Article Text
Abstract
Background Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer with an aggressive phenotype, poor prognosis, and limited therapeutic options. A previous proof-of-concept phase II trial of the Wee1 inhibitor adavosertib in uterine serous carcinoma demonstrated evidence of durable clinical activity.
Primary Objective To evaluate the efficacy of adavosertib in women with recurrent or persistent uterine serous carcinoma.
Study Hypothesis We hypothesize that adavosertib will demonstrate significant clinical activity, as measured by objective response rate, in women with recurrent or persistent uterine serous carcinoma.
Trial Design Eligible participants will receive adavosertib monotherapy until disease progression or unacceptable toxicity, starting at the recommended phase II dosing of adavosertib 300 mg daily days 1 through 5 and 8 through 12 of a 21-day cycle. Participants will have restaging studies every 6 weeks for the first 48 weeks and then every 9 weeks thereafter.
Major Inclusion/Exclusion Criteria Patients with histologically confirmed recurrent or persistent uterine serous carcinoma, including endometrial carcinoma of mixed histology where the serous component comprises at least 10% of the tumor, and who have received at least one prior platinum-based chemotherapy regimen for the management of uterine serous carcinoma, are eligible for inclusion in the trial. Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants with carcinosarcoma are not eligible.
Primary Endpoint The primary endpoint is the objective response rate by RECIST 1.1 criteria, as determined by blinded independent central review.
Sample Size Approximately 120 patients will be enrolled in this trial.
Estimated Dates for Completing and Presenting Results Study completion and presentation of results are projected to be at the end of 2022.
Trial Registration ClinicalTrials.gov: NCT04590248.
- uterine cancer
Data availability statement
There are no data in this work.
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INTRODUCTION
Uterine cancer is one of the most common malignancies in the female genital tract, with an estimated 417 367 new cases worldwide in 2020,1 and an estimated 66 750 new cases will be diagnosed in the USA in 2021.2 There is an increasing prevalence of endometrial cancer in developed countries, and the highest incidences have been observed in North America and Eastern and Northern Europe.1 Uterine cancer is also one of the few cancers with both increasing incidence and mortality; since the mid-2000s the incidence rate has increased by about 1% per year, and from 2009 to 2018 the mortality rate has increased by about 2% per year.3
Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer. While one of the less common subtypes, it accounts for up to 39% of endometrial cancer-related deaths.4 Treatment options for recurrent or persistent uterine serous carcinoma remain limited, with carboplatin and paclitaxel chemotherapy and combined lenvatinib and pembrolizumab with reported efficacy. Beyond these regimens, activity for standard chemotherapy in uterine serous carcinoma is modest, with response rates in the range of 10–15%.4 New therapies for uterine serous carcinoma are therefore greatly needed.
Molecular characterization of uterine serous carcinoma has suggested that it is a tumor type that may harbor high intrinsic levels of replication stress. The vast majority of uterine serous carcinoma (>90%) harbor mutations in TP53, often in combination with high rates of alterations or amplification in other cell cycle regulators, including CCNE1 or RB1.5 6 These frequently occur in combination with alterations in oncogenic drivers, such as ERBB2, MYC, or RAS; these molecular alterations can result in increased vulnerability to DNA damage and strain on the DNA repair and replication machinery. Inhibition of the Wee1 kinase is expected to result in a further increase in replication stress as well as abrogation of the G2/S cell cycle checkpoint, of which Wee1 is a key regulator (Figure 1). Because of these underlying molecular alterations, uterine serous carcinoma may therefore be specifically vulnerable to the effects of Wee1 inhibition.
Adavosertib is an oral highly potent small molecule inhibitor of Wee1 kinase, with a half maximal inhibitory concentration (IC50) value of 5.2 nmol/L in in vitro kinase assays.7 A proof-of-concept phase II trial of adavosertib demonstrated significant clinical activity in uterine serous carcinoma, with a response rate of 29.4% and a median progression-free survival of 6.1 months.8 Responses were durable, with a median duration of response of 9.0 months. This international phase IIb single-arm trial of adavosertib is being conducted to confirm the efficacy of adavosertib monotherapy in women with recurrent or persistent uterine serous carcinoma.
METHODS
Trial Design
ADAGIO is a phase IIb, single-arm, multicenter international study to assess the efficacy and safety of adavosertib in eligible participants with histologically confirmed recurrent or persistent uterine serous carcinoma. All participants will receive adavosertib monotherapy starting at the recommended phase II dose of 300 mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Tumor imaging assessments will be conducted every 6 weeks for the first 48 weeks, and subsequently once every 9 weeks. Participants will remain on study treatment until disease progression by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, unacceptable toxicity, or withdrawal from study treatment. The trial schema is shown in Figure 2.
