Sensitive Relapse Research Articles

A phase II study of amrubicin, a synthetic 9-aminoanthracycline, in patients with previously treated lung cancer

Purpose This study was designed to confirm the efficacy and safety of amrubicin, a new anthracycline agent, in patients with previously treated non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Methods Eligible patients were required to have recurrent or refractory NSCLC and SCLC after one or two previous chemotherapy regimens. All patients received intravenous amrubicin 35 mg/m 2 on days 1–3 every 3 weeks. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. Results Sixty-six patients (37 NSCLC and 29 SCLC) were assessable for efficacy and safety evaluation. Grade 3 or 4 neutropenia was observed in 39.4% of all patients (NSCLC, 37.8%; SCLC, 41.4%). Nonhematological toxicities were mild. No treatment-related death was observed. The ORRs were 13.5% (95% CI, 4.5–28.8%) in NSCLC and 44.8% (95% CI, 26.4–64.3%) in SCLC. In SCLC, ORRs were 60.0% in the sensitive relapse and 36.8% in the refractory relapse ( p = 0.2332). In NSCLC, the PFS, OS, and 1-year survival were 3.3 months, 12.0 months, and 35.3%, respectively. In SCLC, the PFS, OS, and 1-year survival were 4.0 months, 12.0 months, and 46.7%, respectively. Conclusions Amrubicin is an active and well-tolerated regimen in patients with previously treated lung cancer. Amrubicin 35 mg/m 2 seems to achieve similar efficacy with less toxicity than amrubicin 40 mg/m 2 in this patient population. These results warrant further evaluation in previously treated lung cancer.

An open label phase II trial of the Plk1 inhibitor BI 2536, in patients with sensitive relapse small cell lung cancer (SCLC)

8108 Background: BI 2536 is a potent, selective inhibitor of polo-like kinase 1 (Plk1), a regulator of mitotic progression. BI 2536 demonstrated favorable tolerability and antitumor activity in phase I trials. We investigated the antitumor efficacy, safety and PK of BI 2536 in patients (pts) with sensitive relapse SCLC. Methods: This open label single arm phase II study followed a Gehan two-stage design. Primary objective was to determine the antitumor efficacy of BI 2536 in SCLC pts with disease recurrence ≥60 days after completion of first-line chemotherapy. 18 pts had to complete 2 courses to be evaluable for stage 1 analysis. In case of ≥2 partial or complete antitumor responses (RECIST criteria), stage 2 accrual would continue until 40 pts were entered. Patients received 200 mg BI 2536 as a 1h i.v. infusion on Day 1 every 3 weeks. Dose escalation to 250 mg (cycle 3 onwards) was encouraged in pts with <Grade 2 drug related non-hematologic and <Grade 3 hematologic toxicity. Results: 23 pts (14 female, 9 male, 21 extensive disease, 2 limited disease), median age 60 yrs (range: 35–77) were treated. All patients had disease recurrence >60 days after completion of first-line therapy. Of 23 pts, no objective antitumor responses were observed, 7 had stable disease as best response, 14 had progression, 2 were not evaluable. A median of 2 courses were given, up to a maximum of 12 in 1 pt. The PFS rate at 3 months was 25%. Due to the lack of antitumor responses, trial accrual was terminated after stage 1. Overall, BI 2536 was well tolerated. Frequent AEs were neutropenia (48%), fatigue (39%), nausea (30%), anemia, vomiting, constipation (26% each), and thrombocytopenia (22%). Drug related grade 3/4 AEs were neutropenia (13%/26%), grade 3/4 thrombocytopenia (1 pt each), grade 3/4 anemia (1 pt each), grade 4 sepsis (1 pt), Grade 4 ARDS (1 pt) and Grade 3 fatigue (1 pt). PK analyses indicate that BI 2536 has high clearance (>1,000 mL/min) and quickly distributes in multiple compartments in a large volume of distribution (>1,000 L). Estimated elimination half-life was >25 h. Conclusions: BI 2536 was well tolerated in relapsed SCLC pts, but demonstrated no convincing antitumor efficacy after stage I of the study. Therefore, BI 2536 will not be assessed further as a single agent in SCLC. [Table: see text]

Pre-Transplant Clonal Cytogenetic Abnormalities in Stem Cells Used for Autologous Stem Cell Transplant for Relapsed Non-Hodgkin Lymphoma is a Predictor of Relapse

Autologous stem cell transplant is used for chemotherapy sensitive relapsed Non-Hodgkin Lymphoma (NHL). Patients who receive an autologous stem cell transplant after high dose chemotherapy for relapsed NHL have significantly superior survival compared to those receiving conventional chemotherapy. Relapsed patients who achieve a second remission are treated with myeloablative chemotherapy followed by autologous stem cell transplant. These patients can achieve 5-year event free survival close to 50% and 5-year overall survival of greater than 50%.

