Simon Two-stage Design Research Articles

Abstract OT2-16-01: The SMILE study: A phase 2 trial of onapristone in combination with fulvestrant for patients with ER+ and HER2- metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors

Abstract Background Antiprogestins, including selective progesterone receptor (PgR) modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance including in patients who develop activating estrogen receptor 1 (ESR1) mutations after prior endocrine therapy (ET). The SMILE study (NCT04738292) is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone in combination with fulvestrant as second-line therapy for patients with ER+,PgR+, HER2 -metastatic breast cancer (MBC). Methods Patients with locally advanced or MBC who progress on ≥2 lines of prior therapy with ET as a single agent or in combination with CDK4/6 inhibitors, mTOR inhibitors and one line of chemotherapy in the metastatic setting are eligible. Other criteria include ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, adequate organ function, availability of an archived tumor biopsy block confirming the diagnosis of MBC, optional biopsy at disease progression on trial, and optional 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging. Ovarian suppression is allowed. Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Patients with prior exposure to fulvestrant, antiprogestins, or CDK inhibitors in the adjuvant setting are ineligible. Following consent, all subjects will receive fulvestrant at the recommended dosing schedule plus onapristone 50 mg orally, twice daily, until disease progression, unacceptable toxicity, or discontinuation for any other reason. Using the Simon Two-Stage design, a total of 39 patients will be enrolled over two years from 6-8 sites within Wisconsin Oncology Network (WON). In the first stage of the trial, 21 subjects will be enrolled; if ≥2 responses are observed, then 18 additional subjects will be enrolled in the second stage. This design yields a one-sided type I error rate of 5% if the ORR is 7% and power of 80% when the combination's true response rate is 20%. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis). The study was approved in January 2021, and enrollment is active at the time of this submission. Citation Format: Sailaja Kamaraju, Amy Fowler, Chung Yee Cheng, Lubna N Chaudhary, John Burfeind, Janet Retseck, Amye J Tevaarwerk, Mark Burkard, Elisavet Paplomata, Amanda M Parkes, Julie M Jorns, Sergey Tarima, Douglas Yee, Hallgeir Rui, Carol Lange, Tarek Sahmoud, Kari B Wisinski. The SMILE study: A phase 2 trial of onapristone in combination with fulvestrant for patients with ER+ and HER2- metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-16-01.

Abstract PD10-11: Keyriched-1- A prospective, multicenter, open label, neoadjuvant phase ii single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype

Abstract Background: De-escalating strategies seem promising in HER2-positive early breast cancer (EBC) and chemo-free regimens are thus of key interest. Recent data have underlined the role of tumor immunogenicity in response to de-escalated neoadjuvant anti-HER2 therapy. Therefore, the prospective single arm hypothesis-generating phase II KEYRICHED-1 trial (NCT03988036) investigates the pCR-rate in patients with HER2-enriched EBC receiving four cycles of the dual anti-HER2 blockade in combination with the checkpoint inhibitor pembrolizumab. Initial studies with dual antibody-based HER2 blockade alone were able to achieve pCR-rates of 20-40%, which did not quite match the pCR-rates obtained with concurrent chemotherapy. KEYRICHED-1 aims at achieving pCR-rates comparable to standard chemotherapy-containing regimens by incorporating appropriate molecular selection and immune oncology.. Methods: A total of 48 pre- and postmenopausal patients with newly diagnosed HER2 2+ or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 were enrolled in this single-arm study. All patients received four cycles of study treatment with pembrolizumab (200mg), trastuzumab biosimilar (Trazimera®, loading dose 8mg/kg bodyweight (BW), maintenance dose 6mg/kg BW), and pertuzumab (loading dose 840mg/kg BW, maintenance dose 420mg/kg BW) q21d. Primary endpoint was centrally confirmed pCR (ypT0/is, ypN0). The trial was planned as a Simon's two-stage design (null and alternative pCR were 40% and 60%); interim analysis after 16 patients had to show a pCR rate of at least 50% to continue recruitment.. Results: Between 05/2020 and 03/2021, 98 patients were screened. N=52 (55%) had HER2-E subtype, of whom 48 patients entered the treatment phase. Median patient age was 57 years (28-83). 65% had tumors > 2 cm and 30% positive lymph node status. Centrally confirmed pCR-rate in surgical specimens was 46% (95% CI 0.31-0.62) in the 43 patients of the per-protocol-population, and 52% (95%CI 0.37-0.67) in all 46 evaluable patients (local assessment; two pCRs verified only by core biopsy) (p=0.22 and p=0.06 for null hypothesis, respectively). Despite HER2-E subtype, no pCR was observed in the four patients with immunohistochemical (IHC) HER2 2+/ISH-positive status in contrast to 20/39 (51.2%) pCR in IHC HER2 3+ tumors. Centrally confirmed pCR-rate in HR+/HER2+ tumors was 38.5% compared to 58.5% in HR-/HER2+ tumors. No new safety signals were observed.. Conclusions: These are the first results of a neoadjuvant chemotherapy-free 12-week de-escalation anti-HER2-regimen with trastuzumab and pertuzumab in combination with the PD-1 inhibitor pembrolizumab in patients with a HER2-E EBC. In the context of the WSG ADAPT HER2+ de-escalation trials the observed pCR-rates compare favorably in HR+ as well as HR- HER2+ EBC. Moreover, KEYRICHED-1 demonstrates that with appropriate molecular patient selection clinically meaningful pCR-rates in the range of those obtained with longer, more toxic chemotherapy-containing regimens can be achieved. Citation Format: Sherko Kuemmel, Oleg Gluz, Mattea Reinisch, Athina Kostara, Iris Scheffen, Monika Graeser, Rachel Wuerstlein, Ulrike Nitz, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens Blohmer, Christine zu Eulenburg, Matthias Christgen, Stephan Bartels, Hans Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. Keyriched-1- A prospective, multicenter, open label, neoadjuvant phase ii single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-11.

