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Journal of Clinical Oncology
Background The WEE1 inhibitor adavosertib (AZD1775) has been investigated in Western patients. Objective This open-label Phase Ib study (NCT02341456) investigated the safety, pharmacokinetics, and clinical activity of adavosertib in combination with carboplatin alone or paclitaxel plus carboplatin in Asian patients with advanced solid tumors and defined the recommended Phase II dose. Patients and methods Nineteen patients received adavosertib 175 mg twice daily (bid) for 2.5 days (five doses) in combina- tion with carboplatin (AUC 5) alone or paclitaxel (175 mg/m ) plus carboplatin, or adavosertib 225 mg bid for 2.5 days in combination with paclitaxel plus carboplatin in 21-day cycles. Preliminary safety and dose-limiting toxicity analyses were performed and dose escalation/de-escalation conducted as appropriate. Results Adavosertib 175 mg bid for 2.5 days with carboplatin alone or paclitaxel plus carboplatin was considered tolerable. Two patients receiving adavosertib 225 mg bid in combination with paclitaxel plus carboplatin experienced dose-limiting toxicities (grade 4 sepsis; grade 5 acute respiratory distress syndrome); this regimen was not considered tolerable. Grade ≥ 3 adverse events reported most commonly in any cohort included: anemia; decreased white blood cell count; decreased neu- trophil count; neutropenia; decreased platelet count; thrombocytopenia; and febrile neutropenia. Exposure to adavosertib, as determined by pharmacokinetic analysis, in Asian patients was higher than that previously seen in Western patients. A partial response occurred in 2/12 evaluable patients (16.7%) at the recommended Phase II dose. Conclusions Adavosertib 175 mg bid for 2.5 days was chosen as the recommended Phase II dose in combination with pacli- taxel and carboplatin in Asian patients. Following DNA damage, WEE1 inhibits CDK1, leading 1 Introduction to cell cycle arrest and allowing time for DNA repair . Inhibiting WEE1 abrogates G2 cell cycle arrest, resulting The tyrosine kinase WEE1 regulates cyclin-dependent kinase in premature entry into mitosis and leading to aberrantly 1 (CDK1), which drives cells from the G2 phase into mitosis, high CDK2 activity in S-phase cells, with the deregulated and CDK2, which drives cells into and through the S phase DNA replication resulting in replication stress [1, 5]. WEE1 of the cell cycle [1, 2]. The tumor suppressor protein p53 is inhibition also exploits the G1 checkpoint deficiency seen involved in regulation of the G1 checkpoint. Many human in p53-deficient cells [3 ]. Thus, WEE1 inhibition sensitizes cancers have loss-of-function TP53 mutations, meaning that tumor cells to DNA-damaging chemotherapy and can lead to they become more dependent on the G2/M- and S-phase unstable DNA replication, DNA damage and mitotic catas- checkpoints to halt progression of the cell cycle [3, 4]. trophe [1, 3]. Adavosertib (AZD1775) is a first-in-class, potent, selec- Electronic supplementary material The online version of this tive WEE1 inhibitor. Adavosertib showed acceptable toxic- article (https ://doi.org/10.1007/s1152 3-020-00701 -5) contains ity, linear pharmacokinetics, and target engagement when supplementary material, which is available to authorized users. administered in combination with cisplatin, carboplatin, or gemcitabine in patients with advanced solid tumors in a * Yung-Jue Bang email@example.com Phase I study (NCT00648648, PN001) . Extended author information available on the last page of the article Vol.:(0123456789) 76 H. Kato et al. solid tumor (excluding lymphoma), failure to respond to Key Points standard therapy, disease progression despite standard ther- apy, or cancers for which standard therapy did not exist. Adavosertib 175 mg twice daily (bid) for 2.5 days (five Patients also had to have at least one measurable lesion that doses) in combination with carboplatin (AUC 5) alone or could be accurately assessed at baseline by computed tomog- paclitaxel (175 mg/m ) plus carboplatin was considered raphy or magnetic resonance imaging and Response Evalua- tolerable in Asian patients with advanced solid tumors. tion Criteria in Solid Tumors (RECIST) v1.1. Patients were required to have an absolute neutrophil count ≥ 1.5 × 10 /L, Exposure to adavosertib, as determined by pharmacoki- hemoglobin ≥ 90 g/L, platelets ≥ 100 × 10 /L, alanine ami- netic analysis, was 30–45% higher in Asian patients than notransferase and aspar tate