Untreated Extensive-stage Small-cell Lung Cancer Research Articles

Randomized phase II study of recombinant human endostatin in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer (NCT00912392).

7091 Background: Endostar (recombinant human endostatin) is a novel antiangiogenesis drug developed in China for non-small cell lung cancer (NSCLC). Because of promising efficacy signals, we performed a randomized phase II trial to assess the efficacy and safety of adding endostar to first-line standard chemotherapy for treatment of chemonaive extensive-stage small-cell lung cancer (SCLC). Methods: Extensive-stage SCLC patients with a performance status 0-2 were randomly assigned to endostar group (endostar 7.5mg/m2 D1-D14 with carboplatin AUC=5 plus etoposide 60mg/m2 D1-D5 of a 21-day cycle for six cycles) or the control group (the same dose of carboplatin plus etoposide). Patients in endostar treatment group with CR, PR and SD were treated with single-agent endostar until progression or unacceptable toxicity. The primary end point is progression-free survival (PFS). The secondary end points are overall survival (OS) and response rate (RR). Results: 140 patients were enrolled from June 2009 to June 2011, and 137 patients were included in full analysis set. 68 patients were randomly assigned to the endostar treatment and 69 patients to the control group. Median age was 57 years and 80.9% for male in the endostar group while median age was 58 years and 85.5% for male in the control group. Median PFS was similar for endostar and control group (6.2 v 5.9 months, P=0.163, HR 0.762; 95%CI 0.519-1.119). Median overall survival (OS) was also similar for both groups (12.4 v 12.3 months, P=0.475, HR 0.835; 95%CI 0.508-1.371). Overall RR were 76.5% for endostar group and 68.1% for the control group (p=0.275). 20 patients in the endostar group completed six cycles of therapy and subsequently treated with single-agent endostar as maintenance therapy and the median PFS and OS were 6.8 and 12.4 months respectively. The rate of ≥ 3 grade adverse events occurred in both groups was similar and no new or unexpected safety signals for endostar were observed. Conclusions: The addition of endostar to carboplatin plus etoposide for treatment of extensive stage SCLC didn’t improve the PFS significantly, with an acceptable toxicity profile. And no improvement in OS was observed.

Amrubicin and carboplatin with pegfilgrastim in patients with extensive-stage small-cell lung cancer (ES-SCLC): A phase II study of the Sarah Cannon Research Institute (SCRI).

7100 Background: Amrubicin is a novel anthracycline associated with high objective response rates (ORR) in patients (pts) with relapsed SCLC. Amrubicin improved the ORR and progression-free survival (PFS) in relapsed SCLC vs. topotecan, but not overall survival (OS) in a phase III study. Amrubicin with cisplatin/carboplatin for elderly Japanese pts was safe and active. We conducted a multicenter phase II study evaluating amrubicin and carboplatin in newly diagnosed ES-SCLC. Methods: Eligible pts had untreated ES-SCLC, measurable/evaluable disease (RECIST v. 1.1) and an ECOG PS <2. Pts received 4 cycles of amrubicin 30 mg/m2 on days 1-3 and carboplatin AUC=5 both IV day 1 every 21 days with restaging every 6 weeks. Pegfilgrastim 6 mg sq was administered on day 4 of each cycle. The primary endpoint was 1-year OS. Secondary endpoints included ORR, PFS, OS, and toxicity. Results: 78 pts were enrolled from 3/2010 to 7/2011. Baseline characteristics included: median age 65 yrs (range 45-84); 56% female. 64% completed 4 cycles of treatment. Eleven (14%) pts showed complete responses and 47 (60%) pts partial responses, for an ORR of 74% (95% confidence interval 65%-82%). Twelve (15%) pts had stable disease. Median PFS and OS were 5.3 and 9.5 months, respectively. The 1-year OS was 36%. Grade 3/4 myelosuppression was the most common toxicity (thrombocytopenia 44%, neutropenia 34%, febrile neutropenia 12%, anemia 26%), but was manageable. Severe non-hematologic toxicities (>5%) included hypokalemia 17%, fatigue 13%, dehydration 10%, hyponatremia 10%, pneumonia 9%, and nausea/vomiting 8%. 1 pt died from sepsis and another from aspiration pneumonia. Conclusions: First-line ES-SCLC treatment with amrubicin and carboplatin induced several complete responses and is considered highly active. Myelosuppression was managed effectively with growth factor support. These results are comparable to historical data with platinum-doublet chemotherapy. A larger randomized study would be required to best assess this regimen’s impact on survival.

