Sensitive-relapsed Small-cell Lung Cancer Research Articles

Real-World Outcomes of Second-Line Treatment in Sensitive Relapsed Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study

Real-World Outcomes of Second-Line Treatment in Sensitive Relapsed Small-Cell Lung Cancer: A Multicenter Retrospective Cohort Study

A randomised phase 2b study comparing the efficacy and safety of belotecan vs. topotecan as monotherapy for sensitive-relapsed small-cell lung cancer

BackgroundThis study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).MethodsOne-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m2) or belotecan (0.5 mg/m2), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint.ResultsIn the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48–0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3–6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022).ConclusionsThe efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.

OA15.02 Carboplatin-Etoposide Versus Topotecan as Second-Line Treatment for Sensitive Relapsed Small-Cell Lung Cancer: Phase 3 Trial

OA15.02 Carboplatin-Etoposide Versus Topotecan as Second-Line Treatment for Sensitive Relapsed Small-Cell Lung Cancer: Phase 3 Trial

Paclitaxel for relapsed small-cell lung cancer patients with idiopathic interstitial pneumonias.

Although first-line chemotherapy is highly sensitive against small-cell lung cancer (SCLC), most patients subsequently experience disease progression. Topotecan is the standard therapy for sensitive-relapsed SCLC patients, and subgroup analysis of a randomized phase III trial suggests that amrubicin is effective for refractory-relapsed SCLC. However, because of the lack of the evidence based on clinical trials, the effectiveness of systemic chemotherapy for relapsed SCLC patients with idiopathic interstitial pneumonias (IIPs) is unclear. In the presentstudy, 17 relapsed SCLC patients with IIPs who received a paclitaxel (PTX)-containing regimen as a second-line chemotherapy were retrospectively reviewed. The overall response rate and the disease control rate of the PTX-containing regimens were 29.4 and 47.1%, respectively. The median progression-free survival and the overall survival of the regimens were 2.7 months [95% confidence interval (CI), 1.6-3.6 months] and 3.6 months (95% CI, 2.3-14.0 months), respectively. Grade 3-4 neutropenia and febrile neutropenia occurred in 12 (70.6%) and 2 (11.8%) patients, respectively. During the treatment period, acute exacerbation (AE) of IIPs was observed in five patients (29.4%). Treatment-associated fatality was observed in 1 patient with febrile neutropenia and in 1 patient with AE of IIPs. PTX had promising anti-tumor activity against refractory-relapsed SCLC with IIPs. However, the survival benefit of the treatment was limited because of the high incidence of AE of IIPs and treatment-related death.

Re-challenge chemotherapy in patients with sensitive relapse small-cell lung cancer and interstitial lung disease.

Treatment modalities for small-cell lung cancer (SCLC) with pre-existing interstitial lung disease (ILD) are limited. Although re-challenge with first-line chemotherapy can be effective for sensitive relapse SCLC, its safety and efficacy are uncertain in cases with ILD. This study aimed to investigate both the efficacy and safety of re-challenge chemotherapy in patients with sensitive relapse SCLC with ILD. Patients with sensitive relapse SCLC with ILD who received re-challenge chemotherapy were studied retrospectively. Sensitive relapse was defined as a treatment-free interval (TFI) of more than 60 days after first-line platinum-based treatment. The endpoints were progression-free survival (PFS), overall survival (OS), and safety. Re-challenge platinum and etoposide were administered in 11 patients, with the median re-challenge cycle of 3. The overall response rate was 55%. The median PFS and OS from the time of re-challenge treatment were 4 months (95% CI, 2.9-NA) and 9.2 months (95% CI, 8.0-NA), respectively. One patient developed acute exacerbation of ILD 173 days after the last course of re-challenge treatment. Re-challenge chemotherapy can be effective and considered in SCLC patients with pre-existing ILD.

Efficacy of Second-line Chemotherapy in Patients With Sensitive Relapsed Small-cell Lung Cancer.

To evaluate treatment efficacy of cisplatin, etoposide, and irinotecan combined therapy (PEI), platinum-rechallenge chemotherapy (Pt-Re) and amrubicin monotherapy (AMR) for patients with sensitive relapsed small cell lung cancer (SCLC). We defined sensitive relapse as treatment-free interval (TFI) ≥90 days. We retrospectively collected patients' data from medical records between September 2002 and December 2016. Patients with sensitive relapsed SCLC who received second-line chemotherapy were separated into those treated with PEI, with Pt-Re, or with AMR. Seventy-one patients (16 PEI group, 27 Pt-Re group, and 28 AMR group) were assessable for efficacy. No significant differences in patient characteristics were found among the three groups. The median overall survival (MST) was 29.3 months in the PEI group, 24.6 months in the Pt-Re group, and 20.6 months in the AMR group (p=0.042). A significant difference was observed in the overall survival of patients treated with PEI, Pt-Re and AMR and the MST of PEI was the longest.