aminotransferase ≤ 2.5 × the that previously seen in Western patients. upper limit of normal (ULN) or ≤ 5 × ULN if there were In Asian patients, the recommended Phase II dose of known hepatic metastases, and total bilirubin ≤ 1.25 × ULN adavosertib (175 mg bid for 2.5 days in combination or total bilirubin ≤ 3.0 × ULN with documented Gilbert’s with paclitaxel plus carboplatin) is lower than the recom- syndrome (unconjugated hyperbilirubinemia). Patients who mended Phase II dose in Western patients, most likely had undergone radiotherapy with a limited field of radia- reflecting the increased exposure of adavosertib in Asian tion for palliation within 1 week of the first dose of study patients. treatment, with the exception of patients receiving radiation to > 30% of the bone marrow, or with a wide field of radia- In Phase II studies, adavosertib showed antitumor tion within 4 weeks of the first dose of study treatment were activity when administered in combination with carbopl- excluded from the study, as were patients with refractory atin in women with TP53-mutated ovarian cancer refrac- nausea and vomiting. Full eligibility criteria are summarized tory or resistant to first-line platinum-based chemother - in the Supplementary Material. apy (NCT01164995, PN009) , or in combination with paclitaxel plus carboplatin in women with TP53-mutated 2.2 Study Design and Treatment platinum-sensitive ovarian cancer (NCT01357161, PN004) . In study PN004, progression-free survival was longer This non-randomized, open-label, multicenter, Phase Ib in patients receiving adavosertib with paclitaxel plus carbo- study was conducted in seven centers in Australia, Japan, platin than in those receiving placebo with paclitaxel plus and South Korea. carboplatin . Patients were initially recruited into cohorts 1 and 1a, A Phase I study established a maximum tolerated dose with three to six patients planned for each cohort. Based on of adavosertib of 225 mg twice daily (bid) for 2.5 days the data from earlier studies [6, 10], patients in these cohorts (five doses; day 1, day 2, and the morning of day 3) per received a single starting dose of oral adavosertib 175 mg on 21-day cycle when administered as monotherapy to Western day 1 (cycle 0) (Fig. 1 and Supplementary Material). This patients with advanced solid tumors (NCT01748825) . was followed 5 ± 2 days later by adavosertib 175 mg bid In Western patients, the recommended Phase II regimen of for 2.5 days (five doses) in combination with intravenous adavosertib for use in combination with paclitaxel (175 mg/ paclitaxel (175 mg/m as a 3-h infusion on day 1) plus intra- m ) and carboplatin (AUC 5) is also 225 mg bid for 2.5 days venous carboplatin (AUC 5 on day 1) (cohort 1; A175PC) per 21-day cycle, which was used successfully in the PN004 or carboplatin alone (AUC 5 on day 1) (cohort 1a; A175C) study . The aim of this Phase Ib study (NCT02341456) in subsequent 21-day cycles. was to evaluate the safety and tolerability of the combination Preliminary safety and dose-limiting toxicity (DLT) anal- of adavosertib with carboplatin alone or with paclitaxel plus yses were performed and dose-escalation/de-escalation con- carboplatin in Asian patients with advanced solid tumors ducted as appropriate (Supplementary Material). A DLT was and to define the recommended Phase II dose. It is the first defined as an adverse event or abnormal laboratory value study to investigate this treatment regimen in this patient that occurred from the first dose of study treatment up to population. the last day of cycle 1. Dose increases were permitted after review of data from a minimum of three evaluable patients. If no DLT was observed in a cohort of three to six evaluable 2 Methods patients, then dose escalation could occur. Based on these assessments, a planned three to six patients were recruited 2.1 Patient Selection in a dose-escalation cohort (cohort 2) in which they received a single dose of adavosertib 225 mg in cycle 0, followed Eligibility criteria included patients who had histologic or 5 ± 2 days later by adavosertib 225 mg bid for 2.5 days in cytologic confirmation of a locally advanced or metastatic combination with paclitaxel plus carboplatin in subsequent Adavosertib in Asians with Advanced Solid Tumors 77 cycles (A225PC). If two or more patients experienced a DLT 2.3 Study Objectives in a group of up to six patients, irrespective of the number of patients enrolled, the dose was considered not tolerated The primary objective was to assess