Addition of Umbilical Cord Blood (UCB) Unit to Reduced Intensity Conditioning (RIC) Regimen to Augment Graft Versus Tumor (GVT) in Patients (pts) with Advanced Hematologic Malignancies

Allogeneic stem cell transplantation (SCT) is associated with a potent GVT effect, mediated by donor immunocompetant cells. The major risk of SCT is graft versus host disease (GVHD), and a major goal is to separate GVT from GVHD. UCB is an effective alternative source of hematopoietic stem cells for transplantation. UCB T-cells have a lower potential to produce GVHD despite transplantation of HLA partially mismatched units, and confer potent GVT effects. We hypothesized that cord blood could be an effective cell source for adoptive immunotherapy. We examined the efficacy of adding one HLA partially mismatched UCB unit to a conventional RIC peripheral blood (PB) SCT from an HLA matched sibling donor in efforts to augment GVT without increasing the rate of GVHD.Methods: The conditioning regimen consists of Fludarabine 30 mg/m2 administered daily for 4 days (days -10 to -7) followed by one dose of Melphalan 140mg/m2 (day -7). One UCB unit, 4/6 HLA matched with pt, containing at least 1.5 x 107TNC/kg is infused on day -5, followed by infusion of HLA-matched sibling PBSC 5 days later (day 0). Patients with CD20+ disease receive rituximab 375 mg/m2 x 4 doses on day -7, -1, +7, +14. GVHD prophylaxis consists of tacrolimus and mini-dose methotrexate for all pts. Hematopoietic chimerism was evaluated in bone marrow and in GVHD biopsy specimens by restriction fragment length polymorphisms for existing recipient and donor cells (PBSC and cord).Results: 14 pts (10 M/4 F) with median age 54 years (range 21–67) have been enrolled to date: ALL (n=4), AML or MDS (n=6), MM (n=1), NHL (n=1), CLL (n=2). The median number of prior chemotherapy regimens was 3 (range 1–7), with 8 pts having had a prior allogeneic SCT. At time of study entry, 2 pts were beyond CR1, 3 were in sensitive relapse, 8 were in refractory relapse, and 1 in PR with concurrent NHL and therapy-related AML. The median PB CD34+ cell dose infused was 4.85 x 106/kg (range 2.6–7.7). The median UCB TNC dose infused was 2.8 x 107/kg (range 1.5–4.6). Median time to ANC ≥ 0.5 x 109/L and platelet count ≥ 20 x 109/L were 15 days (range 11–22) and 25 days (range 16–92), respectively. All pts achieved full donor chimerism from the matched sibling donor at a median of 18 days (range 15–147), except for 1 pt with primary graft failure. This patient had slower engraftment from the cord blood unit. UCB cells were noted in the day 30 chimerism analysis of only 1 other pt: 96% sibling donor, 3% recipient, 1% UCB. Of note, this pt relapsed at day 100 post SCT. Six pts are alive at a median follow-up of 4.4 months from SCT (range 1–16.6). The incidence of acute GVHD, grades II–IV and III–IV were 50% and 21%, respectively; 4 pts developed hyperacute GVHD, manifested by fever and diffuse skin rash, occurring 3 to 10 days following SCT (8 to 15 days following UCB infusion); symptoms resolved promptly with initiation of steroids. UCB cells were noted in the GVHD biopsies of 1 pt who developed GI GVHD at day 14, and 1 pt who developed skin GVHD at day 44. The incidence of TRM at 100 days was 21%. Five pts progressed at a median of 4.3 months (range 1.3–11). Among 8 deaths, 2 were related to disease recurrence, 4 related to infection and 2 related to GVHD.Conclusion: This novel SCT approach is feasible, with a favorable toxicity profile, and without excess GVHD, as compared to the historic data for the FM140 regimen [Giralt et al. Blood 1997, 89(12):4531]. Hyperacute GVHD occurring shortly after UCB infusion suggests an immunologic effect of the cord blood cells. Preliminary data suggests favorable disease control for pts with advanced disease. Longer follow-up is needed to assess the long-term efficacy of this approach.

Detection of Pre-Transplant Clonal Cytogenetic Abnormalities in Stem Cells Used for Autologous Stem Cell Transplant in Relapsed Non-Hodgkin Lymphoma Is a Predictor of Relapse