Abstract P2-13-03: KEYRICHED-1 - A prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype

Abstract Background: De-escalating strategies seem promising inHER2-positive early breast cancer (EBC) and chemo-free regimens are thus of keyinterest. Recent data have underlined the role of tumor immunogenicity inresponse to de-escalated neoadjuvant anti-HER2 therapy. Therefore, theprospective single arm hypothesis-generating phase II KEYRICHED-1 trial (NCT03988036)investigates the pCR rate in patients with HER2-enriched EBC receiving fourcycles of the dual anti-HER2 blockade in combination with the checkpointinhibitor pembrolizumab. Initial studies with dual antibody-based HER2 blockadealone were able to achieve pCR-rates of 20-40%, which did not quite match the pCRrates obtained with concurrent chemotherapy. KEYRICHED-1 aims at achieving pCR-ratescomparable to standard chemotherapy-containing regimens by incorporating appropriatemolecular selection and immune oncology. Methods: A total of 48 pre- and postmenopausal patients with newly diagnosed HER22+ or 3+ EBC (stage I-III) and HER2-enriched (HER2-E) subtype by PAM50 wereenrolled in this single-arm study. All patients received four cycles of studytreatment with pembrolizumab (200mg), trastuzumab biosimilar (Trazimera®,loading dose 8mg/kg bodyweight (BW), maintenance dose 6mg/kg BW), and pertuzumab(loading dose 840mg/kg BW, maintenance dose 420mg/kg BW) q21d . Primaryendpoint was centrally confirmed pCR (ypT0/is, ypN0). The trial was planned asa Simon's two-Stage design (null and alternative pCR were 40% and 60%); interimanalysis after 16 patients had to show a pCR rate of at least 50% to continuerecruitment. Results: Between 05/2020 and 03/2021, 98 patients werescreened. N=52 (55%) had HER2-E subtype,of whom 48 patients entered thetreatment phase. Median patient age was 57 years (28-83). 65% had tumors > 2cm and 30% positive lymph node status. Centrally confirmed pCR rate in surgicalspecimens was 46% (95% CI 0.31-0.62) in the 43 patients of the per protocolpopulation, and 52% (95%CI 0.37-0.67) in all 46 evaluable patients (localassessment; two pCRs verified only by core biopsy) (p=0.22 and p=0.06 for nullhypothesis, respectively). Despite HER2-E subtype, no pCR was observed in the 4patients with immunohistochemical (IHC) HER2 2+/ISH-positive status in contrastto 20/39 (51.2%) pCRs in IHC HER2 3+ tumors. Centrally confirmed pCR rate in HR+/HER2+tumors was38.5% compared to 58.5% in HR-/HER2+ tumors. No new safety signals wereobserved. Conclusions: These are the first results of a neoadjuvant chemotherapy-free12-week de-escalation anti-HER2-regimen with trastuzumab and pertuzumab incombination with the PD-1 inhibitor pembrolizumab in patients with a HER2-E EBC.In the context of the WSG ADAPT HER2+ de-escalation trials the observed pCRrates compare favourably in HR+ as well as HR- HER2 EBC. Moreover, KEYRICHED-1demonstrates that with appropriate molecular patient selection clinicallymeaningful pCR rates in the range of those obtained with longer, more toxicchemotherapy-containing regimens can be achieved. Citation Format: Sherko Kuemmel, Oleg Gluz, Mattea Reinisch, Athina Kostara, Iris Scheffen, Monika Graeser, Kerstin Luedtke-Heckenkamp, Andreas Hartkopf, Felix Hilpert, Angela Kentsch, Carsten Ziske, Reinhard Depenbusch, Michael Braun, Jens Blohmer, Christine zu Eulenburg, Matthias Christgen, Stephan Bartels, Hans Kreipe, Enrico Pelz, Peter Schmid, Nadia Harbeck. KEYRICHED-1 - A prospective, multicenter, open label, neoadjuvant phase II single arm study with pembrolizumab in combination with dual anti-HER2 blockade with trastuzumab and pertuzumab in early breast cancer patients with molecular HER2-enriched intrinsic subtype [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-03.