the safety and toler- and recruitment to the cohort and dose escalation ceased. A ability of adavosertib in combination with carboplatin or lower intermediary dose (de-escalation) could be considered paclitaxel plus carboplatin. Secondary objectives were to in order to better define the combination recommended dose characterize the pharmacokinetic profiles of adavosertib for further clinical evaluation (Supplementary Material). (after single dosing and at steady state after multiple dosing After six cycles, patients in cohorts 1 and 2 could con- with carboplatin or paclitaxel plus carboplatin), paclitaxel tinue adavosertib monotherapy, whereas patients in cohort (in combination with adavosertib and carboplatin) and car- 1a continued combination therapy until disease progression boplatin (in combination with adavosertib or adavosertib or unacceptable toxicity. and paclitaxel). An additional secondary objective was to An additional three to six patients could be recruited to obtain a preliminary assessment of the antitumor activity of the cohort in which the recommended combination dose was adavosertib in combination with carboplatin alone or with defined for further evaluation of the safety, tolerability, and paclitaxel plus carboplatin. pharmacokinetics of adavosertib. Pre-medication with antiemetics (excluding aprepitant) 2.4 Assessments was allowed. The study was performed in accordance with the Declara- Adverse events (AEs) were monitored throughout the study tion of Helsinki, Good Clinical Practice, applicable regula- until the end of the follow-up period (28 ± 7 days after study tory requirements, and the AstraZeneca policy on bioethics treatment was discontinued or completed) and were graded . The institutional review boards or independent ethics using the National Cancer Institute’s Common Terminology committees of all investigational sites approved the protocol, Criteria for Adverse Events (v4.03). Laboratory parameters, and all patients provided written, informed consent. electrocardiogram (ECG) changes, and vital signs were also monitored. Hematology laboratory evaluations were per- formed at screening, on day 1 of cycle 0, and on days 1, 8, and 15 for cycles 1 and beyond. Coagulation laboratory eval- uations were performed at screening and on day 1 of every Cycle 0 Cycles 1– 6 After 6 cycles 5 ± 2 days washout Cohort 1 Patients could Cohort 1 Adavosertib 175 mg bid for 2.5 days per continue Adavosertib 175 mg cycle, paclitaxel 175 mg/m², carboplatin adavosertib AUC 5 in 21-day cycles monotherapy in the absence of discontinuation Cohort 2 criteria at the Cohort 2 Adavosertib 225 mg bid for 2.5 days per investigator’s Adavosertib 225 mg cycle, paclitaxel 175 mg/m², carboplatin discretion AUC 5 in 21-day cycles Patients continued Cohort 1a combination therapy Cohort 1a Adavosertib 175 mg bid for 2.5 days per until disease Adavosertib 175 mg cycle, carboplatin AUC 5 in 21-day cycles progression or unacceptable toxicity Fig. 1 Treatment cohorts. Patients were initially recruited into tional 3–6 patients could be recruited to the cohort in which the rec- cohorts 1 and 1a, with 3–6 patients planned for each cohort. Based on ommended combination dose was defined for further evaluation of safety and dose-limiting toxicity assessments, a planned 3–6 patients the safety, tolerability and pharmacokinetics of adavosertib. bid twice were then recruited in a dose-escalation cohort (cohort 2). An addi- daily 78 H. Kato et al. cycle. Chemistry laboratory evaluations were performed at Exposure to adavosertib, paclitaxel, and carboplatin is screening, on day 1 of cycle 0, on days 1 and 15 of cycle 1, summarized in Supplementary Table S1. There were no ada- and on day 1 of each additional 21-day cycle. vosertib dose reductions during cycle 0 or 1, and no pacli- Blood samples for pharmacokinetic analysis of ada- taxel or carboplatin dose reductions during cycle 1. After vosertib were collected pre-dose and up to 8 h post-dose cycle 1, adavosertib dose reductions occurred in three of six on: cycle 0, day 1 following a single dose; cycle 1, day 1 patients (50.0%) from cohort 2, paclitaxel dose reductions following a single dose in combination with chemotherapy; occurred in two of seven patients (28.6%) from cohort 1 and and cycle 1, day 3 following multiple doses in combination three of six patients (50.0%) from cohort 2, and carboplatin with chemotherapy (Supplementary Material). Additional dose reductions occurred in one of seven patients (14.3%) samples were