ADAGIO is being conducted in six countries: Canada, France, Germany, Italy, Spain, and the USA. A total of 45 sites are expected to participate in this study. The study is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, and will be approved by the appropriate institutional review board for each participating site. The study is sponsored by AstraZeneca, who are providing funding and the study drug, and is registered on ClinicalTrials.gov (NCT04590248).
Participants
Key inclusion criteria include histologically confirmed recurrent or persistent uterine serous carcinoma for which the patient has received at least one prior line of platinum-based chemotherapy. Endometrial cancers of mixed histology where the serous component comprises at least 10% of the tumor are considered eligible for the study, with the exception of carcinosarcomas, which are not eligible. In addition to a prior line of platinum-based chemotherapy, participants may have received prior immune checkpoint inhibitors, vascular endothelial growth factor (VEGF) inhibitor, or human epidermal growth factor receptor 2 (HER2)-targeted therapy. Participants with known high microsatellite instability (MSI-high) or mismatch repair deficient tumors will not be eligible unless they have already received prior therapy with a programmed death-ligand 1 (PD-1)/PD-L1 immune checkpoint inhibitor, in territories where this treatment is available for this indication, or unless they are deemed not to be a candidate for immune checkpoint therapy. Prior receipt of a cell cycle checkpoint inhibitor is not allowed. There is no restriction on the number of prior lines of systemic therapy a participant may have received.
Participants must have evidence of measurable disease according to RECIST 1.1 criteria and a European Cooperative Oncology Group (ECOG) performance status of 0 or 1. Additionally, a formalin-fixed paraffin-embedded tumor sample is required for enrollment for retrospective central confirmation of uterine serous carcinoma histology and biomarker analysis.
Endpoints
The primary objective of the study is to evaluate the efficacy of adavosertib in uterine serous carcinoma. The primary endpoint is the objective response rate as the proportion of participants with measurable disease at baseline who have a confirmed complete response or partial response, as determined by blinded independent central review (BICR) per RECIST 1.1 criteria. Secondary efficacy endpoints include duration of response, depth of response (as defined by the best percentage change from baseline in target lesions), progression-free survival by BICR, PFS6 (defined as the proportion of participants alive and progression-free at 6 months), overall survival, and disease control rate.
Additional secondary endpoints include evaluation of the pharmacokinetics of adavosertib as measured by pre-dose and Cmax plasma concentrations. Safety and tolerability of adavosertib will also be evaluated in terms of adverse events, vital signs, clinical laboratory assessments, electrocardiograms, and adverse events leading to dose interruptions, dose reductions, and dose discontinuations. Exploratory endpoints include an assessment of the effects of adavosertib on symptoms, functioning, and overall health status and health-related quality of life, as measured by patient-reported outcome instruments, including the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-EN24, and Patient Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Sample Size and Statistical Methods
Approximately 120 participants will be enrolled and dosed. The primary objective is to estimate the objective response rate. With 120 patients, if the observed objective response rate is 30%, the width of the two-sided 90% confidence interval will be ±7.6%. The primary analysis population will be the full analysis set, which will include all participants who received at least one dose of study treatment. This population will be used for the primary analyses of both the efficacy and safety endpoints. Additionally, a centrally confirmed analysis set will be defined, and will include all participants with centrally-confirmed uterine serous carcinoma who received at least one dose of study treatment. This population will be used for the analysis of efficacy.
The objective response rate will be derived using the BICR data to define a confirmed response of complete response or partial response, with the denominator defined as a subset of all treated participants with measurable disease at baseline per BICR. The objective response rate per investigator review will be included as a sensitivity analysis. The primary analysis will be performed, in both the full analysis set and in the centrally-confirmed uterine serous carcinoma populations, 6 months after the last patient’s first dose, or when all participants have progressed or died due to any cause, whichever is earlier. The final analysis will be performed when the last participant has their last scheduled visit, or 12 months after the last participant’s first dose, whichever is earlier.