Abstract PD8-03: Palbociclib and trastuzumab for HER2-positive metastatic breast cancer (SOLTI-1303 PATRICIA): Final results from cohort A and B, prospective, open-label, multicenter phase II study

Abstract Background: CDK4/6 inhibition combined with anti-HER2 therapy is currently being explored in HER2-positive (HER2+) breast cancer (BC). Here, we report the final efficacy and genomic analysis of cohort A and B of the PATRICIA phase II trial evaluating palbociclib in combination with trastuzumab in advanced HER2+ BC. Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2-4 prior lines of anti-HER2-based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). Patients with ER-positive tumors were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival (PFS) rate at 6 months (PFS6). Secondary objectives included PFS, overall survival (OS) and the association of the research-based PAM50 intrinsic subtyping with PFS and OS. PAM50 was performed from FFPE samples using the nCounter platform. For each sample we calculated the PAM50 signature scores (Basal-like, HER2-E, Luminal A and B, Normal-like), CES, ROR-Subtype, ROR-proliferation and the proliferation signature score. Multivariable Cox regression analyses evaluating PAM50 subtypes, age, performance status, treatment line, type of biopsy, and ER status. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). Median follow-up was 42.3 months (IQR 34.7-54.8). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Median PFS was 4.2 months (95% CI 0.7-6.7) in cohort A, 6.0 months (95% CI 4.0-10.6) in cohort B1 and 5.1 months (95% CI 3.7-9.1) in cohort B2. Regarding PAM50, 59 (83.1%) tumors samples (42.4% metastasis) were profiled. 49.2% of the tumor samples were identified as HER2-E, followed by Luminal B (22.0%), Luminal A (16.9%), normal-like (10.2%), and Basal-like (1.7%). Luminal disease defined by PAM50 was independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio [HR] = 0.34; P = 0.007). Median OS was 21.8 months (95% CI 13.8-32.2) in cohort A, 28.0 months (95% CI 14.2-48.8) in cohort B1 and 34.3 months (95% CI 20.6-47.6) in cohort B2. Luminal disease defined by PAM50 was not independently associated with OS compared with non-luminal disease (34.3 vs. 26.1 months; adjusted HR = 0.753; P = 0.365). Among the 9 PAM50 signatures, expression of 3 signatures were found significantly associated with OS: CES (HR = 0.50; p=0.021), Luminal A score (HR=0.33; p=0.022) and ROR-S (HR=1.018; p=0.027). Conclusion: Our analysis shows that the promising PFS previously reported in trastuzumab pretreated ER-positive/HER2+ advanced breast cancer with a PAM50 Luminal A or B subtype were maintained after a median of >3 years of follow-up. A longer OS was seen in patients with luminal tumors, but results were not statistically significant and could have been influenced by the low sample size. Cohort C of PATRICIA is currently randomizing patients with HR-positive/HER2+, PAM50 Luminal A or B tumors to palbociclib and endocrine therapy plus trastuzumab or treatment of physician’s choice (NCT02448420). Acknowledgements: This study is sponsored by SOLTI and financially supported by Pfizer Citation Format: Eva Ciruelos, Tomás Pascual, Mafalda Oliveira, Santiago Escrivá-de-Romaní, Sonia Pernas, Laia Paré, Barbara Adamo, Eduardo Martínez, Javier Cortés, Antonia Perelló, Maria Galan, Mireia Melé, Pablo Tolosa, Blanca González-Farré, Patricia Galván, Jordi Canes, Paolo Nuciforo, Xavier Gonzalez, Patricia Villagrasa, Aleix Prat. Palbociclib and trastuzumab for HER2-positive metastatic breast cancer (SOLTI-1303 PATRICIA): Final results from cohort A and B, prospective, open-label, multicenter phase II study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-03.

Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer.