collected pre-dose at day 3 of odd-numbered from cohort 1, four of six patients (66.7%) from cohort 2, cycles. Plasma concentrations of adavosertib were deter- and one of six patients (16.7%) from cohort 1a. mined by using a validated liquid chromatography–tandem mass spectrometry assay with a lower limit of quantitation 3.2 Safety and Tolerability of 2 ng/mL. Blood samples for pharmacokinetic analysis of pacli- DLTs (grade 4 decreased platelet count) occurred in one taxel and carboplatin were collected pre-dose and up to 8 h patient each in cohorts 1 and 1a. Two patients in cohort 2 after the start of infusion at cycle 1, day 1 (Supplementary experienced DLTs (grade 4 sepsis and grade 5 acute respira- Material). tory distress syndrome). Response was evaluated according to RECIST v1.1 at Treatment-emergent adverse events (TEAEs) reported in screening and then at cycle 1, day 1 and every 6 weeks there- at least one patient after a single dose of adavosertib were after (at Japanese sites, an additional assessment occurred nausea (three of 19 [15.8%] patients), constipation (one at cycle 2, day 1). [5.3%] patient), diarrhea (one [5.3%] patient), and hypersen- sitivity (one [5.3%] patient). All of these TEAEs were grade 2.5 Statistical Analysis 1 and none occurred in more than one patient in each cohort. With combination therapy, the most commonly reported To assess the tolerability of adavosertib in combination with TEAEs (all grades) included nausea, vomiting, anemia, diar- chemotherapy, cohorts of at least six evaluable patients were rhea, and decreased white blood cell (WBC) count (Table 2). required, with an expected sample size of approximately 18 Hematologic AEs were the most commonly reported patients per combination therapy. grade ≥ 3 TEAEs (Table 2). The incidence of TEAEs (all The safety analysis set comprised all patients who grades and grade ≥ 3) was generally highest in cohort 2 and received at least one dose of adavosertib, paclitaxel, or car- lowest in cohort 1a. The small number of patients in each boplatin, the pharmacokinetic analysis set comprised dosed cohort should be considered when interpreting the incidence patients for whom an adequate pharmacokinetic profile had of TEAEs. been obtained, and the tumor-response analysis set com- The most commonly occurring TEAEs (incidence prised dosed patients with measurable disease at baseline. of > 50% in any cohort) considered by the investigator as Safety assessments, pharmacokinetic parameters, and being potentially related to treatment were nausea (85.7%, tumor response were analyzed by descriptive statistics. 83.3%, and 50.0% of patients in cohorts 1, 2, and 1a, respectively), diarrhea (71.4%, 83.3%, and 33.3%), vomit- ing (71.4%, 66.7%, and 33.3%), anemia (71.4%, 66.7%, and 3 Results 33.3%), decreased WBC count (71.4%, 83.3%, and 50.0%), and decreased platelet count (57.1%, 50.0%, and 33.3%). 3.1 Patient Characteristics Fatal TEAEs were reported in one patient each in cohorts 1 and 2 (Table 2). The patient from cohort 1 had abnormal Seven, six, and six patients were treated in cohorts 1, 2, and hepatic function resulting in liver failure and death. This 1a, respectively. One patient in cohort 1 was recruited in patient had advanced head and neck cancer with tumors error (without measurable disease); data from this patient in the liver and a history of hepatomegaly. Extensive liver were used in the safety and pharmacokinetic analyses but metastases were documented on day 15 of cycle 5, and the excluded from the tumor response analyses. One patient patient died on day 19 of cycle 5. The investigator attributed in cohort 2 and one in cohort 1a were still receiving study death “almost certainly” to disease progression and consid- treatment at data cut-off (14 December 2016); the patient ered the event to be unrelated to adavosertib. The patient in cohort 2 was receiving adavosertib monotherapy. All from cohort 2 had acute respiratory distress syndrome in patients were of Asian descent; patient baseline character- association with interstitial pneumonia, which was consid- istics are shown in Table 1. ered by the investigator to be possibly related to adavosertib Adavosertib in Asians with Advanced Solid Tumors 79 Table 1 Patient baseline characteristics Cohort 1 (A175PC) Cohort 2 (A225PC) Cohort 1a (A175C) N = 7 N = 6 N = 6 Age, years Median (min, max) 55.0 (46, 62) 57.0 (34, 66) 49.5 (19, 56) Race, n (%) Asian 7 (100) 6 (100) 6 (100) Sex, n (%) Male 4 (57.1) 1 (16.7) 3 (50.0) Female 3 (42.9) 