2562 Background: Adavosertib (AZD1775; A) is a highly selective inhibitor of WEE1. This Phase I study (NCT02617277) investigated a range of doses and schedules for oral A plus IV durvalumab (DV), a human monoclonal antibody targeting PD-L1, to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) in patients (pts) with advanced solid tumors. Methods: Four 28-day schedules (Sch) were evaluated with pts receiving DV 1500 mg on day (d) 1 of each schedule (Table). Patients continued treatment if they showed clinical benefit in the absence of any discontinuation criteria. Pts received A monotherapy for PK analysis prior to the start of combination therapy in Sch B, C (d –7 to –5) and D (d –9 to –5). MTD was determined using a 3+3 dose-escalation cohort design. Predefined dose-limiting toxicities (DLTs) were evaluated during the first cycle of study treatment. Results: 54 pts received A (most common primary tumor sites: colon, 19%; lung, 13%; breast, 11%). The most common grade ≥3 AEs were fatigue (15%), diarrhea (11%) and nausea (9%). DLTs were nausea (n = 2) and diarrhea (n = 1). 7 pts (13%) had A-related SAEs, including reversible and confounded drug-induced liver injury (Sch B 125 mg and Sch C; 1 each). Disease control rate (DCR) for the total cohort was 36%. Preliminary PK at 150 mg BID suggests adequate coverage for cell kill activity and no drug–drug interaction. Conclusions: The MTD/RP2D was A 150 mg BID (3 d on, 4 d off; treatment d 15–17, 22–24) with DV 1500 mg (d 1 Q4W); safety profile was considered acceptable. Preliminary evidence of antitumor activity was observed. Clinical trial information: NCT02617277. [Table: see text]
Background: AcSé-ESMART is a proof-of-concept, phase I/II platform trial designed to explore targeted agents in a molecularly enriched pediatric population. WEE1 plays a role in DNA repair and cell cycle control and is overexpressed in pediatric cancers. Adavosertib combinations resulted in enhanced antitumor activity compared to single agent in neuroblastoma, rhabdomyosarcoma, medulloblastoma and high-grade glioma in vivo models. The efficacy and safety of the adavosertib-carboplatin combination has been established in adults with focus on TP53 mutated ovarian cancer. Arm C of AcSé-ESMART applied this regimen to children with advanced malignancies enriched for alterations in TP53, DNA repair/replication stress and cell cycle control. Methods: Adavosertib was administered orally, twice daily on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle. Dose finding used the continuous reassessment method starting at adavosertib 100 mg/m2/dose and carboplatin AUC 5. Pharmacokinetic (PK) and retrospective molecular bioinformatic analysis was performed. Results: Twenty patients (median age: 14.0 years, range 3.4-23.5) were included, 18 received a total of 69 cycles. Seven dose-limiting toxicities (DLTs) were observed leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4. All patients with DLT had thrombocytopenia grade 3/4 requiring transfusions for >7 days and/or neutropenia grade 4 for >7 days. Main overall treatment-related toxicities were hematologic and gastrointestinal. Based on the identified DLT risk, no recommended Phase 2 dose was defined. PK analysis demonstrated equivalent adavosertib exposure in children to that in adults and both doses (75 and 100 mg/m2) achieved the cell kill target. Two patients with neuroblastoma achieved partial response (PR), one with medulloblastoma unconfirmed PR, and five had stable disease (SD) >4 cycles. Patients with PR/SD >4 cycles were considered as clinical benefit (CB) for retrospective molecular analysis. There was no correlation between TP53 genomic alteration alone and response. However, 7 of 8 patients with CB but none of the 10 patients without CB had 1 to 3 genomic alterations in the DNA repair (BRCA2 mutation, 11q loss containing ATM, MRE11A, CHEK1), cell cycle control/replication stress (CCNE1 amplification, RB1 mutation/loss, SETD2 mutation/loss) and RAS pathway (KRAS mutation and amplification, NF1 loss, PTPN11 mutation) in their tumor. Conclusions: Adavosertib combined with carboplatin exhibited significant hematologic toxicity. Activity signals and identified potential molecular biomarkers suggest further combination studies with less hematotoxic DNA damaging therapy in molecularly enriched pediatric cancers. Citation Format: Susanne A. Gatz, Anne C. Harttrampf, Caroline Brard, Francisco J. Bautista, Nicolas André, Samuel Abbou, Jonathan Rubino, Windy Rondof, Marc Deloger, Marc Rübsam, Daniel Hübschmann, Lynley V. Marshall, Souad Nebchi, Isabelle Aerts, Estelle Thebaud, Emilie De Carli, Anne-Sophie Defachelles, Xavier Paoletti, Robert Godin, Kowser Miah, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the WEE1 inhibitor adavosertib in combination with carboplatin in children with advanced malignancies: arm C of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT087.