12 Background: Encorafenib (E) and cetuximab (C) offers short-lived response and survival benefit for patients (pts) with MSS, BRAFV600E metastatic colorectal cancer (CRC). BRAF + EGFR inhibition induced a transient MSI-H phenotype in preclinical models of MSS, BRAFV600E CRC and may prime these tumors for response to immunotherapy with anti-PD-1 antibodies like nivolumab (N). Methods: In this single-arm, single-institution, phase I/II clinical trial, pts with treatment-refractory MSS, BRAFV600E metastatic CRC were eligible. No prior BRAF inhibitors, anti-EGFR antibody, or immunotherapy was permitted. Pts received E (300 mg PO daily), C (500 mg/m2 IV q14 days), and N (480 mg IV q28 days). The primary endpoints were best overall response (RECIST 1.1) and safety/tolerability (CTCAE v5). A Simon two-stage design (H0: p≤.22; Ha: p≥.45, where p= percentage of pts with radiographic response) was employed using a one-sided α=.05 and β=.20. In the first stage, ≥ 4/15 responses were needed in order for the trial to enroll 11 additional pts. Median progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier. Results: All 26 pts have been enrolled - 23 patients treated, and 21 evaluable for response so far. Median age is 59 years (range, 32-85), and 14 (54%) are female. No dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events (AE) occurred in 4/22 (18%) patients. Grade 3 AEs included colitis, maculopapular rash, leukocytosis, and elevated amylase/lipase (all N=1). Grade 4 AEs in a single patient were myositis/myocarditis. Overall response rate is 45% (95% CI, 23-68), and disease control rate is 95% (95% CI, 75-100). Median PFS is 7.3 months (95% CI, 5.5-NA). Median OS is 11.4 months (95% CI, 7.6-NA). For the 9 pts thus far with responses, median duration of response is 8.1 months (95% CI, 7.3-NA). Updated results will be presented. Conclusions: E + C + N is effective and well-tolerated for pts with MSS, BRAFV600E metastatic CRC. The E+C+N regimen met its predefined efficacy endpoint and suggests a role for immunotherapy as a novel combination approach for this specific subpopulation of MSS metastatic CRC. A follow-up randomized phase II trial (SWOG 2107) to evaluate encorafenib/cetuximab with or without nivolumab in pts with MSS, BRAFV600E metastatic CRC will activate in early 2022. Clinical trial information: NCT04017650.

GOBLET: A phase 1/2 multiple-indication biomarker, safety, and efficacy study in advanced or metastatic gastrointestinal cancers exploring treatment combinations with pelareorep and atezolizumab.

TPS216 Background: Checkpoint blockade therapy only benefits a small subset of GI cancer patients (approximately 4%) with microsatellite instability-high (MSI-H) tumors, which are characterized as immunologically ‘hot’ (Bonneville et al., 2017). Most GI cancers, however, have microsatellite stable (MSS) tumors, which have an immunologically “cold” phenotype with fewer genetic mutations, reduced immune cell infiltration, and downregulated immune checkpoint proteins. These attributes make MSS tumors resistant to conventional immunotherapy including checkpoint blockade therapy (Ooki et al., 2021). Pelareorep is a naturally occurring, non-genetically modified reovirus. Upon intravenous administration, pelareorep selectively kills tumor cells and promotes several immunologic effects that prime tumors to respond to checkpoint blockade. These include the stimulation of tumor-directed innate and adaptive immune responses, increased T cell infiltration, expansion of new T cell clones, and increased PD-L1 expression in tumors (Samson et al., 2018, Manso et al. 2021 AACR). Given its expected synergy with checkpoint blockade, as well as its encouraging efficacy in prior GI cancer studies (Mahalingam et al. 2020), the GOBLET study is designed to evaluate pelareorep plus atezolizumab in multiple GI cancer indications. Methods: GOBLET is an open-label, non-randomized, multiple-cohort, phase 1/2 study in patients with advanced or metastatic GI cancers. This study employs a Simon two-stage design. Stage 1 comprises four treatment groups: Cohort 1 – First-line pancreatic cancer treated with pelareorep plus atezolizumab and chemotherapy (gemcitabine and nab-paclitaxel) (N = 12); Cohort 2 – First-line MSI-H colorectal cancer (CRC) treated with pelareorep plus atezolizumab (N = 19); Cohort 3 – Third-line CRC treated with pelareorep plus atezolizumab and chemotherapy (trifluridine/tipiracil) (N = 14); and Cohort 4 – Second-line or later squamous cell carcinoma of the anal canal treated with pelareorep plus atezolizumab (N = 10). The first 3-6 patients enrolled into the chemotherapy-containing cohorts (Cohorts 1 and 3) comprise a safety run-in that must be successfully concluded prior to enrolling additional patients into these cohorts. The primary objectives are safety and efficacy based on objective response rate (ORR) at week 16. Any cohort showing a promising ORR in Stage 1, based on pre-specified criteria, may be advanced to Stage 2 and enroll additional patients. Clinical trial information: 2020-003996-16.