5 (83.3) 3 (50.0) Type of cancer, n (%) Breast 0 3 (50.0) 1 (16.7) Head and neck 2 (28.6) 0 0 Cervix 1 (14.3) 0 1 (16.7) Ovary 1 (14.3) 1 (16.7) 0 Uterus 1 (14.3) 1 (16.7) 0 Other 2 (28.6) 1 (16.7) 4 (66.7) Time since metastatic diagnosis, years Median (min, max) 1.61 (0, 2.5) 4.60 (2.2, 9.3) 1.87 (0.9, 4.9) Prior chemotherapy regimens, n (%) 1 0 1 (16.7) 0 2 2 (28.6) 0 1 (16.7) 3 0 1 (16.7) 1 (16.7) 4 1 (14.3) 0 0 ≥ 5 4 (57.1) 4 (66.7) 4 (66.7) Best response to prior cancer therapy, n (%) Partial response 3 (42.9) 2 (33.3) 3 (50.0) Stable disease 4 (57.1) 3 (50.0) 2 (33.3) Disease progression 0 1 (16.7) 1 (16.7) A175C adavosertib 175 mg + carboplatin, A175PC adavosertib 175 mg + paclitaxel + carboplatin, A225PC adavosertib 225 mg + paclitaxel + car- boplatin Including cancer of the nasopharynx, larynx, and trachea Including stomach cancer (n = 1), pancreatic cancer (n = 1), skin/soft tissue cancer (n = 1), lung cancer (n = 1), thymic cancer (n = 2), and gall- bladder cancer (n = 1) and paclitaxel. This patient had advanced lung cancer with distress syndrome, interstitial pneumonia, and diarrhea previous tomotherapy to the lung and prior left upper lung in a second patient). Paclitaxel was discontinued because lobectomy and was hospitalized and died on day 5 of cycle of TEAEs in one patient (14.3%) from cohort 1 and two 1. patients (33.3%) from cohort 2, and carboplatin was dis- Serious TEAEs were reported in seven patients in cohorts continued because of TEAEs in two patients (33.3%) from 1 and 2 (Table 2). Six patients had serious AEs considered cohort 2. to be causally related to adavosertib: nausea and vomiting No trends were observed in vital signs over time, in one patient (cohort 1); decreased platelet count in one and there were no clinically important changes in ECG patient (cohort 1); neutropenia in one patient (cohort 2); recordings. febrile neutropenia in one patient each in cohorts 1 and 2; and diarrhea, acute respiratory distress syndrome, and inter-3.3 Pharmacokinetic Profile stitial pneumonia in one patient (cohort 2). TEAEs resulted in discontinuation of adavosertib in one Adavosertib was steadily absorbed, with a median time to patient (14.3%) from cohort 1 (micturition urgency, nau- maximum plasma concentration (t ) of 2.02–4.04 h, and then max sea, and vomiting) and two patients (33.3%) from cohort slowly eliminated (Fig. 2 and Table 3). After reaching the max- 2 (febrile neutropenia in one patient and acute respiratory imum plasma concentration (C ), adavosertib concentrations max 80 H. Kato et al. Table 2 Adverse events occurring with adavosertib and chemother- apy Patients experiencing TEAEs , Cohort 1 Cohort 2 Cohort 1a n (%) (A175PC) (A225PC) (A175C) N = 7 N = 6 N = 6 TEAEs 6 (85.7) 6 (100.0) 6 (100.0) Nausea 6 (85.7) 5 (83.3) 5 (83.3) Vomiting 6 (85.7) 5 (83.3) 4 (66.7) Anemia 6 (85.7) 5 (83.3) 4 (66.7) Diarrhea 5 (71.4) 5 (83.3) 3 (50.0) 02 46 8 WBC count decreased 5 (71.4) 5 (83.3) 3 (50.0) Time (h) Decreased appetite 4 (57.1) 2 (33.3) 4 (66.7) Cohort 1 (A175PC): Adavosertib 175 mg + paclitaxel 175 mg/m² + carboplatin AUC 5 Platelet count decreased 4 (57.1) 3 (50.0) 3 (50.0) Cohort 1a (A175C): Adavosertib 175 mg + carboplatin AUC 5 Cohort 2 (A225PC): Adavosertib 225 mg + paclitaxel 175 mg/m² + carboplatin AUC 5 Neutrophil count decreased 3 (42.9) 3 (50.0) 4 (66.7) Pyrexia 3 (42.9) 4 (66.7) 1 (16.7) d Fig. 2 Semi-logarithmic plot showing the geometric mean (± stand- Neutropenia 3 (42.9) 2 (33.3) 0 ard deviation) plasma concentration–time profile for adavosertib Constipation 2 (28.6) 3 (50.0) 0 on cycle 1, day 3*.bid twice daily; *Multiple doses of adavosertib Proctalgia 1 (14.3) 3 (50.0) 1 (16.7) 175 mg bid with paclitaxel plus carboplatin (cohort 1), adavosertib 225 mg bid with paclitaxel plus carboplatin (cohort 2), or adavosertib Grade ≥ 3 TEAEs 6 (85.7) 6 (100.0) 4 (66.7) 175 mg bid with carboplatin (cohort 1a) Anemia 4 (57.1) 5 (83.3) 2 (33.3) WBC count decreased 5 (71.4) 5 (83.3) 1 (16.7) Platelet count decreased 4 (57.1) 3 (50.0) 2 (33.3) Systemic exposure to adavosertib increased in a slightly Neutrophil count decreased 3 (42.9) 3 (50.0) 2 (33.3) greater than dose-proportional manner as the adavosertib Neutropenia 3 (42.9) 2 (33.3) 0 dose increased from 175 to 225 mg bid (Table 3). A 1.3-fold Thrombocytopenia 1 (14.3) 2 (33.3) 1 (16.7) increase in adavosertib dose resulted in a 1.3- to 1.8-fold Febrile neutropenia 1 (14.3) 2 (33.3) 0 increase in geometric mean area under the plasma concen- Diarrhea 1 (14.3) 2 (33.3) 0 tration–time curve from time zero until the last quantifiable Hypophosphatemia 1 (14.3) 2 (33.3) 0 concentration (AUC ). 