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A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer.

ABSTRACT: LESSONS LEARNED:Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in unselected, relapsed SCLC patients. BACKGROUND:Treatment of relapsed small-cell lung cancer (SCLC) remains suboptimal. Insulin growth factor-1 receptor (IGF-1R) signaling plays a role in growth, survival, and chemoresistance in SCLC. Linsitinib is a potent IGF-1R tyrosine kinase inhibitor that potentially may be active against SCLC. METHODS:In this phase II study, 8 eligible patients were randomly assigned in a 1:2 ratio to topotecan (1.5 mg/m2 intravenously or 2.3 mg/m2 orally, daily for 5 days for 4 cycles) or linsitinib (150 mg orally twice daily until progression). The primary endpoint was progression-free survival. Patients with relapsed SCLC, platinum sensitive or resistant, performance status (PS) 0-2, and adequate hematologic, renal, and hepatic function were enrolled. Patients with diabetes, cirrhosis, and those taking insulinotropic agents were excluded. Crossover to linsitinib was allowed at progression. RESULTS:Fifteen patients received topotecan (8 resistant, 3 with PS 2) and 29 received linsitinib (16 resistant, 5 with PS 2). Two partial responses were observed with topotecan. Only 4 of 15 patients with topotecan and 1 of 29 with linsitinib achieved stable disease. Median progression-free survival was 3.0 (95% confidence interval [CI], 1.5-3.6) and 1.2 (95% CI, 1.1-1.4) months for topotecan and linsitinib, respectively (p = .0001). Median survival was 5.3 (95% CI, 2.2-7.6) and 3.4 (95% CI, 1.8-5.6) months for topotecan and linsitinib, respectively (p = .71). Grade 3/4 adverse events (>5% incidence) included anemia, thrombocytopenia, neutropenia/leukopenia, diarrhea, fatigue, dehydration, and hypokalemia for topotecan; and thrombocytopenia, fatigue, and alanine aminotransferase/aspartate aminotransferase elevations for linsitinib. CONCLUSION:Linsitinib was safe but showed no clinical activity in unselected, relapsed SCLC patients.

SUBMITTER: Chiappori AA

PROVIDER: S-EPMC5061534 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer.

Chiappori Alberto A AA Otterson Gregory A GA Dowlati Afshin A Traynor Anne M AM Horn Leora L Owonikoko Taofeek K TK Ross Helen J HJ Hann Christine L CL Abu Hejleh Taher T Nieva Jorge J Zhao Xiuhua X Schell Michael M Sullivan Daniel M DM

The oncologist 20160930 10

<h4>Lessons learned</h4>Targeted therapy options for SCLC patients are limited; no agent, thus far, has resulted in a strategy promising enough to progress to phase III trials.Linsitinib, a potent insulin growth factor-1-receptor tyrosine kinase inhibitor, may be one agent with activity against SCLC.Despite lack of a reliable predictive biomarker in this disease, which may have partly contributed to the negative outcome reported here, linsitinib, although safe, showed no clinical activity in uns ...[more]

PMID: 27694157

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Project description:LESSONS LEARNED:The maximum tolerated dose of the combination of linsitinib and irinotecan is linsitinib 450 mg daily on days 1-3 every 7 days and irinotecan 125 mg/m2 days 1 and 8 of a 21-day cycle.The adverse effects associated with the combination are not significantly increased beyond what is expected of each drug as a single agent.Multiple negative trials of insulin-like growth factor-1 receptor inhibitors performed in unselected patient populations led to the early discontinuation of linistinib development and this trial.Earlier integration of assessment of potential predictive biomarkers into clinical trials, as was planned in this study, is vital to the development of targeted therapies in oncology. BACKGROUND:This phase I dose-escalation study was designed to evaluate the safety and tolerability of the combination of irinotecan and insulin-like growth factor-1 receptor (IGF-1R) inhibitor linsitinib in patients with advanced cancer refractory to standard therapy. METHODS:Dose escalation in three specified dose levels was performed according to a standard 3 + 3 design. Dose levels were as follows: (a) linsitinib 400 mg and irinotecan 100 mg/m2, (b) linsitinib 450 mg and irinotecan 100 mg/m2, and (c) linsitinib 450 mg and irinotecan 125 mg/m2. Linisitinib was administered once daily on days 1-3, 8-10, and 15-17, and irinotecan on days 1 and 8. Assessment of a candidate predictive biomarker was planned in all patients, with further evaluation in an expansion cohort of advanced colorectal cancer. RESULTS:A total of 17 patients were treated, with 1 patient in both cohort 2 and 3 experiencing dose-limiting toxicity. Linsitinib 450 mg and irinotecan 125 mg/m2 was the maximum tolerated dose. Sixteen (94%) patients experienced at least one treatment-related adverse event. Neutropenia was the only grade >3 toxicity (4%). No significant hyperglycemia or QT interval prolongation was noted. No objective responses were observed; 47% (n = 8) had stable disease with median duration of 5.25 months. CONCLUSION:Although the combination was determined safe, the study was halted due to termination of linsitinib development, and biomarker testing was not performed.