Targeted Therapy in Lung Cancer; Lessons Learned from Past Experiences

Targeted Therapy in Lung Cancer; Lessons Learned from Past Experiences

A phase I study of R-(-)-gossypol (AT-101) in combination with cisplatin (P) and etoposide (E) in patients (pts) with advanced solid tumors and extensive-stage small cell lung cancer (ES-SCLC).

3040 Background: AT-101 (AT) is an oral BH3 mimetic that lowers the apoptotic threshold by inhibiting heterodimerization of Bcl-2, Bcl-xL, Mcl-1 and Bcl-W, up-regulating pro-apoptotic proteins noxa and puma and inhibiting angiogenesis. Synergistic anti-tumor activity as been observed in vitro with EP in combination with agents that suppress Bcl-2 expression. This study was conducted to determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetic (PK) profile and preliminary anti-tumor activity of AT and EP. Methods: Adult pts with relapsed or refractory advanced solid tumors received AT orally BID days (D) 1-3, P IV D 1, and E IV D 1-3 of a 21-D cycle. We previously reported the MTD without pegfilgrastim (F) was AT 20 mg BID , P 60 mg/m2, and E 100 mg/m2 (Leal, JCO 2009; 27(15S), e13502). Pts were enrolled in 3 additional dose levels (DL) with F support (6 mg SQ day 4): DL1a (AT 30 mg, P 60 mg/m2, and E 100 mg/m2), DL2a (AT 30 mg, P 60 mg/m2, and E 120 mg/m2), and DL3a (AT 40 mg, P 60 mg/m2, and E 120 mg/m2). Results: 12 additional pts were enrolled: 8 men, 4 women. Tumor types: 4 non-small cell lung cancer (NSCLC), 1 ES-SCLC, 2 esophageal, 2 high-grade (HG) neuroendocrine, 1 prostate, 1 adrenocortical, 1 gallbladder. No dose limiting toxicities occurred. Grade 3/4 treatment-related toxicities included: 2 pts with diarrhea (1 at DL1a and 1 at DL3a), and 1 episode, each, of increased ALT (DL1a), hypokalemia (DL1a), fatigue (DL2a), neutropenia (DL2a), anemia (DL3a), hypophosphatemia (DL3a), and pulmonary embolism (DL3a). Dose-proportional PK was observed with a mean AT t1/2 of 3.32 hr (range 2.86-3.94). No PK interactions were observed between the agents. Two pts with NSCLC and 1 with HG neuroendocrine tumor had a PR. Conclusions: The MTD with F was established at AT 40 mg BID D1-3, P 60 mg/m2 D1, and E 120 mg/m2 D1 of a 21 D cycle. F support permitted standard doses of EP without dose limiting neutropenia. Anti-tumor activity was observed in NSCLC and HG neuroendocrine tumor. Accrual to an MTD expansion cohort of pts with untreated ES-SCLC is ongoing. This study was supported by NCI UO1 CA062491, SAIC 25XS097, and 1ULRR025011.

Randomized Phase II Study of Bevacizumab in Combination With Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer: Results From the SALUTE Trial

Because of promising efficacy signals in single-arm studies, a placebo-controlled, double-blind, randomized phase II trial was designed to assess the efficacy and safety of adding bevacizumab to first-line standard chemotherapy for treatment of extensive-stage small-cell lung cancer (SCLC). Patients with SCLC were randomly assigned to receive bevacizumab or placebo, with cisplatin or carboplatin plus etoposide, for four cycles followed by single-agent bevacizumab or placebo until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS). Fifty-two patients were randomly assigned to the bevacizumab group and 50 to the placebo group; 69% versus 66%, respectively, completed four cycles of therapy. Median PFS was higher in the bevacizumab group (5.5 months) than in the placebo group (4.4 months; hazard ratio [HR], 0.53; 95% CI, 0.32 to 0.86). Median overall survival (OS) was similar for both groups (9.4 v 10.9 months for bevacizumab and placebo groups, respectively), with an HR of 1.16 (95% CI, 0.66 to 2.04). Overall response rates were 58% (95% CI, 43% to 71%) for the bevacizumab group and 48% (95% CI, 34% to 62%) for the placebo group. Median duration of response was 4.7 months for the bevacizumab group and 3.2 months for the placebo group. In the bevacizumab and placebo groups, 75% versus 60% of patients, respectively, experienced one or more grade 3 or higher adverse events. No new or unexpected safety signals for bevacizumab were observed. The addition of bevacizumab to cisplatin or carboplatin plus etoposide for treatment of extensive-stage SCLC improved PFS, with an acceptable toxicity profile. However, no improvement in OS was observed.