DISCUSSION
Despite recent advances in the field, the treatment of recurrent advanced endometrial cancer remains a challenge. New advances have included the addition of trastuzumab to carboplatin and paclitaxel chemotherapy in women with advanced HER2-amplified uterine serous carcinoma,9 10 and more recently combination envatinib and pembrolizumab, which has demonstrated improved activity compared with physician’s choice chemotherapy in women with recurrent endometrial cancer.11–13 Nonetheless, many women are not candidates for these therapies or have disease which subsequently progresses after receiving them. Novel therapeutic strategies for these cancers are therefore greatly needed.
A proof-of-concept phase II trial of adavosertib in uterine serous carcinoma previously demonstrated encouraging signals of clinical activity, with an objective response rate of 29.4%, median progression-free survival of 6.0 months, and median duration of response of 9.0 months.8 While these results are encouraging, this initial study was conducted in a relatively small number of patients (n=34) at a single institution. ADAGIO has therefore been designed to provide confirmation and more extensive assessment of the efficacy and safety of adavosertib monotherapy in uterine serous carcinoma patients across a larger patient population and multiple study sites and countries. Confirmation of the previously observed clinical activity of adavosertib in uterine serous carcinoma patients would support further development of this drug as a novel therapeutic drug for women with uterine serous carcinoma.
ADAGIO is also designed to examine the safety of adavosertib monotherapy in uterine serous carcinoma patients. In the prior proof-of-concept study, 61.8% of patients experienced a grade 3 or higher treatment-related adverse event. Most commonly, these were hematologic adverse events, with the only more frequent grade 3 or higher non-hematologic adverse event being fatigue (23.5%). Adverse events could generally be managed with dose holds and dose modifications, with 76.5% of patients requiring at least one dose hold and 58.8% of patients requiring at least one dose reduction. However, with close management, only 5.9% of patients discontinued the drug due to adverse events.7 The secondary endpoint of safety and tolerability in a broader population of patients is therefore also an important focus of the ADAGIO study that will inform future development of adavosertib.
Collection of archival tissue for central confirmation of uterine serous carcinoma histology and for future translational studies is a key element of the ADAGIO trial. Preclinical studies have suggested that cells with high replication stress, such as those harboring CCNE1 or MYC amplifications, may have increased sensitivity to adavosertib.14 15 However, an exploration of potential biomarkers in the proof-of-concept study did not identify specific associations between specific genomic alterations and sensitivity to adavosertib.8 Thus, further investigation for possible biomarkers, including cyclin E or Myc expression or co-alterations in multiple molecular pathways, will be important to gain further insight into which cancers are most likely to be sensitive to Wee1-directed monotherapy.
Data availability statement
There are no data in this work.
Ethics statements
Patient consent for publication
References
Footnotes
Contributors All authors participated in the writing, editing, and approval of this manuscript. JFL accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
Funding This study was funded by AstraZeneca.
Competing interests JL is the international PI for the ADAGIO study and is also a member of the safety review committee for the study. JL has received consulting fees from AstraZeneca, Clovis, Eisai, EpsilaBio, Genentech, GlaxoSmithKline/Tesaro, and Regeneron Pharmaceuticals for advisory board participation; and trial support is provided to JL’s institution for trials on which JL is the PI by 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics. AMO is a member of the Safety Review Committee for the ADAGIO study. NC has received grant and contract support from AstraZeneca and Roche; consulting fees from Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GlaxoSmithKline, Tesaro, Pfizer, BIOCAD, Immunogen, Mersana, Eisai, and Oncxerna; payment or honoraria from AstraZeneca, Tesaro, Novartis, Clovis, MSD, GlaxoSmithKline, and Eisai; and has participated in a data safety monitoring board or advisory board for Roche, PharmaMar, AstraZeneca, Clovis Oncology, MSD, GlaxoSmithKline, Tesaro, Pfizer, BIOCAD, Immunogen, Mersana, Eisai, and Oncxerna. AO has received funding for her institution from Abbvie, Ability Pharmaceuticals, Advaxis Inc, Aeterna Zentaris, AMGEN, SA, Aprea Therapeutics, Clovis Oncology Inc, EISAI LTD, F. Hoffmann – La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme, Millennium Pharmaceutical Inc, Pharma Mar SA, BMS (Bristol Myers Squibb), and Tesaro; support for attending meetings and/or travel from Roche, AstraZeneca, and PharmaMar; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Clovis Oncology Inc, Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono Inc, F. Hoffmann-La Roche, GSK, Got It Consulting, SL, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme, Mersana Therapeutics, Novocure GmbH, PharmaMar, PrIME Oncology, Roche Farma, Sutro Biopharma, Inc, and Tesaro.
Provenance and peer review Commissioned; internally peer reviewed.