Autologous stem cell transplant is used for chemotherapy sensitive relapsed Non-Hodgkin Lymphoma (NHL). Patients who receive an autologous stem cell transplant after high dose chemotherapy for relapsed NHL have significantly superior survival compared to those receiving conventional chemotherapy. Relapsed patients who achieve a second remission are treated with myeloablative chemotherapy followed by autologous stem cell transplant. These patients can achieve 5-year event free survival close to 50% and 5-year overall survival of greater than 50%. We performed a retrospective analysis of our center's transplant data and reviewed pre-transplant cytogenetic analysis on the patient's collected stem cells. 259 patients underwent autologous stem cell transplant from 1998 through 2007 for relapsed NHL. Cytogenetic evaluations of the patient's pre-transplant stem cells had been done to look for evidence of MDS or characteristics of their lymphoma. Clonal cytogenetic abnormalities were found in 12 of the 259 patients. Two of these patients died within 45 days of transplant without evidence of relapse. One from infection and a second from non-treatment related causes. Nine of the remaining 11 (81%) patients with clonal cytogenetic abnormalities have relapsed and died. All patients relapsed with their original lymphoma. The cytogenetic abnormalities were varied. Out of the 9 relapses, 3 had cytogenetic abnormalities in the stem cells that are associated with lymphoma, 2 that are associated with AML, 1 that is associated with MDS, and 2 were abnormalities whose significance was unknown. In one patient cytogenetic changes of the original lymphoma were identified. The patients that had clonal cytogenetic abnormalities in their collected stem cells had an 81% relapse rate as opposed to 30% in the patients whose stem cells had a normal karyotype. Our findings show that cytogenetic changes in the collected stem cells are associated with a higher rate of lymphoma relapse.

Randomized Phase II Trial Comparing Amrubicin With Topotecan in Patients With Previously Treated Small-Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 0402

Amrubicin, a new anthracycline agent, and topotecan are both active for previously treated small-cell lung cancer (SCLC). No comparative study of these agents has been reported. This randomized phase II study was conducted to select amrubicin or topotecan for future evaluation. Patients with SCLC previously treated with platinum-containing chemotherapy were randomly assigned to receive amrubicin (40 mg/m(2) on days 1 through 3) or topotecan (1.0 mg/m(2) on days 1 through 5). Patients were stratified by Eastern Cooperative Oncology Group performance status (0, 1, or 2) and type of relapse (chemotherapy sensitive or refractory). The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival, and toxicity profile. From February 2004 to July 2007, 60 patients were enrolled, and 59 patients (36 patients with sensitive and 23 patients with refractory relapse) were assessable for efficacy and safety evaluation. Neutropenia was severe, and one treatment-related death owing to infection was observed in the amrubicin arm. ORRs were 38% (95% CI, 20% to 56%) for the amrubicin arm and 13% (95% CI, 1% to 25%) for the topotecan arm. In sensitive relapse, ORRs were 53% for the amrubicin arm and 21% for the topotecan arm. In refractory relapse, ORRs were 17% for the amrubicin arm and 0% for the topotecan arm. Median PFS was 3.5 months for patients in the amrubicin arm and 2.2 months for patients in the topotecan arm. Multivariate analysis revealed that amrubicin has more influence than topotecan on overall survival. Amrubicin may be superior to topotecan with acceptable toxicity for previously treated patients with SCLC. Further evaluation of amrubicin for relapsed SCLC is warranted.

28 years of high-dose therapy and SCT for neuroblastoma in Europe: lessons from more than 4000 procedures

Between 1978 and 2006, the European Group for Blood and Marrow Transplantation registered 4098 high-dose therapy (HDT) procedures followed by stem cell rescue (SCR) (3974 autologous/124 allogeneic) in patients with neuroblastoma. The 5-year rates for overall (OS) and event-free survival are 37 and 32%, respectively. The median age at diagnosis is 3.9 years (0.3-62 years) with 76 patients older than 18 years. Patients above 10 years carry a 2.5-fold higher risk. Younger patients cure significantly (<0.001) better with OS rates of 40 and 30% for age groups 2-4 years and 4-10 years, respectively. Their risks are about twofold higher than that of patients below 2 years with OS rates of 60%. The better the quality of remission status before HDT/SCT the better are the observed OS rates: 43% in CR1 (1199 patients) and 42% for CR2 (140 patients), and 36% for those in very good partial or partial remission (1413 patients) and 21% for those with sensitive relapse (134 patients). Patients reported with stable disease in first remission still had an OS rate of 30%. Multivariate analysis shows significantly better OS in the age group of less than 2 years (<0.0001), as well as a better quality of remission status before HDT/SCT (P<0.0001), with the use of peripheral stem cells (P=0.014), autologous SCT (P=0.031) and busulphan/melphalan HDT (P<0.001). Busulphan/melphalan HDT/SCT in first remission achieves an OS of 48%, while it is only 35% with other regimens (P<0.001), including melphalan alone, other melphalan-containing regimens, a variety of other drugs given as a single HDT as well as the addition of TBI or sequential HDT/SCT procedures. Further progress in the field may only be expected from large-scale international randomized trials.

