting of pixantrone 80 mg/m2 over 1 h on day 1, methylprednisolone 500 mg on days 1 - 5, cisplatin 25 mg/m2 on days 1 - 4, and cytarabine 2000 mg/m2 on day 5. Cycles were repeated every 21 days, in the outpatient setting. Dose limiting toxicity, consisting of bone marrow suppression, occurred at the first dose level (80 mg/m2), which was defined as the recommended dose. Grade 3 and 4 toxicities were mainly hematologic. Only one patient had grade 4 febrile neutropenia. No significant decreases in ejection fraction greater than 20% occurred. Overall response rate was 58%, with 37% complete and 21% partial responses. Six of the 11 responders (55%) underwent stem cell transplant. Median time to progression and overall median survival were 5.7 months and 14.5 months, respectively. There is no significant interaction between pixantrone and the combined drugs. The recommended dose of pixantrone in combination with methylprednisolone, cytarabine, and cisplatin (PSHAP) is 80 mg/m2. PSHAP is an active salvage regimen and should be further evaluated as a pretransplant cytoreductive regimen.     

Improved survival and chemotherapy response among patients with AIDS-related non-Hodgkin's lymphoma receiving highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) became available in the US in 1996. Using the population-based cancer registry, we identified 233 patients with AIDS-related systemic NHL diagnosed in San Diego or Orange County in 1994-1999, of whom 137 were diagnosed 1996-1999. We performed Kaplan-Meier analyses to compare survival between patients who received HAART at NHL diagnosis or thereafter versus untreated patients and Cox proportional hazard models for adjusted survival. We used logistic regression to determine if concomitant HAART changed the probability of complete response to chemotherapy and the Mann-Whitney U-test to compare the median number of chemotherapy cycles between patients who received HAART during chemotherapy versus those who did not. Among patients diagnosed with NHL in 1996-1999, 40 (29%) were taking HAART at NHL diagnosis. The median survival was three months among patients who did not receive HAART versus 16 months among HAART-treated patients. HAART, chemotherapy, high performance status, and NHL stage < IV were associated with improved survival. Concomitant HAART, completion of > or = 6 chemotherapy cycles, and NHL stage < IV were associated with complete response to chemotherapy. The median number of chemotherapy cycles was five among patients who received HAART concomitant with chemotherapy versus three among untreated patients. We conclude that HAART should be initiated or continued after NHL diagnosis, including during the period of chemotherapy administration.     

Phase I trial of (90)Y-ibritumomab tiuxetan in patients with relapsed B-cell non-Hodgkin's lymphoma following high-dose chemotherapy and autologous stem cell transplantation

Between January 2001 and September 2005, 19 patients with progressive B-cell non-Hodgkin's lymphoma were treated with a cohort-specific dose of yttrium-90 ibritumomab tiuxetan (0.10 - 0.20 mCi/kg) to determine appropriate dosing in patients who had previously received high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients were required to have adequate end organ function and bone marrow status. Patients had been treated with a median of three prior therapies (range, 1 - 9). The median time from ASCT to radioimmunotherapy was 28 months. Hematologic toxicities were dose-limiting and included grade 3 - 4 thrombocytopenia (53%), neutropenia (32%), and anemia (21%). The majority of grade 3 - 4 events occurred at the 0.2 mCi/kg dose level. Nine patients responded (complete response, complete response unconfirmed, or partial response) to the therapy. At a median follow-up of 37 months, the 1-year event-free and overall survival rates were 26% and 57%, respectively. A dose of 0.2 mCi/kg ibritumomab tiuxetan is safe and effective for patients with progressive disease after high-dose chemotherapy and ASCT.     

A randomized trial of two types of adjuvant chemotherapy in radiotherapy-treated patients with clinical stages I and II high-grade non-Hodgkin's lymphoma

Summary This paper reports the 8-year results of comparing the use of two types of adjuvant chemotherapy following involved field radiotherapy for clinical stages I and II high-grade non-Hodgkin's lymphoma. Twenty-four patients received 6 weeks of VAP plus 2 years of oral maintenance chemotherapy, and 30 had six cycles of CMOPP. Four patients were not in complete remission at completion of i. v. chemotherapy (CR rate 91%). Ten patients (18.5%) have relapsed (VAP/M=5; CMOPP=5), with only two of these remaining alive, both of them being disease free. There have been three deaths from intercurrent causes, one from malignant melanoma and the other two from myocardial infarction. The relapse-free survivals at 2, 5 and 8 years were 80%, 76% & 76% respectively. The overall survivals at the same time points were 86%, 72% & 68%. There were no significant differences in either relapse-free or overall survival for either of the two treatment groups. The shorter period of weekly intravenous chemotherapy (VAP/M) was better tolerated than 36 weeks of CMOPP, and the former appears to produce equivalent results.     

Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin's lymphoma

A phase I/II trial was performed to investigate the safety and tolerance of zosuquidar.3HCL, a potent inhibitor of P-glycoprotein (P-gp), when administered orally alone and in combination with the CHOP regimen in patients with untreated non-Hodgkin's lymphoma and to determine whether zosuquidar.3HCL affects pharmacokinetics of doxorubicin and vincristine. Doses of CHOP remained constant and the doses of zosuquidar.3HCL were increased from 200 to 500 mg per dose. A total of 15 patients were treated at three dose levels. A target dose providing peak and trough levels compatible with prolonged modulation of P-gp function was obtained in patients receiving three doses of 500 mg of zosuquidar.3HCL p.o. At this dose level, toxicity was minimal and no enhancement of CHOP-related toxicity was observed. Zosuquidar.3HCL did not significantly affect the pharmacokinetics of doxorubicin and had moderate effects on the pharmacokinetics of vincristine. Zosuquidar.3HCL can be safely administered with CHOP therapy using a 24-h schedule.     