Rechallenge treatment with a platinum-based regimen in patients with sensitive relapsed small-cell lung cancer.

Among patients with relapsed small-cell lung cancer (SCLC), those who relapse > 90days after first-line chemotherapy are classified sensitive relapse. Rechallenge with a first-line platinum-based regimen has been used in sensitive relapsed SCLC patients, but its importance is not known. We evaluated the outcome of rechallenge with platinum-based chemotherapy for sensitive relapse patients. We reviewed consecutive patients with sensitive relapsed SCLC who received second-line chemotherapy between January 1999 and December 2016. We evaluated the treatment outcomes of platinum-based rechallenge and non-rechallenge regimens for second-line chemotherapy in sensitive relapse patients. Of 245 patients, 81 sensitive relapse patients received second-line chemotherapy. Sixty-seven patients (82.7%) were treated with rechallenging platinum-based regimens ("rechallenge group") and 14 patients (17.3%) were treated with other regimens ("non-rechallenge group") as second-line chemotherapy. Median progression-free survival (PFS) was 5.1months in the rechallenge group and 3.5months in the non-rechallenge group, and median survival time was 10.8 and 8.2months, respectively. There were no significant differences in PFS or overall survival (OS) between the two groups. Sub-analyses of patients who received chemotherapy alone as first-line treatment showed that the rechallenge group had longer PFS than that of the non-rechallenge group (median 5.4 vs. 3.6months, p = 0.0038), and the rechallenge group had a tendency to have longer OS than non-rechallenge group. These data suggest that rechallenge treatment with a platinum-based regimen could be second-line chemotherapy in patients with sensitive relapsed SCLC, especially those treated with chemotherapy alone as first-line therapy.

An open-label, phase II study of the polo-like kinase-1 (Plk-1) inhibitor, BI 2536, in patients with relapsed small cell lung cancer (SCLC)

ObjectivesThis phase II, open-label study was designed to evaluate the response rate to the polo-like kinase 1 (Plk-1) inhibitor BI 2536 in patients with sensitive-relapsed small cell lung cancer (SCLC). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, and safety. Materials and methodsPatients were treated with the recommended phase II dose of 200mg of BI 2536 intravenously every 21days. This was a two-stage design with an early stopping rule in place if responses were not seen in at least 2 of the first 18 enrolled patients. Results and conclusionTwenty-three patients were enrolled in the study and 21 patients were evaluable for response. No responses were observed and all 23 patients have progressed. The median PFS was 1.4 months. Treatment was generally well tolerated and the most frequent adverse events were neutropenia, fatigue, nausea, vomiting, and constipation. BI 2536 is not effective in the treatment of sensitive relapsed SCLC. The criteria for expanding the trial to the second stage were not achieved, and the study was terminated for a lack of efficacy.

Thriving where others have faltered—a critical appraisal of the role of patient factors versus treatment effect in JCOG0605 trial in relapsed small cell lung cancer

Small cell lung cancer (SCLC) makes up approximately 13–15% of all lung cancer cases (1). Despite initial response to treatment, a large majority of patients with extensive stage SCLC relapse within 6 months (2). Improved outcome for SCLC patients remains stunted in major part because of lack of effective therapies for progressive disease following frontline therapy. Topotecan is the only salvage therapy with worldwide approval but its efficacy is quite modest and may be ineffective in patients with platinum insensitive disease (3-5). Contemporary comparative phase III studies of cytotoxic agents such as cabazitaxel and amrubicin against topotecan for relapsed SCLC have been negative especially in Western patient populations (6,7). It is therefore intriguing and interesting to observe that the randomized phase III JCOG0605 trial recently reported by Goto et al . showed an impressive benefit of the combination of cisplatin, etoposide and irinotecan, which significantly outperformed topotecan as second line therapy for patients with sensitive relapsed SCLC (8).

Can combination chemotherapy be standard therapy for sensitive relapsed small-cell-lung cancer?

Small-cell-lung cancer (SCLC) is a histological type of lung cancer with distinct clinical phenotypes, such as higher response and relapse rates due to rapid acquisition of resistance to chemotherapy. Therefore, second-line treatment is critical for improving survival in SCLC and is delivered with different regimens after the patients are classified into either sensitive or refractory relapse with a cutoff of 2 or 3 months after the first-line treatment. Topotecan monotherapy (1.5 mg/m 2 on days 1 to 5 every 3 weeks) has been a standard of care for sensitive relapse SCLC. Overall survival in relapsed SCLC with topotecan monotherapy was reported to range from 6.2 to 8.7 months in previously conducted phase III trials (1-3).