Project description:BackgroundTo undertake a systematic review of the available data for oral and intravenous topotecan in adults with relapsed small cell lung cancer (SCLC) for whom re-treatment with the first line regimen is not considered appropriate.MethodsWe searched six databases from 1980 up to March 2009 for relevant trials regardless of language or publication status. Relevant studies included any randomised trial of any chemotherapeutic treatment against any comparator in this licensed indication. Where possible we used opposite quantitative methods. Where meta-analysis was considered unsuitable for some or all of the data, we employed a narrative synthesis method. For indirect comparisons we used the method of Bucher et al., where available data allowed it, otherwise we used narrative descriptions.ResultsSeven unique studies met the inclusion criteria, four of which could be used in our analyses. These included one study comparing oral topotecan plus best supportive care (BSC) to BSC alone, one study comparing intravenous topotecan to cyclophosphamide, adriamycin and vincristine (CAV), and two studies comparing oral topotecan with intravenous topotecan. All four studies appear to be well conducted and with low risk of bias. Oral topotecan plus BSC has advantages over BSC alone in terms of survival (hazard ratio = 0.61; 95% CI, 0.43 to 0.87) and quality of life (EQ-5 D difference: 0.15; 95% CI, 0.05 to 0.25). Intravenous topotecan was at least as effective as CAV in the treatment of patients with recurrent small-cell lung cancer and resulted in improved quality-of-life with respect to several symptoms. CAV was associated with significantly less grade 4 thrombocytopenia compared with IV topotecan (risk ratio = 5.83; 95% CI, 2.35 to 14.42). Survival (hazard ratio = 0.98; 95% CI, 0.77 to 1.25) and response (pooled risk ratio = 1.04; 95% CI, 0.58 to 1.85) data were similar for the oral and IV topotecan groups. Symptom control was also very similar between the trials and between the oral and IV groups. Toxicity data showed a significant difference in favour of oral topotecan for neutropenia (pooled risk ratio = 0.65; 95% CI, 0.47 to 0.89). Indirect evidence showed that oral topotecan was at least as good as or better than CAV on all outcomes (survival, response rates, toxicities, and symptoms) that allowed indirect comparisons, with the only exception being grade four thrombocytopenia which occurred less often on CAV treatment.ConclusionsConcerning topotecan both the oral and intravenous options have similar efficacy, and patient preference may be a decisive factor if the choice would be between the two formulations. The best trial evidence for decision making, because it was tested versus best supportive care, exists for oral topotecan. Indirectly, because we have two head-to-head comparisons of oral versus intravenous topotecan, and one comparison of intravenous topotecan versus CAV in similar patients as in the trial against best supportive care, one might infer that IV topotecan and CAV could also be superior to best supportive care, and that oral topotecan has similar effects to CAV with possibly better symptom control. From the evidence discussed above, it is evident that oral topotecan has similar efficacy to IV topotecan (direct comparison) and CAV (indirect comparison). There is no further evidence base of direct or possible indirect comparisons for other comparators than CAV of either oral or IV topotecan.

Dataset Information

A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer.

Publications

A Randomized Phase II Study of Linsitinib (OSI-906) Versus Topotecan in Patients With Relapsed Small-Cell Lung Cancer.

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