Randomized Phase II Study of Bevacizumab in Combination With Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer: Results From the SALUTE Trial

Randomized Phase II Study of Bevacizumab in Combination With Chemotherapy in Previously Untreated Extensive-Stage Small-Cell Lung Cancer: Results From the SALUTE Trial

A Meta-Analysis of Randomized Controlled Trials Comparing Irinotecan/Platinum with Etoposide/Platinum in Patients with Previously Untreated Extensive-Stage Small Cell Lung Cancer

To compare the efficacy and toxicities of irinotecan/ platinum (IP) with etoposide/platinum (EP) in patients with previously untreated extensive-stage small cell lung cancer (E-SCLC). The PubMed database, the Cochrane Library, conference proceedings, databases of ongoing trials, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. The relative risk for overall response to treatment, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the different types of toxicity were pooled by STATA package. Six trials involving 1476 patients with previously untreated E-SCLC were ultimately analyzed. The intention-to-treatment analysis indicated that IP regimens could acquire more overall response than EP regimens (relative risk = 1.10, 95% confidence interval [CI]: 1.00 -1.21, p = 0.043). The pooled HR showed that IP could prolong OS (HR = 0.81, 95% CI: 0.66 -0.99, p = 0.044). Nevertheless, the pooled HR failed to show a favorable PFS in IP regimens (HR = 0.82, 95% CI: 0.64 -1.06, p = 0.139). IP regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than EP regimens. Treatment-related deaths were comparable between the two groups. Although the PFS was similar from this meta-analysis, our results suggest that IP might have an advantage in overall response and OS compared with EP with less hematological toxicities. The IP regimens may be an alternative of EP regimens in the first-line treatment of E-SCLC.

Tumor response and progression-free survival (PFS) as potential surrogate endpoints for overall survival (OS) in extensive-stage small cell lung cancer (ES-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials.

7637 Background: We investigated the putative surrogate endpoints (PSEs) of best response (BR), confirmed response (CoR), and PFS for association with OS, and as possible surrogate endpoints for OS. Methods: Individual patient (pt) data for 870 untreated ES-SCLC pts from 6 single-arm (274 pts) and 3 randomized trials (596 pts from 32 participating centers) containing platinum or paclitaxel-based regimens were pooled. Patient-level associations between the PSEs and OS were assessed by Cox models using a landmark analyses at 2, 4, and 6 months post-study entry. Model discrimination was evaluated using the concordance (c) index. Trial-level surrogacy of PSEs was assessed by the association of the treatment effects on OS and individual PSEs. Treatment effects were estimated through log hazard ratios and log odds ratios. Trial-level surrogacy measures included: R2 from a weighted least squares regression model (R2 WLS), Spearman rank correlation coefficient (Spearman), and R2 from a bivariate survival model (R2 Copula). Results: The median OS and PFS were 9.6 and 5.5 months, respectively; the BR and CoR rates were 44% and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (HR=0.42 [95% CI: 0.35, 0.51]; c-index = 0.63; p < 0.01), with 6-month PFS being the strongest (HR=0.41 [95% CI: 0.35, 0.49]; c-index = 0.66; p < 0.01). At the trial level, PFS showed the highest level of surrogacy for OS (R2 WLS = 0.79; R2 Copula = 0.80), which indicates that PFS explained 79% of the variance in OS and is a good surrogacy measure (see Table). Conclusions: PFS was strongly associated with OS, where PFS status as early as 4 months was a strong predictor of subsequent survival. PFS also shows promise as a potential surrogate for OS, and needs further validation using data from a larger number of randomized phase III trials. This data, if substantiated, will allow faster yet valid evaluation of drugs for ES- SCLC. Trial-level surrogacy measures Endpoint R2 WLS R2 Copula Spearman PFS 0.79 0.80 (95% CI: 0.67, 0.93) 0.75 BR 0.21 NA 0.52 CoR 0.40 NA 0.60 No significant financial relationships to disclose.