Efficacy of Rechallenge Chemotherapy in Patients With Sensitive Relapsed Small Cell Lung Cancer

To evaluate the efficacy of rechallenge with current induction regimens for sensitive-relapse small cell lung cancer (SCLC) patients. We defined sensitive relapse as treatment-free interval (TFI≥90 d). Sensitive-relapse SCLC patients who received second-line chemotherapy were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group). The endpoints were overall survival (OS), progression-free survival, and toxicity. Sixty-five patients (19 rechallenge group and 46 other group) were assessable for efficacy and safety evaluation. No significant differences in age, sex, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the 2 groups, but TFI was significantly longer in the rechallenge group. Twenty-one patients of the other group received amrubicin. There was no significant difference in OS between the 2 groups (median survival time [MST]: rechallenge group, 14.4 mo; other group, 13.1 mo; P=0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (P=0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI≥180 d). There was no significant difference in OS between the 2 groups (MST 15.7 vs. 26.9 mo, P=0.46). Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.

Final Result of Randomized Phase 2 Trial Comparing Amrubicin (A) with Re-Challenge of Platinum Doublet (P) in Patients (Pts) with Sensitive-Relapsed Small-Cell Lung Cancer (Sclc): Njlcg0702

ABSTRACT Aim: When this trial was planned, A was believed to be a promising new anthracycline agent for sensitive-relapsed SCLC. While re-challenge of P that had been used for the first-line treatment was also believed to be effetive for sensitive-relapsed SCLC, although prospective evaluation of it had not been reported. Thus this randomized phase 2 study was conducted to select A or P for future phase 3 trial. Methods: Sensitive-ralapsed SCLC pts were randomized to receive A (40mg/m2, day1-3, every 3 weeks) or P (every 3-4 weeks). The modification of P such as the 20%-dose reduction of combined third-generation or change of platinum agent from cisplatin to carboplatin according to patient's condition was permitted. The primary endpoint was overall response rate (ORR), and secondary endpoint were progression-free survival (PFS), overall survival (OS), and toxicity profile. According to the Simon's two-stage phase 2 design, 28 pts were required in each arm (p0=0.3, p1=0.5, alpha=0.01, beta=0.02), and the treatment that achieved not less 12 out of 28 pts with partial response would be judged as effective. Results: From February 2008 to June 2013, 60 pts were enrolled from 14 institutions. Two patients in the A arm and one patient in the P arm did not receive any protocol treatment due to rapid disease progression. Evaluated patients' characteristics were as follows: Male/Female, 53/4; median age, 66 (range 44-80); performance status 0/1/2, 32/21/4. The median number of treatment cycles was 4 (range 2-8) in A arm and 3 (range 1-7) in P arm. ORRs and disease control rates were 67% (95%CI, 50-84) and 86% for A, and 43% (95%CI, 25-61) and 80% for P, respectively. Mdian PFS and OS were 5.4 months and 14.4 months in A arm, and 5.1 months and 14.3 months in P arm. Grade 3 toxicity was observed in 33% of patients in A arm including 19% of febrile neutorpenia, while 17% in P arm without any febrile neutropenia. There was no grade 4 toxicity or treatment-related death in this trial. Conclusions: Both treatments met the primary endpoint. Since A produced higher ORR and longer median PFS than P with acceptable toxicity, we select A for subsequent phase 3 trial. Disclosure: All authors have declared no conflicts of interest.

Randomized phase 2 trial comparing amrubicin (A) with re-challenge of platinum doublet (P) in patients (pts) with sensitive-relapsed small-cell lung cancer (SCLC).

7520 Background: When this trial was planned, A was believed to be a promising new anthracycline agent for sensitive-relapsed SCLC. While re-challenge of P that had been used for the first-line tre...