Phase II trial of belotecan in patients with sensitive relapsed small-cell lung cancer after irinotecan-containing chemotherapy

8118 Background: Belotecan (CKD 602) is a novel camptothecin analogue, topoisomerase-I inhibitor. This phase II trial was conducted to evaluate the activity of belotecan against irinotecan-sensitive relapsed small-cell lung cancer (SCLC). Methods: A sensitive relapsed SCLC patients, who were defined as relapsed at least 3 months after having achieved complete or partial response to 1st line irinotecan-containing chemotherapy, were eligible for this trial. Belotecan was administered as a 30-minute daily intravenous injection at a dose of 0.5mg/m2/day for 5 consecutive days every 3 weeks. From the second cycle, the daily dose of belotecan was adjusted to one of three dose levels, 0.4, 0.5, or 0.6 mg/m2/day, based on the toxicities after the each cycle. The primary endpoint was response rate. The group sequential design of Chang et al. was utilized and the estimated sample size was 50 patients (stage I - 20 patients; stage 2 - 15 patients; stage 3 - 15 patients). The study has a 80% power to detect a response rate of 15%, with an alpha error 5%. Results: Between March 2006 and May 20007, a total of 20 patients were enrolled (median age 64, 16M/4F, ECOG PS 0–1 95%). A total of 96 cycles of belotecan were delivered with a median of 6 cycles. The dose level of belotecan was 0.4 mg/m2/ day in 23 cycles, 0.5 in 56, and 0.6 in 17. The most frequent grade 3/4 toxicities were related to myelosuppression including neutropenia in 95% of patients and thrombocytopenia in 45%. No febrile neutropenia or bleeding was observed. Nonhematol- ogic toxicities were mild. There was no treatment- related death. Overall objective response rates were 25% (95% CI, 4.2 - 45.8; 0 CR, 5 PR, 10 SD, 5 PD). With a median follow-up duration of 8.0 months, median time to progression was 4.7 months (95% CI, 3.9 - 5.5) and median overall survival wasn’t reached. Conclusions: Belotecan shows promising activity in relapsed SCLC, with predictable and manageable toxicities. Therefore, this topoisomerase-I inhibitor is a treatment option for patients with sensitive relapsed SCLC, who have responded to irinotecan-containing chemotherapy. No significant financial relationships to disclose.

Phase II study of RAD001 (Everolimus) in previously treated small cell lung cancer (SCLC)

19017 Background: The mammalian Target of Rapamycin (mTOR) plays a central role in the PI3K/AKT signaling pathway, which may be important in the proliferative and antiapoptotic signaling in SCLC. RAD001 is an orally administered mTOR inhibitor with dose-dependent in vitro activity in SCLC cell lines and potent in vivo growth inhibition in xenograft models. Methods: Eligible patients (pts) had pathologically documented SCLC that relapsed after 1–2 prior chemotherapy regimens, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Pts with untreated or symptomatic brain metastasis were excluded. RAD001 was administered orally continuously at a daily dose of 10 mg until disease progression or unacceptable toxicity. A cycle was 3 weeks with response assessment after every 2 cycles. The primary endpoint was the disease non-progression rate. Using a 2-stage design, 21 pts will be enrolled in the first stage. If ≥7 pts show disease stability or response, 21 additional pts will be accrued in the second stage. PI3K/AKT signaling pathway proteins (PTEN, AKT, pAKT, p-S6, p-4E-BP1) expression will be assessed by immunohistochemistry in baseline tumor tissue and will be correlated with response. Results: 17 pts have been enrolled: median age- 63 years (44 - 80); males- 6 (35%); PS0- 35%; PS1- 65%. Prior chemotherapy: Platinum/etoposide: 17 (100%), 2nd line- 2 (12%); prior radiation: chest- 8/17 (47%); brain- 9/17 (53%). 11 pts had sensitive relapses (i.e. >60 days from first-line chemotherapy completion). 1 pt did not complete the first cycle of RAD001, 5 received 1 cycle, and 10 (59%) ≥2 cycles; number of days on treatment: median- 42 days (3−117+). In 16 evaluable pts, there were no objective responses; 3 pts had stable disease (19%) as best response while 13 pts had progressive disease (81%). Duration of stable disease: 69 - 117+ days. No grade 3 or 4 toxicities were encountered. Grade 2 toxicities were as follows: fatigue (4), thrombocytopenia (3), elevated transaminases (2), anemia (2), rash (2), hypertriglyceridemia (1), and hypermagnesemia (1). Conclusions: Preliminary results show that RAD001 is well tolerated but has low activity as a single agent in unselected, previously treated pts with SCLC. Updated results and biomarker analysis will be available for presentation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis

Randomized, phase II trial comparing amrubicin with topotecan in patients (pts) with previously treated small cell lung cancer (SCLC)

