Phase I clinical trial of namitecan (ST1968): Results with D1-3 q3wks schedule.

Fasolo, Angelica; Conte, Gianluca Del; Calderone, Rosa Gioia; Gallerani, Elisa; Hagner, Nicole; Barbieri, Paola; Luraghi, L.; Pace, Silvia; Capocasa, F.; Coceani, N.; Maccioni, Elias; Hess, D.; Sessa, Cristiana; Gianni, Luca

doi:10.1200/jco.2011.29.15_suppl.e13570

Cited by 2 publications

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“…The present analysis quantified all population PK and PD parameters to evaluate the safety of various dose levels of namitecan, taking into account the variability between patients. Namitecan was found to exhibit a long terminal elimination phase, resulting in an average half‐life of 48 h, slightly higher compared with what has been estimated in the ST1968‐DM‐09‐001 study (40–45 h) . Therefore, the terminal half‐life of namitecan is substantially longer compared with the well known topoiromerase I inhibitors, topotecan (2–3 h) and irinotecan (10 h).…”

Section: Discussionmentioning

confidence: 72%

“…With a target for DLT of <20%, the recommended dose was defined as namitecan 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week (D1) regimen and 7 mg for the D1–3 regimen. This is somewhat lower compared with the recommended 15 mg dose for the D1,8 regimen and one dose level higher for the D1–3 dosing regimen . With regards to the D1,8 dosing regimen, the next higher simulated dose of namitecan (15 mg) produced an estimated rate of DLT of 21%, which is close to the target.…”

Section: Resultsmentioning

confidence: 86%

“…For the once every 3 weeks dosing regimen, 23 mg is suggested to be the recommended dose, although DLT for the next higher dose of 25 mg is only marginally higher than the targeted 20% for haematological DLT. For the D1–3 regimen, 7 mg is the recommended dose as calculated from data simulations, that is one dose step higher compared with the experience from study ST1968‐DM‐09‐001 . However, patients in this dosing cohort also have a risk for dose‐limiting thrombocytopenia of 11% that has to be accounted for.…”

Section: Discussionmentioning

confidence: 99%

“…The recommended dose for the D1, 8 regimen was defined to be 15 mg, and the study continued to accrue patients with a once every 3 week (D1) administration of namitecan to optimize the treatment schedule . In the second phase 1 study, namitecan was given as a 2 h infusion on 3 consecutive days and repeated every 3 weeks (D1–3) . Dose‐limiting neutropenia was found at the 7 mg daily dose of namitecan and the 6 mg flat dose was defined to be the recommended dose with the D1–3 regimen.…”

Section: Introductionmentioning

confidence: 99%

“…Dose‐limiting neutropenia was found at the 7 mg daily dose of namitecan and the 6 mg flat dose was defined to be the recommended dose with the D1–3 regimen. Promising clinical activity has been seen in patients with bladder, endometrial, colorectal, head‐and‐neck as well as cervical cancer . Dose‐limiting neutropenia was the predominant and dose‐limiting toxicity in both early stage clinical studies of namitecan, and the understanding of the relationship between namitecan PK and myelosuppression is important for future development of the compound.…”

Section: Introductionmentioning

confidence: 99%

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Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968)

Joerger

Hess

Delmonte

et al. 2015

Brit J Clinical Pharma

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AIMSNamitecan is a new camptothecan compound undergoing early clinical development. This study was initiated to build an integrated pharmacokinetic (PK) and pharmacodynamic (PD) population model of namitecan to guide future clinical development. METHODSPlasma concentration-time data, neutrophils and thrombocytes were pooled from two phase 1 studies in 90 patients with advanced solid tumours, receiving namitecan as a 2 h infusion on days 1 and 8 every 3 weeks (D1,8) (n = 34), once every 3 weeks (D1) (n = 29) and on 3 consecutive days (D1-3) (n = 27). A linear three compartment PK model was coupled to a semiphysiological PD-model for neutrophils and thrombocytes. Data simulations were used to interrogate various dosing regimens and give dosing recommendations. RESULTSClearance was estimated to be 0.15 l h -1 , with a long terminal half-life of 48 h. Body surface area was not associated with clearance, supporting flat-dosing of namitecan. A significant and clinically relevant association was found between namitecan area under the concentration-time curve (AUC) and the percentage drop of neutrophils (r 2 = 0.51, P < 10 À4) or thrombocytes (r 2 = 0.49, P < 10 À4). With a target for haematological dose-limiting toxicity of <20%, the recommended dose was defined as 12.5 mg for the D1,8 regimen, 23 mg for the once every 3 week regimen and 7 mg for the D1-3 regimen. CONCLUSIONThis is the first integrated population PK-PD analysis of the new hydrophilic topoisomerase I inhibitor namitecan, that is currently WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Camptothecans are an important class of anticancer drugs that are frequently used in colorectal, small cell lung and gynaecological cancer and in glioblastoma.• The new camptothecan compound ST1968 (namitecan) is promising as it shows activity in several preclinical models including those with resistance to conventional camptothecans.• Two phase 1 clinical studies using different schedules of single agent namitecan have shown dose-limiting haematological and very limited non-haematological toxicity. WHAT THIS STUDY ADDS• This is a detailed population pharmacokinetic and pharmacodynamic study of ST1968 (namitecan), supporting flat-dosing and full dose proportionality.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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