0–t Sepsis 0 2 (33.3) 0 Adavosertib accumulated in plasma after administration Treatment-related TEAEs 6 (85.7) 6 (100.0) 4 (66.7) of multiple doses, with a geometric mean (coefficient of Serious TEAEs 3 (42.9) 4 (66.7) 0 variation) accumulation ratio of 2.1 (38%) in cohort 1, 2.7 Fatal TEAEs 1 (14.3) 1 (16.7) 0 (17%) in cohort 2, and 2.3 (15%) in cohort 1a. A175C adavosertib 175 mg + carboplatin, A175PC ada- No drug–drug interactions were observed for any of the vosertib 175 mg + paclitaxel + carboplatin, A225PC adavosertib agents administered in this study (Table 3 and Supplemen- 225 mg + paclitaxel + carboplatin, TEAE treatment-emergent adverse tary Tables S2 and S3). event, WBC white blood cell TEAE defined as any AE that occurred after administration of the 3.4 Antitumor Activity first dose of study drug and through 28 days after the last dose of study drug, or any event that was present at baseline and continued after the first dose of study drug but worsened in intensity The best overall response observed was a partial response in TEAEs occurring with an incidence of > 40% in any cohort one of six evaluable patients (16.7%) in both cohorts 1 and None of the patients reported to have a decreased platelet count were 1a, and in three of six evaluable patients (50.0%) in cohort 2 also reported to have thrombocytopenia (n = 1 [14.3%] in cohort 1; (Table 4). The overall median duration of response in these five n = 2 [33.3%] in cohort 2; n = 1 [16.7%] in cohort 1a) patients was 20.7 weeks (95% confidence interval 18.1, not None of the patients reported to have a decreased neutrophil count evaluable; Kaplan–Meier estimate). Stable disease occurred in were also reported to have neutropenia e two of six evaluable patients (33.3%) in each cohort. Grade ≥ 3 TEAEs occurring with an incidence of > 30% in any cohort None of the patients reported to have a decreased platelet count were also reported to have thrombocytopenia 4 Discussion remained relatively stable over the 8-h sampling period, with Results of Phase II studies indicate that adavosertib sensi- the geometric mean plasma concentration at 8 h (C ) being tizes patients to chemotherapy [7, 12]. Adavosertib showed 8h 53–77% of the corresponding geometric mean C values. efficacy when combined with carboplatin in women with max Plasma concentration (nM) Adavosertib in Asians with Advanced Solid Tumors 81 Table 3 Single-dose and multiple-dose pharmacokinetics of adavosertib a b c Parameter Cycle 0, day 1 Cycle 1, day 1 Cycle 1, day 3 Cohort 1 Cohort 2 Cohort 1a Cohort 1 Cohort 2 Cohort 1a Cohort 1 Cohort 2 Cohort 1a d e f f f (N = 7) (N = 6) (N = 5) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) (N = 6) AUC , 0–t nM·h Gmean 3521 5331 3387 4191 5606 2902 8300 14,870 7154 CV, % 44.91 37.42 12.54 34.89 20.02 33.21 32.85 34.05 32.29 C , nM max Gmean 689.1 1066 649.2 705.4 1133 654.8 1271 2289 1129 CV, % 51.79 38 10.74 28.03 16.3 32.27 30.52 32.82 25.51 C , nM 8h Gmean 370.1 612 343.5 446.6 805.9 378.2 982 1700 774.6 CV, % 29.15 36.6 29.97 27.83 27.5 27.61 30.17 37.6 32.96 t , h max Median 2.02 3.96 3.95 4.00 4.04 4.04 4.00 4.04 3.09 Min, max 1.00, 8.00 1.00, 5.87 2.00, 8.00 0.95, 8.02 3.98, 6.00 4.00, 8.00 2.05, 4.08 1.00, 7.95 1.95, 4.08 t , h last Median 8.00 8.00 7.98 8.01 8.03 7.65 7.96 7.98 7.98 Min, max 7.83, 8.00 7.97, 8.02 7.20, 8.00 7.92, 8.17 7.95, 8.08 7.20, 8.00 7.85, 8.00 7.85, 8.15 7.20, 8.17 AUC area under the plasma concentration–time curve from time zero until the last quantifiable concentration, C plasma concentration at 8 h, 0–t 8h C maximum plasma concentration, CV coefficient of variation, Gmean geometric mean, t time to the last quantifiable concentration, t max last max time to maximum plasma concentration Cycle 0, day 1: single dose of adavosertib 175 mg (cohorts 1 and 1a) or adavosertib 225 mg (cohort 2) Cycle 1, day 1: single dose of adavosertib 175 mg with paclitaxel plus carboplatin (cohort 1), single dose of adavosertib 225 mg with paclitaxel plus carboplatin (cohort 2), or single dose of adavosertib 175 mg with carboplatin (cohort 1a) Cycle 1, day 3: multiple doses of adavosertib 175 mg with paclitaxel plus carboplatin (cohort 1), multiple doses of adavosertib 225 mg with paclitaxel plus carboplatin (cohort 2), or multiple doses of adavosertib 175 mg with carboplatin (cohort 1a) N = 6 for AUC and C 0–t max N = 4 for AUC and C 0–t max N = 5 for