Phase 2 trial of pemetrexed disodium and carboplatin in previously untreated extensive‐stage small cell lung cancer, N0423

In extensive-stage small cell lung cancer (SCLC), the combination of pemetrexed plus carboplatin has shown activity and appeared to be well-tolerated. We conducted a trial to confirm the efficacy and to assess the tolerability of this chemotherapy combination. Patients with untreated extensive-stage SCLC were enrolled in this phase 2 open-labeled study. They receive pemetrexed 500 mg/m(2) and carboplatin (area under the curve of 5) every 21 days for a maximum 6 cycles. The primary endpoint for this trial was the confirmed response rate and the accrual goal was 70 patients. Forty-six eligible patients (29 aged <70 years, 17 aged >or=70 years) were accrued to this study. The efficacy outcomes were similar between the 2 age groups. Overall, the confirmed response rate was 35% (16 of 46; 95% confidence interval [CI], 21%-50%), where all 16 were partial responses. On the basis of these results, we had strong evidence that the study would not meet the preset efficacy criteria and was, therefore, closed before full accrual. The median duration of response was 4.4 months (95% CI, 2.9-5.2). Median overall survival for patients aged <70 years and aged >or=70 years was 9.2 months (95% CI, 5.4-11.6) and 10.8 months (95% CI, 2.2-14.3), respectively. Grade 3 or higher toxicity rates were similar between the younger and older patients. Grade 3/4 and grade 4 hematological toxicities were observed in 46% and 26% of patients, respectively. Although well-tolerated, the combination of pemetrexed and carboplatin is not as effective as standard therapy in patients with untreated extensive-stage SCLC.

Safety and Efficacy of Darbepoetin Alfa in Previously Untreated Extensive-Stage Small-Cell Lung Cancer Treated With Platinum Plus Etoposide

A placebo-controlled, double-blind, randomized, phase III study was conducted in patients with extensive-stage small-cell lung cancer receiving first-line platinum-containing chemotherapy to determine if increasing or maintaining hemoglobin concentration with darbepoetin alpha could increase patient survival. Darbepoetin alpha (300 microg) or placebo was administered once per week for 4 weeks then every 3 weeks for up to six cycles of chemotherapy (carboplatin plus etoposide or cisplatin plus etoposide) plus 3 weeks after the last dose of chemotherapy. Patients with disease progression were observed until death or until all patients completed their end-of-study visit and 496 deaths had occurred. The two coprimary end points were change in hemoglobin concentration from baseline to the end of the chemotherapy period and overall survival; statistical testing of survival was done if change in hemoglobin was significant at P < .05. The study enrolled 600 patients. Patients' hemoglobin levels dropped due to the myelosuppressive chemotherapy; however, treatment with darbepoetin alpha maintained hemoglobin levels significantly higher than placebo (P < .001). There was no statistically significant difference in overall survival between the treatment groups (hazard ratio [HR], 0.93; 95% CI, 0.78 to 1.11; P = .431). As expected, darbepoetin alpha was associated with a higher incidence of thromboembolic events (darbepoetin alpha, 9%; placebo, 5%). The transfusion risk was lower in the darbepoetin versus placebo group (HR, 0.40; 95% CI, 0.29 to 0.55). The results of this study did not demonstrate improved survival after treatment with darbepoetin alpha; however, they reinforce the benefit of erythropoiesis-stimulating agents in reducing transfusions and their neutral impact on survival in patients with chemotherapy-induced anemia.

