FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4255358765> ?p ?o ?g. }

• W4255358765 endingPage "4736" @default.
• W4255358765 startingPage "4736" @default.
• W4255358765 abstract "Abstract Introduction: SCLC is an aggressive high-grade neuroendocrine malignancy in which targeting DNA-damage repair pathways has shown efficacy in pre-clinical and clinical contexts. We previously conducted a phase I/II trial combining the PARP inhibitor olaparib (O) tablets with the alkylating agent temozolomide (T) in patients with relapsed SCLC, in which O and T were both given days (d) 1-7 of each 21 d cycle. The recommended phase 2 dose (RP2D) was O 200 mg PO BID and T 75 mg/m2 PO daily, and the response rate among the first 29 evaluable patients was 41.4%, with the primary toxicities being hematologic (Farago et al., ASCO 2018). Continuous PARP inhibition with O may improve efficacy, though it is unknown how best to incorporate T onto this backbone. Simultaneous clinical testing of multiple dosing schedules for concurrent OT would be impractical. Here we present an optimization of the OT regimen using PDX models generated from patients treated with OT. Methods: SCLC PDX models derived from two patients prior to their durable responses to OT, MGH1518-1B and MGH1528-1, were used for dose optimization. Based on a human-murine comparison of serum Cmax for OT, the estimated murine-equivalents for the RP2D doses were O 25 mg/kg BID and T 6.25 mg/kg/d. The RP2D regimen was then modulated in both dose intensity and duration in a 9-arm PDX trial. The arms included 3 schedule categories, with doses varied within each category: discontinuous regimens (OT d 1-7); continuous O regimens (O d1-21 + T d 1-7); and rapid- or slow-alternating regimens administering O and T on non-overlapping days. Tumor bearing mice were treated when subcutaneous tumors reached a volume of 400-800 cc, enabling measurement of tumor regression (PDX response) and time to volume doubling (PDX TTP). Findings: The RP2D regimen resulted in near-complete response in both models. This degree of regression was recapitulated with nearly all dosing schedules, and was not improved by increasing T to 2x-RP2D. However, the PDX TTP varied. In both models, the longest TTP was seen with continuous O at full- or half-RP2D and d 1-7 T at half-RP2D. This regimen prolonged TTP by 12% in MGH1518-1B and 20% in MGH1528-1, versus discontinuous OT at RP2D. Based on these results, we initiated clinical treatment in a new cohort of patients on OT, with a phase 1 dose escalation starting with O 50 mg BID d 1-21 and T 50 mg/m2 d 1-7 of each 21 d cycle (NCT02446704). At this first dose level, a partial response by RECIST 1.1 criteria was observed in a heavily pre-treated patient, indicating clinical activity of this combination with this new dosing strategy. Conclusions: In PDX models sensitive to OT at our previously determined RP2D, we find that continuous O with intermittent T permits dose reduction of both O and T without loss of efficacy. A clinical trial is ongoing to determine whether this strategy may enable longer-term dosing and improve efficacy in patients. Citation Format: Benjamin J. Drapkin, Sarah Phat, David T. Myers, Jun Zhong, Beow Y. Yeap, Elisabetta Leo, Anna Stansiszewska, Aaron Smith, Elaine Cadogan, Maria C. Pietanza, Nicholas J. Dyson, Anna Farago. Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4736." @default.
• W4255358765 created "2022-05-12" @default.
• W4255358765 creator A5000115998 @default.
• W4255358765 creator A5008491342 @default.
• W4255358765 creator A5011596517 @default.
• W4255358765 creator A5032331306 @default.
• W4255358765 creator A5037908617 @default.
• W4255358765 creator A5053107465 @default.
• W4255358765 creator A5054890414 @default.
• W4255358765 creator A5056153255 @default.
• W4255358765 creator A5066069221 @default.
• W4255358765 creator A5075300224 @default.
• W4255358765 creator A5077262131 @default.
• W4255358765 creator A5088958973 @default.
• W4255358765 date "2019-07-01" @default.
• W4255358765 modified "2023-09-27" @default.
• W4255358765 title "Abstract 4736: Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation" @default.