O2–009 - Re-Challenge Treatment with Platinum-Containing Regimen in Patients with Sensitive Relapsed Small Cell Lung Cancer

Among relapsed small cell lung cancer (SCLC) patients, sensitive relapse is relatively chemosensitive and re-challenge with the same regimen as used in the induction chemotherapy has been used historically, however, its efficacy for sensitive relapsed SCLC remains unclear. In our institution, we defined sensitive relapse as treatment-free interval of 90> days, and have tried re-challenge treatment with platinum-containing regimen. Therefore, we retrospectively reviewed SCLC patients who received the first-line chemotherapy (CT) or chemoradiotherapy (CRT) between April 2009 and December 2012. Fifty-four patients received CT or CRT in that period, and sensitive relapse was observed in 16 patients [12 male and 4 female; median age 71 (range 56-83); PS 0/1, 11/5; LD/ED, 6/10]. Median treatment-free interval was 162 days (range 83-238). Three of 16 patients could not receive second line chemotherapy because of rapid progression and poor PS. One had refused all chemotherapies after first progression. Median number of cycles in second line chemotherapy was 4. Four partial responses and 7 stable disease were observed (response rate and disease control rate were 25% and 92%, respectively). Median progression-free survival time was 5.3 months (95% CI, 3.8-6.9 months) and median survival time was 13.4 months (95% CI, 9.4-17.4 months). Toxicities were generally tolerable and manageable. In conclusion, re-challenge treatment with platinum-containing regimen for sensitive relapsed SCLC is worth further evaluation.

Efficacy of rechallenge chemotherapy in patients with sensitive relapsed small cell lung cancer.

7088 Background: Treatment efficacy of rechallenge chemotherapy recommended for patients with sensitive-relapse small cell lung cancer (SCLC) has not been fully clarified. Methods: We defined sensitive relapse as treatment-free interval (TFI) ≥ 90 days. Sixty-five sensitive-relapse SCLC patients who received second-line chemotherapy at the Shizuoka Cancer Center between September 2002 and May 2011 were separated into those treated with rechallenge chemotherapy (rechallenge group) and those treated with other regimens (other group) for comparison and analysis of treatment efficacy. Results: No significant differences in age, gender, ECOG performance status at relapse, disease extent at diagnosis, or response to first-line treatment were found between the two groups, but TFI was significantly longer in the rechallenge group, which included 19 sensitive-relapse patients. The other group included 46 sensitive-relapse patients, 21 of whom received amrubicin. There was no significant difference in overall survival (OS) between the two groups (median survival time (MST): rechallenge group 14.4 months, other group 13.1 months, p = 0.51). In the patients treated with amrubicin, MST was 12.6 months. Comparing the rechallenge group with the patients treated with amrubicin, there was also no significant difference in OS (p = 0.38). Both the rechallenge and other group included 11 patients with ex-sensitive relapse (TFI ≥ 180 days). There was no significant difference in OS between the two groups (MST 15.7 vs. 26.9 months, p = 0.46). Conclusions: Rechallenge chemotherapy did not prove superior to other chemotherapies, suggesting that monotherapy, such as amrubicin, might be reasonable as second-line chemotherapy for sensitive-relapse SCLC patients.

Phase II study of NK012 in relapsed small cell lung cancer.

7079 Background: NK012 is a topoisomerase I (TI) inhibitor designed as a micelle-forming macromolecule to release a gradual and sustained concentration of SN-38, the active metabolite of irinotecan. Phase I studies have shown safety and antitumor activity of NK012 in patients (pts) with refractory tumors including small-cell lung cancer (SCLC). This phase II trial was designed to evaluate NK012 in pts with sensitive relapsed (SR) and refractory relapsed (RR) SCLC. Methods: Pts with relapsed SCLC following 1 chemotherapy regimen for extensive-stage SCLC or chemoradiation for limited-stage SCLC were eligible. Pts had measurable disease, an ECOG performance status (PS) of 0-2, and adequate organ function. Pts with untreated brain metastases or prior TI therapy were excluded. NK012 was given IV over 30 minutes once every 28 days at a dose based on pretreatment UGT1A1 genotyping: 28 mg/m2 (wild-type [wt]/wt and wt/*28) or 18 mg/m2 (*28/*28). Pts were restaged every 8 weeks and remained on therapy until disease progression or unacceptable toxicity. The trial used a two-stage design to assess the objective response rate (ORR) in both SR (H1 30%, α.10, β.20) and RR cohorts (H1 20%, α.05, β.20). Results: 40 SR pts were enrolled over 11 months. The RR cohort remains open to enrollment. Pt characteristics of the SR pts: median age 62 years, female 48%, ECOG 0-1 95%. Pts received a median of 4 cycles (range 1-10) of NK012. The ORR assessed in 37 SR pts was 22% including 2 complete responses; the disease control rate (DCR=ORR+stable disease) was 68%. Survival analyses are in progress. NK012 was well-tolerated with the following grade 3/4 toxicities (> 5%): neutropenia (44%, 1 pt with febrile neutropenia), thrombocytopenia (13%), anemia (5%), diarrhea (8%), and no treatment-related deaths. Conclusions: NK012 exhibited positive efficacy in pts with sensitive relapsed SCLC with a 22% ORR and a 68%DCR. Toxicity was expected and manageable with relatively low rates of serious toxicity. NK012 is currently in a phase I platinum combination study.