AUC and C 0–t max TP53-mutated ovarian cancer refractory or resistant to first- with paclitaxel plus carboplatin, or adavosertib 225 mg bid line platinum-based chemotherapy, with sustained responses for 2.5 days in combination with paclitaxel plus carboplatin. of over 30 months seen in two patients . Adavosertib also Pharmacokinetic analyses indicated that adavosertib was showed activity in combination with single-agent chemo- steadily absorbed and then slowly eliminated, and that co- therapy (carboplatin, paclitaxel, gemcitabine, or pegylated administration of paclitaxel and carboplatin had no appar- liposomal doxorubicin) in women with primary platinum- ent effect on the pharmacokinetics of adavosertib. It should resistant ovarian cancer . Results of these studies sup- be noted that the terminal elimination phase of adavosertib port a role for adavosertib in tumors that respond inade- could not be fully characterized because blood sampling was quately to chemotherapy. only conducted up to 8 h post-dose. Data suggest that expo- This Phase Ib study investigated the optimal adavosertib sure of adavosertib was 30–45% higher in Asian patients in dosage in Asian patients. Various factors, including race, this study than in Western patients , which explains, at affect drug pharmacokinetics. Differences observed between least in part, the tolerability findings. Additional investiga- Western and Asian patients in exposure to some drugs may tion to better understand these differences is ongoing. be attributable to factors such as body weight and drug Adavosertib 175 mg bid was considered tolerable when metabolism [13, 14]. The recommended Phase II regimen of administered for 2.5 days per 21-day cycle in combination adavosertib for use in combination with paclitaxel and car- with paclitaxel plus carboplatin, or with only carboplatin, boplatin in Western patients is 225 mg bid for 2.5 days . in Asian patients. However, adavosertib 225 mg bid for This study investigated regimens of adavosertib 175 mg 2.5 days administered in combination with paclitaxel plus bid for 2.5 days in combination with carboplatin alone or carboplatin was not considered tolerable, with two patients 82 H. Kato et al. Table 4 Antitumor activity of adavosertib in combination with chemotherapy Cohort 1 (A175PC) Cohort 2 (A225PC) Cohort 1a (A175C) N = 6 N = 6 N = 6 Best overall response, n (%) Complete response 0 (0) 0 (0) 0 (0) Partial response 1 (16.7) 3 (50.0) 1 (16.7) Stable disease 2 (33.3) 2 (33.3) 2 (33.3) Progressive disease 2 (33.3) 0 (0) 1 (16.7) Not evaluable 1 (16.7) 1 (16.7) 2 (33.3) Objective response , n (%) 1 (16.7) 3 (50.0) 1 (16.7) Clinical benefit , n (%) 3 (50.0) 5 (83.3) 3 (50.0) Median duration of r esponse , weeks (95% CI) 18.1 (NE, NE) 20.7 (NE, NE) NE (NE, NE) A175C adavosertib 175 mg + carboplatin, A175PC adavosertib 175 mg + paclitaxel + carboplatin, A225PC adavosertib 225 mg + paclitaxel + car- boplatin, CI confidence interval, NE not evaluable Confirmed complete response or partial response Confirmed complete response, partial response, or stable disease Kaplan–Meier estimates experiencing DLTs (grade 4 sepsis and grade 5 acute res- tumor response endpoints. In addition to small patient num- piratory distress syndrome). The event of acute respiratory bers, interpretation of the duration of response is limited by distress syndrome was considered by the investigator to be the fact that patients were not followed up for progression possibly related to adavosertib and paclitaxel; other poten- after discontinuation of treatment. tial contributing factors included the patient’s underlying Although adavosertib 225 mg bid for 2.5 days demon- disease (metastatic lung cancer), prior chemotherapy and strated antitumor activity, based on the tolerability findings, radiotherapy, and possible infection. Dose escalation in the adavosertib 175 mg bid for 2.5 days was chosen as the rec- cohort receiving adavosertib with only carboplatin was not ommended Phase II dose in combination with paclitaxel and evaluated in this study. carboplatin in Asian patients. The tolerability profile of adavosertib 175 mg bid for In terms of other adavosertib trials, results of Phase I 2.5 days plus chemotherapy in this study was generally studies indicate that combination therapy with adavosertib similar to that reported in Western women who received plus olaparib  or durvalumab  had a manageable adavosertib 225 mg bid for 2.5 days plus chemotherapy [7, tolerability profile in patients with advanced solid tumors. 