Abstract P032: Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study

Abstract Background: Nearly 50% of patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma possess somatic TP53 mutations, with most mutations falling within exons 2 or 4-11. Though the presence of TP53 mutations has historically been considered a poor prognostic factor in advanced gastric/GEJ adenocarcinoma, cancer cells with mutations in TP53 tend to depend on ataxia telangiectasia and Rad3-related protein kinase (ATR) as a primary mediator of DNA damage repair (DDR). In preclinical studies, topoisomerase 1 inhibitors and ATR inhibitors demonstrate synergy in TP53 mutant gastrointestinal cancer cell lines. Based on the dearth of active later-line treatments in patients with advanced gastric/GEJ adenocarcinoma, we initiated a combinatorial study of the highly selective ATR inhibitor berzosertib (formerly VX-970/M6620) with irinotecan in this disease population. Methods: The study is a single arm phase II trial of berzosertib plus irinotecan in patients with advanced (progressive on at least one prior line of therapy) TP53 mutant (with mutations in exons 2 or 4-11) gastric/GEJ adenocarcinoma and is sponsored by the National Cancer Institute [NCT03641313]. The primary endpoint of the study is objective response rate (ORR) with key secondary endpoints of overall survival (OS), progression-free survival (PFS), duration of response (DOR) and measuring pharmacodynamic biomarkers of DNA damage induction (γ-H2AX, KAP1 p-Ser 824 and p-ATR) from on-treatment biopsies in select patients. Exploratory aims of the study are to assess ORR, OS, PFS and DOR in patients based upon the presence of other tumor DDR mutations (e.g. BRCA1, BRCA2, MRE11, RAD50, RAD51, NBN, ATM). The study utilizes a Simon's Optimal two-stage design to assess ORR. If 2 or more responses are not observed in the first 9 response-eligible patients on the study, it will close for futility. If the interim efficacy threshold is achieved, 14 more response-eligible patients will be enrolled for a total of 23. A safety lead-in is being utilized for the initial 6 patients as the RP2D of the experimental combination had not yet been fully defined from its preceding phase I study. Results: The initial 6 patients have been treated with irinotecan (180 mg/m2 D1,D15 every 28 days) and berzosertib (270 mg/m2 D1,D15 every 28 days). No dose limiting toxicities were observed during cycle 1 in these patients and thus this dose was established as a safe dose for the remainder of the study patients. Patients have experienced grade 3/4 adverse events in 7 instances (most have been hematologic with 1 case of grade 4 neutropenia and 1 case each of grade 3 anemia, neutropenia and thrombocytopenia). Of the initial 6 patients, 1 has demonstrated a partial response while 3 others have demonstrated stable disease on initial response assessment (by RECIST 1.1). Conclusion: Berzosertib plus irinotecan appears to be safe in patients with TP53 mutated gastric/GEJ adenocarcinoma. The interim efficacy analysis, along with pharmacodynamic assessments of DNA damage induction, remain pending. Citation Format: Satya Das, G. Dan Ayers, Jennifer Whisenant, Anwaar Saeed, Edward Kim, Vaia Florou, George Yacoub, Percy Ivy, Charles Kunos, Jordan Berlin. Berzosertib plus irinotecan in patients with TP53 mutant gastric/gastroesophageal junction adenocarcinoma: A phase II study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P032.

CTIM-02. PHASE II STUDY OF IPILIMUMAB AND NIVOLUMAB IN LEPTOMENINGEAL CARCINOMATOSIS

Abstract Leptomeningeal disease (LMD) is an increasingly common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We conducted a single arm Phase II study of combined ipilimumab and nivolumab in patients with LMD from solid tumor malignancies (NCT02939300). Patients received manufacturer-specific dosing regimens of combined ipilimumab and nivolumab based on primary-tumor histology until definitive progression or unacceptable toxicity. The primary end point was rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Eighteen patients with diverse primary tumor histologies were enrolled and all received at least one dose of combined ipilimumab and nivolumab. Median follow up based on patients still alive was 8.0 months (range: 0.5 to 15.9 months). The study met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients were alive at three months after enrollment. One third of patients experienced one (or more) grade-3 or higher adverse events possibly related to treatment. Two patients discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events overall included fatigue (N=7), nausea (N=6), fever (N=6), anorexia (N=6) and rash (N=6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients; this therapeutic approach should be studied in larger, multicenter clinical trials to validate these results as well as better identify patients who will benefit.

CTIM-01. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES

Abstract Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.

The Efficacy and Safety of Low-Dose Inotuzumab Ozogamicin in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia: Interim Results of a Phase 4 Study

The Efficacy and Safety of Low-Dose Inotuzumab Ozogamicin in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia: Interim Results of a Phase 4 Study

Interim Efficacy Analysis of a Phase II Study Demonstrates Promising Activity of the Combination of Pembrolizumab (PEM) and Entinostat (ENT) in Relapsed and Refractory (R/R) Hodgkin Lymphoma (HL)

Interim Efficacy Analysis of a Phase II Study Demonstrates Promising Activity of the Combination of Pembrolizumab (PEM) and Entinostat (ENT) in Relapsed and Refractory (R/R) Hodgkin Lymphoma (HL)

Two-Stage Single-Arm Trials Are Rarely Analyzed Effectively or Reported Adequately.

PURPOSETwo-stage single-arm designs have historically been the most common design used in phase II oncology. They remain a mainstay today, particularly for trials in rare subgroups. Consequently, it is imperative such studies be designed, analyzed, and reported effectively. We comprehensively review such trials to examine whether this is the case.METHODSOncology trials that used Simon's two-stage design over a 5-year period were identified and reviewed. They were evaluated for whether they reported sufficient design (eg, required sample size) and analysis (eg, CI) details. Articles that did not adjust their inference for the incorporation of an interim analysis were also reanalyzed.RESULTSFour-hundred twenty-five articles were included. Of these, just 47.5% provided the five components that ensure design reproducibility. Only 1.2% and 2.1% reported an adjusted point estimate or CI, respectively. Just 55.3% provided the final stage rejection bound, indicating many trials did not test a hypothesis for their primary outcome. Trial reanalyses suggested reported point estimates underestimated treatment effects and reported CIs were too narrow.CONCLUSIONKey design details of two-stage single-arm trials are often unreported. Their inference is rarely performed such as to remove bias introduced by the interim analysis. These findings are particular alarming when considered against the growing trend in which nonrandomized trials make up a large proportion of all evidence on a treatment's effectiveness in a rare biomarker-defined patient subgroup. Future studies must improve the way they are analyzed and reported.