A Phase II Study of Higher Dose Weekly Topotecan in Relapsed Small-Cell Lung Cancer

BackgroundFive-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m2 intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR) < 10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity. Patients and MethodsThis multicenter phase II trial sought a 25% ORR (α = 0.04; β = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m2 I.V. for 6 weeks) and were restaged every 8 weeks. ResultsBaseline characteristics were N = 38, enrolled 5/2006-10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (> 10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths. ConclusionWeekly topotecan (6 mg/m2 I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC.

Phase II trial of amrubicin and carboplatin in patients with sensitive or refractory relapsed small-cell lung cancer

Amrubicin is a novel, totally synthesized anthracycline derivative, and has antitumor activity against several human tumor xenografts. The combination of amrubicin with platinum derivative showed additive effect against a human small-cell lung cancer (SCLC) cell line. Until now, the combination of amrubicin plus carboplatin has not been studied in patients with previously treated SCLC. Therefore, we examined the safety and efficacy of the combination of amrubicin plus carboplatin in patients with sensitive or refractory relapsed SCLC. Patients with previously treated SCLC were eligible if they had a performance status of 2 or less, were 75 years or younger, and had adequate organ function. Twenty-five patients were enrolled (21 men and 4 women; median age, 65 years; age range 55–73 years). Patients received the combination of amrubicin (30mg/m2 on days 1–3) plus carboplatin (with a target area under the concentration-versus-time curve of 4mgmin/ml using the Calvert formula on day 1) every 3 weeks. The overall response rate was 36.0% (95% confidence interval [CI], 18.0–57.5%). Response rates differed significantly between patients with sensitive relapse (58.3%; 95% CI, 27.7–84.8%) and those with refractory relapse (15.4%; 95% CI, 1.9–15.4%; p=0.03). The median survival time (MST) from the start of this treatment was 7 months (range: 1–42 months); the MST of patients with sensitive relapse (10 months) was significantly longer than that of patients with refractory relapse (5 months: p=0.004). The median progression-free survival (PFS) time was 3 months (range: 1–14 months): the median PFS time of patients with sensitive relapse (5 months) was significantly longer than that of patients with refractory relapse (2 months; p=0.01). The most frequent grade 3–4 toxicity was myelosuppression, especially neutropenia, which developed in 88% of patients. Grade 3–4 thrombocytopenia developed in 44% of patients, and anemia developed in 56%. Nonhematologic toxicities were generally mild to moderately severe and temporary. None of the patients had cardiotoxicity. In conclusion, this therapy is effective and well tolerated for previously treated SCLC.

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 &lt;Grade 2 drug related non-hematologic and &lt;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 &gt;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 (&gt;1,000 mL/min) and quickly distributes in multiple compartments in a large volume of distribution (&gt;1,000 L). Estimated elimination half-life was &gt;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]

A Phase I Study of Topotecan Plus Carboplatin for Relapsed SCLC: WJTOG Trial

A phase I study on relapsed small cell lung cancer (SCLC) was conducted to establish the toxicity and maximum tolerated dose of carboplatin with topotecan, and to observe the antitumor activity. Thirty-two SCLC patients who had received one previous line of chemotherapy were enrolled. Topotecan was infused for 30 minutes on days 1 to 5, and carboplatin for 60 minutes after the topotecan infusion on day 5 every 3 weeks. Granulocyte colony-stimulating factor prophylaxis was administered from day 8 to white blood cell or neutrophil recovery. The most frequent toxicities were neutropenia and thrombocytopenia. Nonhematological toxicities were generally mild. Three of six patients experienced a dose-limiting toxicity, thrombocytopenia, at dose level 6: 0.85 mg/m topotecan with area under curve 5 carboplatin (maximum tolerated dose). Of 29 evaluable patients, 5 (17.2%) had partial responses. Of 21 patients who relapsed more than 90 days after completion of first-line chemotherapy, 5 (23.8%) had partial responses. Median overall survival time and 1-year survival rate were 11.3 months and 50.0%, respectively. The recommended dose for further studies is 0.75 mg/m of topotecan on days 1 to 5 with area under curve 5 of carboplatin on day 5 every 3 weeks. This combination is well tolerated, and is promising for sensitive relapsed SCLC. A comparative study against single-agent topotecan for sensitive relapsed SCLC is warranted.