Phase II Study of a 3-Week Schedule of Irinotecan Combined with Cisplatin in Previously Untreated Extensive-Stage Small-Cell Lung Cancer

Background: Irinotecan has been introduced to improve the treatment of small-cell lung cancer (SCLC). We conducted a trial involving a 3-week schedule of irinotecan combined with cisplatin (IP) to validate the efficacy and toxicity of this regimen in patients with previously untreated extensive-stage SCLC (ES-SCLC). Patients and Methods: Twenty-eight patients with previously untreated ES-SCLC were enrolled in the study between January 2003 and December 2005. Irinotecan 60 mg/m² was administered intravenously on days 1 and 8 in combination with cisplatin 60 mg/m² on day 1 every 21 days. Results: Twenty-eight patients were followed until July 2007. The median follow-up time was 15.6 months. The actual dose intensities (DIs) of cisplatin and irinotecan were 97.7 and 92.2%, respectively. Among the 28 ES-SCLC patients, the objective response rate was 89.3% (25 patients). The major grade 3/4 hematological toxicity was neutropenia (26.9% of cycles). Grade 3/4 non-hematological toxicities were rare. The median progression-free and overall survival times were 8.7 and 16.5 months, with a 1-year survival rate of 66.6% and 2-year survival rate of 22.2%. Conclusion: The 3-week schedule of IP was feasible and showed a high DI of irinotecan and decreased toxicity.

Irinotecan, Carboplatin, and Imatinib in Untreated Extensive-Stage Small-Cell Lung Cancer: A Phase II Trial of the Minnie Pearl Cancer Research Network

The tyrosine kinase KIT has variable expression in small-cell lung cancer (SCLC) and may be a prognostic factor. Imatinib targets KIT expression, providing rationale for studying its role in combination with chemotherapy in SCLC in a multicenter phase II trial. Patients with untreated extensive-stage SCLC received carboplatin area under the concentration-time curve of 4 on day 1; irinotecan 60 mg/m2 on days 1, 8, and 15; and imatinib 600 mg/day. Treatment cycles were 28 days. Patients remained on imatinib until progressive disease or significant toxicity. Between September 2002 and May 2004, 68 patients were enrolled in this multicenter trial. Median age was 60 years (range, 37-81). The objective response rate was 66% (95% confidence interval: 54%-76%). Median progression-free survival was 5.4 months (95% CI: 4.3-6.0 months). Median overall survival was 8.4 months (95% CI: 6.3-10.5 months). Thirty-five percent of patients were alive at 1 year. Grade 3/4 hematologic toxicity included neutropenia (43%), anemia (16%), and thrombocytopenia (9%). Grade 3 nonhematologic toxicity included diarrhea (19%), fatigue (24%), and nausea (26%). Forty-eight of 56 patients (86%) with available tumor specimens had KIT expression detected. KIT expression did not appear to correlate with progression-free survival or overall survival in a retrospective analysis. Irinotecan, carboplatin, and imatinib is a safe and generally well-tolerated regimen in patients with SCLC. However, the addition of imatinib did not improve results from those expected with chemotherapy alone.

D1-05: Irinotecan, carboplatin, and bevacizumab in untreated extensive-stage small-cell lung cancer

D1-05: Irinotecan, carboplatin, and bevacizumab in untreated extensive-stage small-cell lung cancer

A phase II study of cisplatin (P) plus etoposide (E) plus bevacizumab (B) for previously untreated extensive stage small cell lung cancer (SCLC) (E3501): A trial of the Eastern Cooperative Oncology Group

7564 Background: Scientific evidence supports the concept that the growth of solid tumors, including SCLC, is dependent on angiogenesis. Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), has been shown to improve survival when combined with chemotherapy in non-small cell lung cancer. PE is a standard regimen for use in SCLC. Thus, we proposed this study of PE plus B in patients (pts) with previously untreated extensive stage SCLC. Methods: Pts with previously untreated extensive SCLC with a performance status 0–2, received P (60 mg/m2) IV followed by E (120 mg/ m2) IV followed by B (15 mg/kg) IV infusion on day 1, with E repeated on days 2 and 3 of a 21-day cycle for 4 cycles or until progressive disease (PD). Pts not experiencing PD continued bevacizumab until disease progression or unacceptable toxicity. The primary endpoint was per cent of patients alive at 6 months. Results: From 6/8/04 to 8/18/06 (includes a ten month accrual suspension to evaluate data), 64 eligible pts were accrued. Patient characteristics: median age of 65.5 years (range: 45–83), 44% males, 95% Caucasian and 9% were performance status = 2. A median of 6 cycles of treatment were administered (range: 1–12). There is toxicity data on 58 pts. The most common treatment-related grade 3 &amp; 4 toxicities were: neutropenia (7 &amp; 26 pts), thrombocytopenia (8 &amp; 2 pts), fatigue (10 pts, grade 3 only), hypertension (4 pts, grade 3 only), febrile neutropenia (2 pts) and dehydration (3 pts, grade 3 only). Two pts experienced grade 5 toxicities (hypotension and infection with grade ¾ neutropenia). There were no grade ≥3 hemorrhagic events. Response information is available on 39 pts. There have been 4 complete responses and 23 partial responses for an overall response rate of 69% (90% exact CI: (55%, 81%). The proportion of pts alive and progression- free at 6 months was 33% (95% CI: 17%, 49%). Conclusions: Preliminary results indicate that the addition of B to the combination of PE in patients with previously untreated extensive stage SCLC appears promising. A randomized phase III trial comparing PE to PE + B is under consideration. No significant financial relationships to disclose.