Phase II study of ipilimumab and nivolumab in leptomeningeal carcinomatosis

Leptomeningeal disease (LMD) is a common complication from solid tumor malignancies with a poor prognosis and limited treatment options. We present a single arm Phase II study of 18 patients with LMD receiving combined ipilimumab and nivolumab until progression or unacceptable toxicity (NCT02939300). The primary end point is overall survival at 3 months (OS3). Secondary end points include toxicity, cumulative time-to-progression at 3 months, and progression-free survival. A Simon two-stage design is used to compare a null hypothesis OS3 of 18% against an alternative of 44%. Median follow up based on patients still alive is 8.0 months (range: 0.5 to 15.9 months). The study has met its primary endpoint as 8 of 18 (OS3 0.44; 90% CI: 0.24 to 0.66) patients are alive at three months. One third of patients have experienced one (or more) grade-3 or higher adverse events. Two patients have discontinued protocol treatment due to unacceptable toxicity (hepatitis and colitis, respectively). The most frequent adverse events include fatigue (N = 7), nausea (N = 6), fever (N = 6), anorexia (N = 6) and rash (N = 6). Combined ipilimumab and nivolumab has an acceptable safety profile and demonstrates promising activity in LMD patients. Larger, multicenter clinical trials are needed to validate these results.

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial

PurposeMonalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity. Experimental designThe UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients. ResultsTwenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7–NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5–1.8) and 6.7 months (95% CI: 3.0–9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%). ConclusionsMonalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.

SYST-06. PHASE II TRIAL OF PAXALISIB (GDC-0084) IN COMBINATION WITH TRASTUZUMAB FOR PATIENTS WITH HER2-POSITIVE BREAST CANCER BRAIN METASTASES (BCBM)

Abstract BACKGROUND The PI3K/Akt/mTOR is an important pathway in BCBM. Mutations in PIK3CA or PTEN loss are associated with trastuzumab resistance. Inhibition of PI3K and mTOR led to durable responses in 3 of 5 patient-derived xenografts (PDX) models of BCBM. Paxalisib is a potent, brain-penetrant inhibitor of class I PI3K and mTOR. METHODS This is a single-center, phase II study to evaluate the efficacy of the combination of paxalisib with trastuzumab for the treatment of central nervous system (CNS) metastases in patients with HER2-positive breast cancer. Patients will receive paxalisib (45 mg daily) and trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). Two cohorts will be enrolled: Cohort A: a single-arm, two-stage, phase II cohort; and Cohort B: a pre-surgical window cohort. Inclusion criteria include unequivocal evidence of new and/or progressive HER2-positive CNS metastases, at least one measurable (≥10 mm) CNS metastasis (Cohort A), clinical indication for CNS metastasis resection (Cohort B). Primary endpoint for Cohort A is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. For Cohort B, the primary endpoint is the correlation between p4EBP1 levels in the resected CNS tumor tissue from patients and intracranial response to paxalisib/trastuzumab in the PDX model generated from the same patient. Secondary endpoints include overall survival, safety and patient-reported outcomes. Mandatory blood and cerebrospinal fluid with optional tumor biopsy will be collected at baseline, on-treatment and at progression. In Cohort A, we will enroll 37 patients in a Simon two-stage design. If ≥4 responses are seen, the regimen will be considered successful. This design has 90% power with alpha <10%. Cohort B will enroll 10 patients. The trial opened in February, 2019 and 8 patients have been enrolled. NCT03765983.