8042 Background: Amrubicin (A), a new anthracycline agent, and topotecan (T) are both active for previously treated SCLC. No comparative study with these two agents has been reported. This randomized phase II study was conducted to select A or T for future evaluation in a phase III setting. Methods: Previously treated SCLC pts were randomized to receive A (40 mg/m2, day1–3, every 3weeks) or T (1.0 mg/2, day1–5, every 3 weeks). The primary endpoint was overall response rate (ORR), and secondary endpoints were progression-free survival (PFS) and toxicity profile. Assuming that ORR of 40% in eligible pts would indicate potential usefulness while ORR of 20% would be the lower limit of interest, with alpha = 0.05 and beta = 0.10, the estimated accrual was 27 pts in each arm. Results: From February 2004 to July 2007, 60 pts were enrolled from 12 institutions. One patient in A arm did not receive any protocol treatment due to rapid disease progression and 59 pts were evaluable for efficacy and safety. Patient characteristics were: Male/Female 49/10; median age 67 (range 32–78); Performance status 0/1/2 31/19/9; Sensitive relapse (S) / Refractory relapse 36/23. The median numbers of treatment cycles were 3 (range 1–7) in A arm and 2 (range 1–4) in T arm. ORRs and disease control rates (DCRs) were 38% (95%CI: 20–56) and 79% (95%CI: 64–94) for A, and 13% (95%CI: 1–25) and 47% (95%CI: 29–65) for T, respectively. In subset analysis on type of relapse, ORRs and DCRs were 53% and 88% for A, and 21% and 63% for T in S pts, and 17% and 67% for A, and 0% and 18% for T in R pts. Median PFS on A arm was 105 days and on T arm was 60 days. Neutropenia was significantly severe in A arm. One treatment related death due to infection was observed in A arm. Conclusions: A is more active agent than T with acceptable toxicity for previously treated SCLC pts, especially for pts with R. Further evaluation of A as a single agent or in combination is warranted in SCLC. No significant financial relationships to disclose.

Phase II trial of high-dose weekly topotecan in patients with relapsed small-cell lung cancer (SCLC)

19073 Background: Topotecan is FDA approved for the treatment of sensitive relapse SCLC using a 5-day IV schedule. A 4 mg/m2 weekly IV schedule studied by our group was associated with low grade (G...

The Effect of Rituximab on Mobilization with AMD3100 Plus G-CSF in Patients with Relapsed or Refractory NHL or HD.

The optimal therapy for patients with chemotherapy sensitive relapsed or refractory lymphoma is high dose therapy followed by autologous hematopoietic stem cell rescue. Rituximab (R) has been added to salvage regimens to increase response rate, thereby making more patients eligible for high dose therapy. However, when R is used prior to the salvage regimen, it has been associated with a delay in platelet engraftment (Hoerr et al, J Clin Oncol. 2004 Nov 15;22:4561–6). We have previously noted in a retrospective review of 117 patients with lymphoma treated with high dose therapy and autologous HSC transplant that concurrent treatment with R did not impact stem cell collection or post transplant engraftment (Kaufman et al, BBMT, February 2005, Sup 1, [11.2] 6). AMD3100 (plerixafor) is a CXCR4 inhibitor that, when used with G-CSF, more effectively mobilizes stem cells than G-CSF alone. In order to test the hypothesis that R does not negatively impact stem cell collection or post-transplant engraftment when AMD3100 is used with G-CSF, we performed a prospective trial of the use of AMD3100, G-CSF and R for patients with CD20 (+) relapsed chemosensitive lymphoma versus the use of AMD3100 and G-CSF for patients with CD20 (−) relapsed chemosensitive lymphoma. Patients were treated with 2 cycles of ICE ± R depending on CD20 status of the malignant cell. Patients who had a response proceeded to mobilization with AMD3100 and G-CSF for the CD20 (−) group (Arm A) or AMD3100, G-CSF, and four weekly doses of R at 375 mg/m2 (two doses prior to G-CSF and AMD3100, and two doses after) for the CD20 (+) group (Arm B). After collection, patients were treated with high dose therapy with targeted intravenous busulfan, etoposide and cyclophosphamide followed by autologous HSC transplantation. Patient demographics, mobilization characteristics, graft yield, engraftment data, and toxicity were assessed. 21 patients have been accrued. 11 in Arm A (10 Hodgkin Lymphoma {HL} and 1 with Peripheral T Cell Lymphoma) and 10 in Arm B (2 HL and 7 NHL, and 1 with a composite HL/NHL). The median number of days of collection was 2 for each arm. The median CD34 (+) collected was 4.64 * 106 CD34+ cells/kg in Arm A compared to 5.25 * 106 CD34+ cells/kg in Arm B (p=0.6) The median number of CD34(+)/CD38(−) was similar for both arms. As expected from in vivo B-cell depletion, the percentage of CD19 (+) cells in the product was decreased in Arm B compared to Arm A (2.24% vs. 0.09%, p<0.002). R treated patients did not experience increased serious adverse events. All patients in both arms had durable and equivalent neutrophil and platelet engraftment (Table 1). In conclusion, rituximab can be administered safely to patients when AMD3100 and G-CSF are used for collection of hematopoietic stem cells. Importantly, no negative impact on graft characteristics or engraftment was perceived. Further trials are planned.Table 1:EngraftmentArm AArm Bp valueN1110CD 20 statusnegativepositiveMedian Day to Neutrophil Engraftment1211.50.39Median Day to Platelet Engraftment17170.72Median Day 100 Total WBC4.03.50.55Median Day 100 Platelet Count1791780.77