Phase II trial of infusional cyclophosphamide,idarubicin, and etoposide in poor prognosis non-Hodgkin's lymphoma

The purpose of this study was to determine the complete response (CR) rate, failure-free survival (FFS), and overall survival (OS) of patients with poor-prognosis intermediate-grade non-Hodgkin's lymphoma (NHL) after treatment with cyclophosphamide, idarubicin, and etoposide given as a continuous intravenous infusion (CIVI) over 96 hours (infusional CIE), including patients with relapsed/refractory disease and patients with no prior therapy but at least two poor-risk features by the age-adjusted International Prognostic Index. Forty-two patients with previously untreated NHL (N = 24) or relapsed/refractory (N = 18) NHL received cyclophosphamide (200 mg/m2/d), idarubicin (2.5-3.0 mg/m2/d) and etoposide (60 mg/m2/d) given by a 96-hour CIVI every 3 weeks for a maximum of 8 cycles. All patients also received granulocyte-colony-stimulating factor. CR occurred in 10 of 24 patients (42%; 95% confidence intervals [CI] 22%, 62%) treated with CIE as first-line therapy, and in 3 of 18 patients (17%; 95% CI 20%, 32%) treated with CIE as second-line or greater therapy. One-year FFS and OS were 42% and 64%, respectively, in patients with no prior therapy, and 17% and 56% in patients with prior therapy. Severe (grade III) or life-threatening (grade IV) toxicity included leukopenia (59%), anemia (61%), thrombocytopenia (31%), and infection (10%). Two patients (4%) died due to treatment related infectious complications. It is unlikely that infusional CIE produces a CR rate more than about 60% in poor-risk patients with intermediate-grade NHL when used as first-line therapy, or more than about 30% in patients receiving the regimen as second-line therapy. Substitution of idarubicin for doxorubicin in this setting, therefore, is not associated with an improved response rate.     

Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.     

Phase I/II trial of total lymphoid irradiation and high-dose chemotherapy with autologous stem-cell transplantation for relapsed and refractory Hodgkin's lymphoma.

BACKGROUND: The standard approach to treatment of relapsed/refractory Hodgkin's lymphoma (HL) is high-dose chemotherapy conditioning followed by autologous hematopoietic stem-cell transplantation (aHSCT). We report the results of a prospective phase I/II clinical trial of accelerated hyperfractionated total lymphoid irradiation (TLI) immediately followed by high-dose chemotherapy for relapsed/refractory HL. PATIENTS AND METHODS: Forty-eight patients underwent aHSCT with either sequential TLI/chemotherapy (n = 32) or chemotherapy-alone conditioning (n = 16), based on prior radiation exposure. The first 22 patients enrolled on trial received escalating doses of etoposide (1600-2100 mg/m(2)) with high-dose carboplatin and cyclophosphamide. RESULTS: No dose-limiting toxicity was seen and TLI/chemotherapy was well tolerated. The 5-year event-free survival (EFS) estimate for all patients was 44% with overall survival (OS) of 48%. Five-year EFS and OS for the TLI/chemotherapy group was 63% and 61%, respectively, compared with 6% and 27%, respectively, for the chemotherapy-alone group (P < 0.0001 and P = 0.04, respectively). Patients with primary induction failure HL who received TLI/chemotherapy had 5-year EFS and OS rate of 83%. The 100-day treatment-related mortality was 4.2% and two secondary cancers were seen. Significant factors predicting survival by multivariate analysis included TLI/chemotherapy conditioning and B symptoms at relapse. CONCLUSIONS: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL is safe and associated with excellent long-term survival rates.     

Phase I trial of topotecan plus vinorelbine with/without filgrastim (G-CSF) in patients with refractory malignancies

The purpose of this study was to determine the maximum tolerated dose (MTD) of topotecan plus vinorelbine with and without filgrastim (granulocyte colony-stimulating factor) in refractory solid tumors. Cohorts of three patients with recurrent solid tumors previously treated with no more than one chemotherapy regimen were entered. All patients had a performance status of 0 to 1 with adequate hepatic, renal, and bone marrow function and were treated with topotecan 1.5 mg/m2 intravenously on days 1 to 3 followed by vinorelbine 25 mg/m2 intravenously on days 1 and 8 without filgrastim every 3 weeks. Dose escalation was based on standard criteria for phase I escalation with a maximum of five patients in a cohort until an MTD was defined (first without then with filgrastim). Three patients were treated at dose level 1 (topotecan 1.5 mg/m2 days 1-3 and vinorelbine 25 mg/m2 days 1 and 8) without filgrastim. All three experienced hematologic dose-limiting toxicity (DLT) including grade IV neutropenia in two patients and grade III thrombocytopenia in one patient. An additional two patients, supported with filgrastim, treated at dose level 1 experienced DLT. One patient had dose-limiting neutropenia and the other had significant nonhematologic toxicity. No objective responses were seen, and all patients died within 6 months of entering the trial. The combination of topotecan and vinorelbine was poorly tolerated in the dose and schedule tested in this phase I trial. Subsequent combinations of these drugs, if warranted, should focus on alternate doses, schedules, or routes of administration.