IMMU-08. PHASE II TRIAL OF PEMBROLIZUMAB AND LENVATINIB FOR LEPTOMENINGEAL METASTASES

Abstract Leptomeningeal metastasis (LMD) is a late complication of cancer with poor prognosis and median survival of approximately 4-6 weeks without treatment. Whole brain radiation remains the mainstay of treatment, however it can cause significant neurocognitive sequelae and has not been shown to prolong overall survival. Thus, new treatment strategies are urgently needed to improve outcomes in patients with LMD. Results from recent Phase 2 studies of immune checkpoint inhibitors in LMD shows promising improvement in overall survival. Combining anti-VEGF therapy and immunotherapy may control symptoms due to inflammation and tumor-induced irritation, minimize steroid use, and promote improved efficacy of immunotherapy through modulation of the tumor immune microenvironment. We designed a multi-institutional, single-arm Phase 2 study of pembrolizumab in combination with lenvatinib in patients with LMD from any solid tumor. The primary objective is to estimate the overall survival rate at 6 months (OS6). A Simon two-stage design with a total sample size of 19 evaluable patients will be used to compare a null hypothesis of OS6 of 25% against an alternative hypothesis of 55%. Secondary objectives include assessing safety of pembrolizumab and lenvatinib in this patient population, systemic response rate, intracranial/intraspinal response rate, and progression-free survival. We will also explore clinician-reported neurologic outcomes and patient-reported quality of life and symptom burden. Blood, cerebrospinal fluid, and tissue biomarkers will be analyzed to determine predictors of response. Patients must be on minimal doses of steroids prior to study enrollment and cannot have received prior immune checkpoint inhibitor or anti-VEGF therapy. Response to treatment will be determined using RANO-BM for intracranial disease and RECIST 1.1 for systemic disease. Study accrual is anticipated over 12-24 months with anticipated total study duration of 30 months.

Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial

ObjectiveTivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). MethodsThis open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. ResultsThirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1–9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7–5.8) and OS 8.6 months (95% CI: 5.4–12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3–4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). ConclusionsTivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

Abstract CT222: BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Patients with metastatic prostate cancer invariably progress to a lethal state called metastatic castration-resistant prostate cancer (mCRPC). Approximately 23-28% of patients with mCRPC have molecular alterations in genes associated with homologous recombination (HR) DNA repair mechanisms (e.g., BRCA1/2). These alterations are associated with sensitivity to poly ADP-ribose polymerase inhibitors (PARPi). The responses to PARPi can be short-lived, and several mechanisms of resistance have been described. Preclinical studies demonstrated that PI3K suppression impairs HR and sensitizes cancer cells to PARPi even in the absence of mutations in DNA repair genes. The synergy between olaparib and PI3K inhibition led to marked tumor regression both in vitro and in vivo models of prostate cancer. These preclinical results, coupled with the importance of both the PI3K pathway and DNA damage repair mechanisms in mCRPC, support our hypothesis that dual inhibition of PI3K and PARP might improve clinical outcomes in mCRPC. We describe an ongoing phase Ib/II study aimed to evaluate the safety and determine the maximum tolerated dose (MTD) of the combination of copanlisib (pan-class I PI3K inhibitor) and rucaparib (a PARP-1, -2 and -3 inhibitor) followed by an expansion cohort exploring efficacy among patients with mCRPC. Methods: Phase I, dose-escalation part of the study, aims to establish the MTD and/or recommended phase II dose (RP2D) of copanlisib in combination with rucaparib. Dose escalation will follow a standard 3+3 escalation scheme. Evidence of HR-deficiency is not required to enroll in phase I, but is for phase II. All subjects will be treated with rucaparib (continuous oral administration twice daily) 400mg (dose level I), 500mg (II) or 600mg (III-IV) and intravenous copanlisib (D1, D8, D15; 28-day cycle; dose levels I-III: 45 mg; level IV: 60 mg). Once the RP2D of copanlisib and rucaparib in the phase I part of the study is determined, enrollment will commence into the phase II part of the trial. The primary objective of phase II is to estimate the preliminary efficacy of the combination of copanlisib and rucaparib among subjects with mCRPC carrying mutations in DNA repair genes, as measured by prostate-specific antigen (PSA) response. Up to 20 patients will enroll in the phase II using a Simon's two-stage design. In the first stage, 14 patients will be accrued. If there are 7 or fewer PSA responses in these 14 patients, the study will be stopped for futility. Otherwise, an additional 6 patients will be accrued. Patients with mCRPC need to have had disease progression during treatment with abiraterone, enzalutamide, and/or apalutamide. Prior therapy with taxanes is allowed. Translational objectives include the correlation of clinical outcomes with HR mutations and PI3K/mTOR pathway gene alterations in the tumor. Genomic analyses will also investigate biomarkers and mechanisms of action of the combination. The clinical trial is recruiting (NCT04253262). Citation Format: Andre De Souza, Rahul Aggarwal, Howard Safran, Dragan Golijanin, Roxanne Wood, Adam Olszewski, Wafik S. El-Deiry, Anthony Mega, Benedito A. Carneiro. BrUOG360: A phase Ib/II study of copanlisib combined with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT222.