E11-03: Controversy in small cell lung cancer: targeted therapy

E11-03: Controversy in small cell lung cancer: targeted therapy

Prognostic factors for response and survival of second-line chemotherapy in patients with relapsed small cell lung cancer (SCLC)

18023 Background: Despite high response rates to initial chemotherapy, the majority of patients with SCLC experience tumor progression. Previous studies showed that both the response to initial chemotherapy and the response duration are important for predicting the efficacy of second-line chemotherapy. Therefore, relapsed SCLC is commonly classified into two groups: sensitive relapse (respond to initial chemotherapy and relapse more than 3 months after the completion of initial chemotherapy) and refractory relapse (not respond to initial chemotherapy or respond but relapse within 3 months). However, prognostic factors of the second-line chemotherapy have not been fully understood. Methods: From July 1992 to December 2003, four hundred and seventy-four patients with SCLC received chemotherapy as initial treatment, subsequently 229 patients received second-line chemotherapy (144 sensitive relapse and 85 refractory relapse) in our hospital. We analyzed the association of patients’ clinical factors with response and survival of second-line chemotherapy in sensitive relapsed patients and refractory relapsed patients, separately. For sensitive relapsed patients, analyzed clinical factors were as follows: age (&lt;70/=70), gender (M/F), response to initial chemotherapy (CR/PR), PS at relapse (&lt;2/=2) and the extent of disease at relapse (LD/ED). For refractory relapsed patients, analyzed clinical factors were as follows: age (&lt;70/=70), gender (M/F), response to initial chemotherapy (responder/non-responder), PS at relapse (&lt;2/=2) and the extent of disease at relapse (LD/ED). Results: Response to second-line chemotherapy was significantly correlated with PS in sensitive relapsed patients, however, no significant factor was detected in refractory relapsed patients. For survival, PS was the only significant prognostic factor in both sensitive and refractory relapsed patients. The median survival time was 328 days (PS&lt;2) and 128 days (PS=2) in sensitive relapsed patients (p&lt;0.0001), while 195 days (PS&lt;2) and 113 days (PS=2) in refractory relapsed patients (p=0.0001), respectively. Conclusions: PS was the only significant prognostic factor for survival both in sensitive and refractory relapsed SCLC. No significant financial relationships to disclose.

A phase II trial of VNP40101M in patients with relapsed or refractory small cell lung cancer (SCLC) with or without brain metastases

7724 Background: Relapsed or refractory SCLC patients (pts) have a poor prognosis. Median survival at relapse is 2–3 months; brain metastases (mets) are common. Alkylating agents have demonstrated activity in SCLC. Cloretazine is a new alkylator that is active against selected alkylating agent resistant tumor cell lines. Xenograft models show distribution across the blood-brain barrier. This study investigates VNP40101M safety and activity in SCLC patients who have relapsed or are refractory to standard 1st line chemotherapy. Methods: Pts are entered in 2 groups based on response to prior chemotherapy: sensitive relapse (chemotherapy-free interval &gt;3 months); or resistant/refractory (chemotherapy-free interval ≤3 months). Eligibility criteria include: measurable or evaluable disease; life expectancy of ≥2 months; and ECOG PS of 0–2. Pts with brain mets are eligible. 31 pts received VNP40101M IV at a starting dose of 125 mg/m2/wk × 3, every 6 weeks. Due to a high incidence of grade 3–4 thrombocytopenia (34%), an amended protocol reduced the dose of VNP40101M to 100 mg/m2 at the same schedule. 13 pts received the reduced dose. Pts are evaluated by RECIST criteria after each 6-week cycle. Results: 44 of 87 planned pts have been treated at 7 sites. Of 41 evaluable pts, 21 patients have sensitive relapse disease, and 20 have resistant/refractory disease. Median age is 64 years (44–86). Median number of cycles received is 1 (1–3). Grade 3–4 thrombocytopenia was seen in 11/31 pts at the 125 mg/m2 dose and 3/13 pts at the 100 mg/m2 dose. Gr 3–4 non-hematologic toxicity is rare, except for fatigue (10%) and GI effects (10%). The response rate (PR) is 6/21 (29%) in the sensitive relapse group, and 1/20 (5%) in the resistant/refractory group. 2/6 PRs, in the sensitive relapse group, occurred at the reduced dose level. 16 pts had brain mets at study entry. Of these, there were 3 PRs (2 with measurable regression of brain mets) and 3 stable diseases. Conclusions: The study is ongoing to confirm efficacy and safety. VNP40101M has activity against SCLC in the 2nd line setting including pts with brain metastases; further study is warranted. No significant financial relationships to disclose.