Phase II trial of irinotecan, carboplatin, and bevacizumab in patients with extensive-stage small cell lung cancer

18130 Background: Bevacizumab (B) improves survival when combined with chemotherapy in non-small cell lung cancer treatment. Our center previously studied the role of B as maintenance therapy in patients (pts) with limited-stage small cell lung cancer (SCLC). The present multicenter community-based trial was designed to examine the role of B and chemotherapy in previously untreated pts with extensive- stage SCLC (ES-SCLC). Methods: The primary endpoint is to assess the median time to progression (TTP). Eligibility criteria: untreated ES-SCLC, ECOG PS 0–1, measurable disease, and informed consent. Exclusion criteria: hemoptysis, brain metastases, and therapeutic anticoagulation. Treatment: irinotecan (I) 60 mg/m2 IV D1, 8, 15, and carboplatin (C) AUC=4 IV D1, and B 10 mg/kg IV D1 and 15 every 28D. Pts were restaged every 8 weeks. If no evidence of progressive disease (PD) after 4–6 cycles, pts received B x 6 months. This 2- stage trial was designed to achieve a 40% improvement in historical median TTP of 6 months. Results: 34 pts were enrolled from 2/06 to 12/06 (trial ongoing, n=50 planned). Data are available for 23 pts in this analysis. Baseline characteristics: median age 66 years; male/female, 52%/48%; and ECOG PS 0/1, 35%/65%. The objective response rate was 78% (95% CI 58%-90%), all partial responses. One pt had stable disease and no pts had PD. Four pts were not evaluable due to: comorbidity (off study), 2 pts; too early, 2 pts. With a median follow-up of 7 months, the median TTP and overall survival have not been reached. Grade (G) 3/4 non-hematologic toxicity: diarrhea (26%), hyponatremia, pain, arthralgia, fatigue (13% each), and dehydration, confusion, proteinuria (9% each). G3/4 hematologic toxicity was limited to neutropenia (13%). Other G3/4 toxicities were = 5%. There have been no episodes of G3/4 bleeding or treatment-related deaths. Conclusions: I/C/B appears to be safe and generally well tolerated in pts with ES-SCLC in this preliminary analysis. Further accrual and longer follow-up are necessary to assess median TTP. No significant financial relationships to disclose.

CALGB 30306: A phase II study of cisplatin (C), irinotecan (I) and bevacizumab (B) for untreated extensive stage small cell lung cancer (ES-SCLC)