• W4255358765 doi "https://doi.org/10.1158/1538-7445.am2019-4736" @default.
• W4255358765 hasPublicationYear "2019" @default.
• W4255358765 type Work @default.
• W4255358765 citedByCount "0" @default.
• W4255358765 crossrefType "journal-article" @default.
• W4255358765 hasAuthorship W4255358765A5000115998 @default.
• W4255358765 hasAuthorship W4255358765A5008491342 @default.
• W4255358765 hasAuthorship W4255358765A5011596517 @default.
• W4255358765 hasAuthorship W4255358765A5032331306 @default.
• W4255358765 hasAuthorship W4255358765A5037908617 @default.
• W4255358765 hasAuthorship W4255358765A5053107465 @default.
• W4255358765 hasAuthorship W4255358765A5054890414 @default.
• W4255358765 hasAuthorship W4255358765A5056153255 @default.
• W4255358765 hasAuthorship W4255358765A5066069221 @default.
• W4255358765 hasAuthorship W4255358765A5075300224 @default.
• W4255358765 hasAuthorship W4255358765A5077262131 @default.
• W4255358765 hasAuthorship W4255358765A5088958973 @default.
• W4255358765 hasConcept C104317684 @default.
• W4255358765 hasConcept C112705442 @default.
• W4255358765 hasConcept C126322002 @default.
• W4255358765 hasConcept C143998085 @default.
• W4255358765 hasConcept C182979987 @default.
• W4255358765 hasConcept C185592680 @default.
• W4255358765 hasConcept C22979827 @default.
• W4255358765 hasConcept C2776694085 @default.
• W4255358765 hasConcept C2777389519 @default.
• W4255358765 hasConcept C2779138821 @default.
• W4255358765 hasConcept C2779962180 @default.
• W4255358765 hasConcept C2781413609 @default.
• W4255358765 hasConcept C55493867 @default.
• W4255358765 hasConcept C71924100 @default.
• W4255358765 hasConcept C82381507 @default.
• W4255358765 hasConceptScore W4255358765C104317684 @default.
• W4255358765 hasConceptScore W4255358765C112705442 @default.
• W4255358765 hasConceptScore W4255358765C126322002 @default.
• W4255358765 hasConceptScore W4255358765C143998085 @default.
• W4255358765 hasConceptScore W4255358765C182979987 @default.
• W4255358765 hasConceptScore W4255358765C185592680 @default.
• W4255358765 hasConceptScore W4255358765C22979827 @default.
• W4255358765 hasConceptScore W4255358765C2776694085 @default.
• W4255358765 hasConceptScore W4255358765C2777389519 @default.
• W4255358765 hasConceptScore W4255358765C2779138821 @default.
• W4255358765 hasConceptScore W4255358765C2779962180 @default.
• W4255358765 hasConceptScore W4255358765C2781413609 @default.
• W4255358765 hasConceptScore W4255358765C55493867 @default.
• W4255358765 hasConceptScore W4255358765C71924100 @default.
• W4255358765 hasConceptScore W4255358765C82381507 @default.
• W4255358765 hasIssue "13_Supplement" @default.
• W4255358765 hasLocation W42553587651 @default.
• W4255358765 hasOpenAccess W4255358765 @default.
• W4255358765 hasPrimaryLocation W42553587651 @default.
• W4255358765 hasRelatedWork W2003243316 @default.
• W4255358765 hasRelatedWork W2054087836 @default.
• W4255358765 hasRelatedWork W2151288869 @default.
• W4255358765 hasRelatedWork W2969952426 @default.
• W4255358765 hasRelatedWork W3001769037 @default.
• W4255358765 hasRelatedWork W3018583760 @default.
• W4255358765 hasRelatedWork W3113016627 @default.
• W4255358765 hasRelatedWork W3175416687 @default.
• W4255358765 hasRelatedWork W4286296881 @default.
• W4255358765 hasRelatedWork W4362495302 @default.
• W4255358765 hasVolume "79" @default.
• W4255358765 isParatext "false" @default.
• W4255358765 isRetracted "false" @default.
• W4255358765 workType "article" @default.