Pemetrexed in second-line therapy in patients with malignant pleural mesothelioma

18198 Introduction: Based on the study of Vogelzang (2003) standard treatment in patients with malignant pleural mesothelioma (MPM) is pemetrexed cisplatin with a medium survival of 12 months compared to 9 months with cisplatin therapy. As this treatment prolongs survival, but is not a curative treatment, many patients will relapse during the course of their disease. In sensitive relapses (within more than 3 months) our policy was to reintroduce pemetrexed therapy in unselected consecutive patients. Methods: Retrospective analysis of 17 consecutive patients treated in our hospital. Patient characteristics: 17 patients (pat), 14 males, 3 females, with MPM were included between April 2004 and November 2006 with an age between 45 and 82 years, with a median age of 65 years. Histologic subtypes were: 16 epithelial, 1 biphasic MPM. Pretreatment: 8 pat. had undergone palliative debulcing surgery (pleurectomy) 1 pat. underwent EPP. All patients were pretreated with platinum /pemetrexed, 5 pat. were pretreated with platinum/Gemcitabine before the availability of pemetrexed. 2nd line chemotherapy: 9 pat. were treated with carboplatin AUC5 / pemetrexed 500 mg/m2, 1 patient had cisplatinum 75 mg/m2/Pemetrexed 500 mg/m2 and 7 patients had pemetrexed single agent therapy (500 mg/m2 d1, WH d21), repeated on day 22 respectively. Results: Response: 6% (n=1) PR, MR: 12% (n=2 )., NC: 47% (n=8)., PD: 35% (n= 6), clinical benefit (PR, MR, NC) was seen in 65% of ou pat. Toxicity: Pemetrexed/Carboplatin or pemetrexed therapy were well tolerated, toxicity was mild: one patient developed mild sensory neurotoxicity (peripheral sensory neuropathy) (WHO II) under 6 cycles pemetrexed, 35% developed mild fatigue (Who I and II), one patient had mild renal impairment, no alopecia was seen. Survival: Only 3 patients had still died, median survival from start of second-line pemetrexed-therapy was not reached, time to progression was between 25 and 630 days, 4 pat. had not progressed until now. Conclusion: Second line therapy in MPM is not yet standard of care. Nevertheless patients with progressive disease following pemetrexed/platinum therapy may benefit from second line pemetrexed reintroduction therapy. Clinical benefit was seen in 65% with low toxicity. No significant financial relationships to disclose.

Phase II trial of vinflunine in patients with relapsed small cell lung cancer

18091 Background: Vinflunine (VFL) is a novel microtubule inhibitor of the vinca alkaloid class which has demonstrated significant preclinical activity in a small cell lung cancer (SCLC) model and antitumor activity in several other tumor types. This multicenter community- based trial was designed to examine the role of VFL in patients (pts) with relapsed SCLC. Methods: The primary endpoint is objective response rate (ORR). Eligibility criteria: previously treated SCLC (sensitive or refractory relapsed pts; limited to 1 prior platinum or non-platinum therapy for limited- or extensive-stage disease), ECOG PS 0–2, measurable disease, and informed consent. Treatment: VFL 320 mg/m2 IV over 20 minutes day 1 every 21 days for up to 6 cycles. Pts were restaged every 6 weeks. This 2-stage trial was designed to achieve a 20% ORR in platinum-sensitive pts (per RECIST criteria). Results: 29 pts were enrolled from 3/06 to 12/06 (trial ongoing, n=41 planned). Data are available for 16 pts in this analysis. Baseline characteristics: median age 64 years; male/female, 63%/37%; ECOG PS 0/1/2, 25%/50%/25%; and sensitive relapse, 50%. 3 partial response have been observed (ORR 19%, 95% CI 4%-46%). 3 pts (19%) had stable disease and 7 pts (44%) had progressive disease. 3 pts were not evaluable due to: treatment-related toxicity (sepsis; constipation); declining PS, 1 pt each. With a median follow-up of 5 months, the median progression-free survival and overall survival are 1.7 months and 3.6 months, respectively. Grade (G) 3/4 non-hematologic toxicity occurring in more than 1 pt: constipation, dyspnea, fatigue, and hyponatremia (13% each). G3/4 hematologic toxicity: leukopenia (44%), neutropenia (38%), and thrombocytopenia (6%). There have been no treatment-related deaths. Conclusions: VFL appears active as second-line treatment for SCLC. Additional assessment of myelosuppression is needed to better assess VFL’s role. Completion of accrual is anticipated by 4/07. No significant financial relationships to disclose.