7563 Background: VEGF is expressed in 80% of SCLC. Combining chemotherapy with B is effective in advanced non-small cell lung, breast and colon cancers. Methods: This was a phase II study of C 30 mg/m2 and I 65 mg/m2 days 1 and 8 plus B 15 mg/kg day 1 every 21 days for up to 6 cycles in patients with untreated ES-SCLC, PS 0–2, and adequate organ function. Eligibility required no significant bleeding, uncontrolled hypertension, brain mets or other risk factors for B therapy. An initial safety cohort of ten patients was closely followed for unexpected/severe toxicities. Pretreatment blood was collected for biomarker analysis. Statistical design: primary endpoint 12 mo survival rate &gt; 57% (median survival ≥15 mo). Results: 72 pts were enrolled from 3/05–4/06 with one patient deemed ineligible due to diagnosis NSCLC. Demographics: 51% female; median age 62; PS 0–23%, 1–68%, 2–10%. There were no episodes of grade 3 or greater hemoptysis or other primary hemorrhagic episodes. One patient died after an embolic/thrombotic stroke bled secondarily. Other grade 3/4 toxicities included (%): anemia 5, neutropenia 23, platelets 10, hypertension 6, fatigue 12, diarrhea 17, nausea 11, bowel perforation 2, infection 14, all electrolyte 23, stroke 4, vascular access thrombosis 3. Deaths on therapy 3 (4%): pneumonitis 1, stroke 1, heart failure 1. Preliminary efficacy: CR 2 (3%), PR 42 (59%), SD 9 (13%), PD 1 (1%); ORR 62%; ORR excluding unevaluable (4%)/no data (18%): 80%; median progression free survival 7.0 mo (95% C.I. 6.2,8.0); median overall survival 10.6 mo (95% C.I. 8.5, 11.7); median follow-up 9.5 mo. Pretreatment VEGF/PDGF titers have been measured, reported to the CALGB statistics center, and will be analyzed in relation to response and survival outcomes. Conclusions: Although ES-SCLC often has bulky central disease there was no clinically significant hemoptysis. All patients will be at least 12 months from initiation of therapy by 5/07, and mature response and survival data will be presented. No significant financial relationships to disclose.

A phase I and pharmacologic study of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer

18053 Background: Belotecan (CKD602) is a novel camptothecin derivative antitumor agent. This phase I study was designed to determine the maximum-tolerated dose (MTD), toxicity profile, and dose-limiting toxicity (DLT) of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small-cell lung cancer (ED SCLC). Furthermore, pharmacokinetics (PK) and preliminary antitumor activity of belotecan against SCLC were evaluated. Methods: Patients with ED SCLC, age 18–70, ECOG PS 0–2, no prior chemotherapy and adequate organ function were eligible. Cisplatin with fixed dose of 60 mg/m2 was administered intravenously (i.v.) over 2 hours on day 1. Belotecan was administered iv as intermittent 30-minute infusions on days 1 to 4, starting dose of 0.40 mg/m2/day with increment of 0.05 mg/m2/day. Modified Fibonacci escalation was used (3 to 6 patients per cohort) and intra-patient dose escalation was not allowed. PK of belotecan was determined during the first treatment using non-compartmental pharmacokinetic analysis. Results: Seventeen patients were treated at 4 dose levels (0.40 to 0.55 mg/m2/day). At 0.55 mg/m2/day of belotecan, the DLT of grade 4 neutropenia with fever occurred in 2 of 5 patients, and therefore the MTD was 0.50 mg/m2/day. Interestingly, out of 17 patients, there were 14 partial responses (82.4%; 95% CI, 63.4% to 100.0%). PK analysis revealed that at 0.50 mg/m2/day, plasma clearance of belotecan was 5.78 ± 1.32 L/hr and terminal half-life was 8.55 ± 2.12 hr. Fraction of excreted amount in urine was 37.36 ± 5.55 %. PK of belotecan were not altered by administration of cisplatin, as compared with historical control. Conclusions: The MTD of belotecan was 0.50 mg/m2/day for intermittent 30-min i.v. infusion for 4 days in combination with cisplatin 60 mg/m2 on day 1 every 3 weeks. Furthermore, very promising antitumor activity against SCLC was observed. The phase II study is being conducted now. No significant financial relationships to disclose.

Three-week schedule of irinotecan plus cisplatin in patients with previously untreated extensive-stage small-cell lung cancer

Irinotecan and cisplatin demonstrated promising outcomes in extensive-stage small-cell lung cancer. According to the dosage and schedule of irinotecan, efficacy and toxicity profiles showed subtle differences. This study was designed to evaluate efficacy and toxicity of 3-week schedule of irinotecan/cisplatin in patients with previously untreated extensive-stage small-cell lung cancer. The primary objective was to evaluate response rate and secondary objectives were overall survival and progression-free survival. Patients with previously untreated extensive-stage small-cell lung cancer were enrolled. Irinotecan 65 mg m−2 was administered on days 1 and 8 and cisplatin 60 mg m−2 on day 1. Treatment was repeated every 3 weeks. Seven out of 54 patients (13.0%) had complete response, and partial response was observed in 33 (61.1%). The overall response rate was 74.1% (95% CI; 62.0–82.2%). Stable disease was observed in eight (14.8%) and no progressive disease was observed. After a median follow-up duration of 28.7 months, the median overall survival and progressive-free survival were 13.6 and 6.5 months, respectively. Major grade 3/4 toxicities were neutropenia (50.0%), anorexia (42.6%), diarrhoea (29.6%), fatigue (29.6%) and vomiting (13.0%). There was one treatment-related death owing to pneumonia. Three-week schedule of irinotecan/cisplatin showed effective antitumour activity and moderate toxicities in patients with previously untreated extensive-stage small-cell lung cancer.