8]. For example, the most commonly reported TEAEs (all A Phase I study also demonstrated that adavosertib in com- grades) were fatigue (87% of patients), nausea (78%), diar- bination with neoadjuvant docetaxel and cisplatin had an rhea (70%), thrombocytopenia (70%), and anemia (61%) in acceptable tolerability profile in patients with advanced head women with ovarian cancer refractory or resistant to first- and neck squamous cell carcinoma . Ongoing studies line platinum-based chemotherapy who received adavosertib in Asian patients include a Phase II study (NCT02593019) plus carboplatin in the PN009 study . In women with evaluating the efficacy of adavosertib monotherapy in Asian platinum-sensitive ovarian cancer who received adavosertib patients with relapsed small-cell lung cancer. in combination with paclitaxel and carboplatin in the PN004 study, the most commonly reported AEs (all grades) were nausea (78%), diarrhea (75%), vomiting (63%), alopecia 5 Conclusions (54%), and fatigue (54%) . In this study, fatigue was reported in 28.6%, 16.7%, and 33.3% of patients in cohorts In Asian patients, the recommended Phase II dose of ada- 1, 2, and 1a, respectively. vosertib (175 mg bid for 2.5 days per 21-day cycle in com- Preliminary assessment of adavosertib in combination bination with paclitaxel plus carboplatin) is lower than the with paclitaxel plus carboplatin or with only carboplatin recommended Phase II dose in Western patients, most likely indicated antitumor activity in heavily pre-treated Asian reflecting the increased exposure of adavosertib in Asian patients with advanced solid tumors. However, the small versus Western patients. 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Wu HF, Hristeva N, Chang J, et al. Rosuvastatin pharmacokinet- Open Access This article is licensed under a Creative Commons Attri- ics in Asian and White subjects wild type for both OATP1B1 bution-NonCommercial 4.0 International License, which permits any and BCRP under control and inhibited conditions. J Pharm Sci. non-commercial use, sharing, adaptation, distribution and reproduction 2017;106:2751–7. in any medium or format, as long as you give appropriate credit to the 15. Hamilton E, Falchook GS, Wang JS, et al. Phase Ib study of ada- original author(s) and the source, provide a link to the Creative Com- vosertib in combination with olaparib in patients with refractory solid mons licence, and indicate if changes were made. The images or other tumors: Dose escalation. Cancer Res. 2019;79(Suppl):abst CT025. third party material in this article are included in the article’s Creative 16. Patel MR, Falchook GS, Wang JS, et al. Open-label, multicenter, Commons licence, unless indicated otherwise in a credit line to the phase I study to assess safety and tolerability of advavosertib plus material. If material is not included in the article’s Creative Commons durvalumab in patients with advanced solid tumors. J Clin Oncol. licence and your intended use is not permitted by statutory regula- 2019;37(Suppl):abst 2562. tion or exceeds the permitted use, you will need to obtain permission 17. Mendez E, Rodriguez CP, Kao MC, et al. A phase I clinical trial directly from the copyright holder.To view a copy of this licence, visit of AZD1775 in combination with neoadjuvant weekly docetaxel http://creat iveco mmons .org/licen ses/by-nc/4.0/. and cisplatin before definitive therapy in head and neck squamous cell carcinoma. Clin Cancer Res. 2018;24:2740–8. 84 H. Kato et al. Affiliations 1 2,10 3 4 5 6 Hidenori Kato · Paul de Souza · Sang‑We Kim · Jason D. Lickliter · Yoichi Naito · Keunchil Park · 7 8 9 Sanjeev Kumar · Ganesh M. Mugundu · Yung‑Jue Bang 1 8 Division of Gynecologic Oncology, Hokkaido Cancer Quantitative Clinical Pharmacology, Early Clinical Center, Sapporo, Japan Development, IMED Biotech Unit, AstraZeneca, Boston, MA, USA Ingham Institute, Western Sydney University, Liverpool Hospital, Liverpool, NSW, Australia Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Department of Oncology, Asan Medical Centre, Seoul, Seoul 03080, South Korea South Korea Present Address: School of Medicine, University Centre for Clinical Studies, Nucleus Network Limited, of Wollongong, Wollongong, NSW, Australia Melbourne, VIC, Australia National Cancer Center Hospital East, Kashiwa, Japan Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, South Korea AstraZeneca, Cambridge, UK
Targeted Oncology – Springer Journals
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