Background: Danvatirsen (Da) is a generation 2.5 antisense oligonucleotide targeting STAT3 mRNA under clinical development in combination with Durvalumab (NCT03421353). The recommended Phase II dose is intravenous (IV) 200 mg weekly (QW, A). However, alternative 400 mg IV every two weeks (Q2W, B) and subcutaneous 200 mg QW (C) are also under investigation. The JAK-STAT signaling pathway is involved in immunity, cell division, cell death, and tumor formation. Additionally, activation of hepatic STAT3 results in increased secretion of C-reactive protein (CRP) and fibrinogen into blood. Therefore, target engagement in patients may be better understood by analyzing Da exposure and related biomarkers in the blood/plasma. We investigated Da exposure and subsequent impact on target engagement biomarkers such as CRP, platelets, fibrinogen, neutrophils and STAT3 mRNA levels. Methods: Extensive pharmacokinetics (PK) samples were collected at lead-in monotherapy and at steady state (SS) in combination. Plasma biomarker samples were collected at baseline and every two weeks thereafter. Whole blood samples for the analysis of STAT3 mRNA were collected at baseline, after lead-in monotherapy, and every four weeks thereafter. The PK parameters were estimated by non-compartmental analysis by WinNonlin. The biomarkers were analyzed by standard clinical methods and STAT3 mRNA level was measured by NanoString technology. Results: The area under plasma concentration-time curve of Da at SS within dosing interval (AUC0-τ, ng.h/ml) for A, B, and C were 69110 (24.64%), 101600 (22.11%), and 44600 (30.25%), respectively. Additionally, SS Ctrough (ng/ml) levels for A, B, and C were 28.53 (48.86%), 14.56 (36.14%), and 27.66 (49.22%), respectively. Maximum median % decrease from baseline in CRP levels was observed at week 4; A (-91%), B (-94%), C (-82%). Additionally, maximum median % changes from baseline for fibrinogen were -60%, -40%, -53%, in A, B, and C at week 4, respectively. Maximum % decrease from baseline in platelets was observed at week 8 in A (-42%), B (-41%), and C (-69%). In contrast, maximum % change from baseline in neutrophil count was observed at week 6; -37%, -31%, and -32% in A, B, and C, respectively. Additionally, the median maximum change from baseline for STAT3 mRNA was -42.4% and -33.6% for A and C, respectively. Conclusion: Cumulative AUC in A was very similar to B, whereas, AUC in C was 30% lower as compared to A or B. The SS Ctrough values in A and C were similar, although Ctrough value in B was 50% lower. Maximum % decreases in CRP levels were similar across all the doses. Moreover, route of administration did not appear to impact level of STAT3 knockdown. In summary, a similar degree of changes in pharmacodynamic biomarkers were achieved at all three dose levels regardless of route of administration, despite differences in plasma exposure. Citation Format: Kowser Miah, Patricia McCoon, Deanna Russell, Patrick Mitchell, Martin Scott, Amy Rosenfeld, Li Zhang, Pablo Martinez Rodriguez, Alicia Savage, Ganesh Mugundu. Plasma exposure-target engagement biomarker analysis for danvatirsen after multiple dosing schedules and route of administrations in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-105.
Savolitinib is an oral MET (hepatocyte growth factor receptor) tyrosine kinase inhibitor, with demonstrated preliminary efficacy in several cancer types. Previous pharmacokinetics assessments showed that savolitinib is rapidly absorbed but there are limited data on the absolute bioavailability and absorption, distribution, metabolism, and excretion (ADME) of savolitinib. This open‐label, two‐part, phase 1 clinical study (NCT04675021) used a radiolabeled micro‐tracer approach to evaluate absolute bioavailability and a traditional approach to determine the ADME of savolitinib in healthy male adult volunteers (N = 8). Pharmacokinetics, safety, and metabolic profiling and structural identification from plasma, urine, and fecal samples were also assessed. Volunteers received a single oral savolitinib 600 mg dose followed by intravenous 100 μg of [14C]savolitinib in Part 1 and a single oral 300 mg [14C]savolitinib dose (≤4.1 MBq [megabecquerel] [14C]) in Part 2. Following Part 1, absolute oral bioavailability was 69%, the median time of maximum observed concentration was 3.5 hours, and the mean terminal half‐life was 6.1 hours. Following Part 2, 94% of the radioactivity administered was recovered, with 56% and 38% in urine and feces, respectively. Exposure to savolitinib and metabolites M8, M44, M2, and M3 accounted for 22%, 36%, 13%, 7%, and 2%, respectively, of plasma total radioactivity. Approximately 3% of the dose was excreted as unchanged savolitinib in urine. Most savolitinib elimination occurred via metabolism by several different pathways. No new safety signals were observed. Our data show that the oral bioavailability of savolitinib is high and the majority of savolitinib elimination occurs via metabolism and is excreted in the urine.
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