Randomized Phase II Trial of Pemetrexed Combined With Either Cisplatin or Carboplatin in Untreated Extensive-Stage Small-Cell Lung Cancer

Given the activity and tolerability of pemetrexed/platinum combinations in non-small-cell lung cancer, and the success of novel therapeutic strategies employed in recent extensive-stage small-cell lung cancer (ES-SCLC) trials, a randomized phase II trial was initiated to evaluate the use of cisplatin or carboplatin plus pemetrexed in previously untreated ES-SCLC. Patients were randomly assigned to receive pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 or pemetrexed plus carboplatin area under the concentration curve 5. Treatment was administered once every 21 days for a maximum of six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Between December 19, 2002, and May 17, 2004, 78 patients were enrolled onto this multicenter trial. Median age was 63 years (range, 46 to 82 years) for cisplatin/pemetrexed and 66 years (range, 47 to 75 years) for carboplatin/pemetrexed. Median survival time (MST) for cisplatin/pemetrexed was 7.6 months, with a 1-year survivorship of 33.4% and a response rate of 35% (95% CI, 20.6% to 51.7%). The MST for carboplatin/pemetrexed was 10.4 months, with a 1-year survivorship of 39.0% and a response rate of 39.5% (95% CI, 24.0 to 56.6). Median time to progression for cisplatin/pemetrexed was 4.9 months and for carboplatin/pemetrexed was 4.5 months. Median dose-intensity (actual/planned dose) was 98.94% for cisplatin and 99.95% for pemetrexed in the cisplatin/pemetrexed group and 93.21% for carboplatin and 98.50% for pemetrexed in the carboplatin/pemetrexed group. Grade 3/4 hematologic toxicities included neutropenia (15.8% v 20.0%) and thrombocytopenia (13.2% v 22.9%) in the cisplatin/pemetrexed and carboplatin/pemetrexed treatment groups, respectively. Pemetrexed/platinum doublets had activity and appeared to be well-tolerated in first-line ES-SCLC.

Phase II trial of amrubicin in patients with previously treated small cell lung cancer (SCLC)

7061 Background: Amrubicin, a totally synthetic 9-amino-anthracycline, has been shown to have excellent antitumor activity as a single agent against previously untreated extensive-stage SCLC. The objective of this study was to assess the efficacy and safety of amrubicin in patients with refractory or relapsed SCLC. Methods: Patients with histologically or cytologically confirmed SCLC, 20 to 74 years in age, performance status 0–2, with a history of receiving first- or second- line chemotherapy were eligible for the study. Amrubicin (45mg/m2/day) was administered on Days 1–3 every 3 weeks for four to six courses. The primary endpoint was the response rate (RR), and planned sample size for this phase II study was 33 patients (Simon’s two-stage minimax design). Results: From June 2003 to January 2005, 35 patients (26 males/9 females, median age, 64 years) were enrolled, and 34 of these patients were treated with the study drug. Four courses or more were administered in 59% (20/34) of the patients, and dose reduction was required in 52% (15/29) of the patients who had received 2 courses or more. Four complete responses and 14 partial responses were observed among the 34 treated patients, yielding a RR of 53% (95% confidence interval: 35.1%–70.2%). The median survival duration in the patients was 8.8 months, and the 1-year survival rate was 26%. Grade 3/4 leukopenia, neutropenia, and thrombocytopenia were observed in 76%, 97% and 38% of the patients, respectively. Febrile neutoropenia occurred in 12 patients (35%), and one patient died from treatment related pneumonia. Conclusion: Amrubicin (45mg/m2/day) was effective in patients with previously treated advanced SCLC, however, severe hematological toxicities occurred in some patients. No significant financial relationships to disclose.