Topotecan and etoposide as salvage chemotherapy in patients with irinotecan- and platinum-failed small-cell lung cancer: A phase II study

18177 Background: The efficacy and safety of a combined regimen of topotecan and etoposide was tested in patients with relapsed or refractory small-cell lung cancer. Methods: From October 2003 to May 2005, 23 patients who have failed to the previous irinotecan and platinum chemotherapy received intravenous topotecan 1mg/m2 (day 1–5) followed by intravenous etoposide 80mg/m2 (day 1–3). Treatment was repeated every 21 days for a maximum of 6 cycles. Results: Twelve patients were refractory to first-line chemotherapy. Seventeen patients (73.9%) were male and the median age was 63 years. ECOG performance status was 0–1 in 13 (56.5%) patients. The median cycles of chemotherapy was 3. Twenty one patients were assessable for response evaluation. The overall response rate was 17.4% (0 CR, 4 PR, 7 SD, 10 PD) under the intent-to-treat analysis. After a median follow- up of 20.8 months, median progression free survival was 4.7 months and median overall survival was 9.5 months. The estimated 1-year survival rate was 38.7%. In sensitive relapsed patients, 2 achieved tumor response and median progression free survival and overall survival were 5.5 months and 14.5 months. All patients were assessable for toxicity and major toxicities were myelosuppression. Grade 3/4 neutropenia and thrombocytopenia occurred in 18 (78.3%) and 12 (52.2%) patients, respectively. Grade 3/4 febrile neutropenia occurred in 2 patients (8.7 %) and infection in 3 patients (13.0%). There was one treatment-related death due to pneumonia. Conclusions: This salvage regimen failed to demonstrate a considerable response rate compared with monotherapy for relapsed or refractory SCLC. However, the combination of topotecan and etoposide could be further studied for sensitive relapsed patients pretreated with irinotecan and platinum No significant financial relationships to disclose.

Autologous Stem Cell Transplantation using a Modified TAM Conditioning Regimen for Clinically Aggressive Non-Hodgkin's Lymphoma

High-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) have been used for the treatment of clinically aggressive non-Hodgkin's lymphoma (NHL). However, the superiority of specific conditioning regimens has not yet been established. The present study evaluated the efficacy and toxicity of a conditioning regimen involving fractionated total body irradiation (TBI), and the use of Ara-C and melphalan (TAM) for clinically aggressive NHL. Between March 2002 and December 2004, 31 patients with aggressive NHL received fractionated TBI with a dose of 12 Gy over 3 days, and were administered 9 g/m(2) Ara-C and 100 mg/m(2) melphalan followed by autologous peripheral blood stem Cell Transplantation at the Catholic Hematopoietic Stem cell transplantation Center Korea. Patients that responded to first line chemotherapy and achieved complete remission (CR), or were in a first sensitive relapse were defined as having less advanced disease, while the other patients were defined as having more advanced disease. Objective responses were obtained in 24 of 31 patients (77.4%), comprising complete remission in 19 patients (61.3%) and partial remission in 5 (16.1%) patients. The median follow-up time was 28 months (range 1 approximately 62 months). At 3 years, the overall survival and event-free survival (EFS) rates were 62.3% and 47.3%, respectively. Patients with less advanced disease and more advanced disease showed 3-year EFS rates of 73.3% and 22.5 %, respectively (p=0.006). Early (within the first 100 days) treatment-related mortality occurred in 3 (9.7%) patients. Of the 31 total patients, 15 (48.4%) developed grade 3 mucositis, 22 (70.9%) developed neutropenic fever, and two (6.5%) developed interstitial pneumonia syndrome>grade 3. The modified TAM conditioning regimen and ASCT appear to be a feasible treatment regimen for clinically aggressive NHL, particularly for patients with less advanced disease.

Autologous stem cell transplantation for patients with active Hodgkin's lymphoma: Long-term outcome of 61 patients from a single institution

Sixty-one patients with refractory or relapsed Hodgkin's lymphoma (HL) underwent high-dose chemotherapy and autologous stem cell transplantation (ASCT). All patients had active HL at the time of ASCT: 13 patients had partial remission, 14 refractory disease, 18 sensitive relapse, 4 resistant relapse, and 12 nontreated relapse. Overall transplant-related mortality (TRM) was 16.4% at 1 year. Twenty-eight patients (46%) achieved complete remission (CR). Actuarial 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 47%, respectively. Patients with positive gallium-67 scintigraphy at 3 – 6 months after transplantation had a worse PFS at 5 years (28%) than those with negative 67Ga scan (80%) (p = 0.016), whereas no statistical differences were observed between patients with residual mass and those in CR according to computed tomography scan. In multivariate analysis, bulky disease at diagnosis, bone marrow stem cells, and stage IV at transplant were the only adverse prognostic factors significantly influencing OS. Bulky disease at diagnosis and stage IV at transplant adversely influenced PFS. Although long-term outcome of patients with active HL at the time of ASCT is poor due to a high TRM and a low CR after transplantation, a subgroup of patients with no adverse prognostic factors at ASCT gain benefit from this treatment.