Abstract CT106: Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20

Abstract Background EGFR exon 20 insertion gene mutation (ex20ins) accounts for about 4-12% of the total EGFR gene mutations in non-small cell lung cancer (NSCLC) patients. NSCLC patients with EGFR ex20ins is known to be less sensitive to 1st- or 2nd-generation EGFR-TKIs. Although 3rd-generation EGFR-TKI, osimertinib is active against in vitro models of EGFR ex20ins, its efficacy has not yet been fully elucidated. This phase I/II study is conducted to evaluate the clinical efficacy of osimertinib in NSCLC patients with EGFR ex20ins. Method This is a single-arm, multi-center, open-label, non-randomized phase I/II study (UMIN000031929) consisting of stage 1 and stage 2 (Simon's two-stage design). In stage 1, 12 patients receive osimertinib 80mg once daily until they meet the termination criteria, such as, disease progression, severe toxicities, withdrawal etc. In stage 2, 9 patients receive the same dose of osimertinib if more than 1 patient achieve PR or CR in stage 1. At the transition from stage 1 to 2, Independent Data Monitoring Committee (IDMC) will provide recommendation regarding the need for study continuation, termination or dose modification of osimertinib. Patients with advanced or metastatic NSCLC with EGFR ex20ins who have a history of chemotherapy within 0 to 3 regimens are enrolled. Patients with history of EGFR-TKI treatment (gefitinib, erlotinib, afatinib, dacomitinib) can be included if the EGFR-TKI treatment did not show any clinical benefit. Patients with EGFR gene mutations, such as exon 19 deletion, L858R, T790M, G719X, L861Q are excluded. Primary end point is objective response rate (ORR) assessed via Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points are progression-free survival, overall survival, and safety profiles. Blood sampling is obtained at 4-weeks after starting osimertinib to analyze pharmacokinetic parameters. We also perform liquid biopsy for next generation sequencing at before and after acquiring resistance to osimertinib to clarify resistant mechanisms of osimertinib in EGFR ex20ins. We explore the relationship among clinical outcome, side effect, pharmacokinetic parameters and subtype of EGFR ex20ins. Result Recruitment began in June 2018 and by February 2020, 12 patients were enrolled in stage 1 at 6 institutions. Backgrounds of the patients were as follows, the median age was 63 years (range 22-84), female/male 6/6, ECOG PS 0/1 8/4, cStage IIIA/IIIb/IVA/IVB 1/1/2/8. The ORR was 0% (CR/PR 0, SD 8, PD 4), and the DCR was 66.7%. From the result of stage 1, one of the IDMC's recommendations was protocol revision since it is presumed that increasing the dose of osimertinib could be clinically promising. At the conference, the influence of subtype of EGFR ex20ins and blood levels of osimertinib on survival will be evaluated and the results of interim analysis for stage 1 will be presented. Conclusion Regular dose of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. Funding AstraZeneca. Citation Format: Eiki Ichihara, Hiroyuki Yasuda, Yuta Takashima, Yoshitaka Zenke, Shinji Takeuchi, Masahiro Morise, Katsuyuki Hotta, Mineyoshi Sato, Shingo Matsumoto, Azusa Tanimoto, Reiko Matsuzawa, Katsuyuki Kiura, Hideki Terai, Shinnosuke Ikemura, Koichi Goto, Kenzo Soejima. Phase I/II study of osimertinib in EGFR exon 20 insertion mutations in non-small cell lung cancer patients: AEX20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT106.

Abstract 974: Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification

Abstract Background: Wee1 kinase, which prevents premature mitotic entry by inhibiting cyclin-dependent kinases (CDKs), may be essential when cyclin E1 is overexpressed in order to prevent DNA damage and cell death. In preclinical studies, cancer models harboring CCNE1 amplification are highly sensitive to treatment with adavosertib, a Wee1 kinase inhibitor. A multicenter phase 2 study was conducted to assess the antitumor activity of adavosertib in patients with CCNE1 amplified advanced refractory solid tumors. Methods: Patients with advanced refractory solid tumors harboring CCNE1 amplification pre-identified in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. They had refractory disease, on standard options available, or they declined standard-of-care therapy. Eligible patients must be aged ≥ 18 years and had measurable disease per RECIST (Response Evaluation Criteria in Solid Tumors) 1.1, ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and adequate organ functions. After informed consent, patients received adavosertib 300 mg daily on days 1 to 5 and 8 to 12 of a 21-day cycle. The primary endpoint was objective response rate (ORR). The trial employed Simon's two-stage design. Results: Between January 22, 2019 and May 20, 2020, 29 patients with 12 tumor types were enrolled on study: ovarian = 14, breast = 3, endometrial = 2; and carcinosarcoma, cholangiocarcinoma, esophageal, gallbladder, germ cell tumor, melanoma, prostate, sarcoma, sarcomatoid and urothelial = 10 (1 each tumor). Median follow-up was 11.7 months. The median line of prior systemic therapy was 4 (range 1-8). Twenty-seven patients were evaluable for response. In these patients, 7 confirmed partial responses (PR) were observed, for an ORR of 25.9% (95% CI 15.1-47.5%). The median progression-free survival was 4.0 months and one-year overall survival was 55%. In 13 patients with measurable high-grade serous ovarian cancer, 5 achieved PR (38.5%) and 8 had stable disease ≥6 months/PR (61.5%). Other PRs were seen in 1 urothelial carcinoma and 1 melanoma. Fifteen patients experienced grade 3 or higher treatment-related adverse events: neutropenia (24%), thrombocytopenia (17%), anemia (14%), nausea (17%), diarrhea (17%) and fatigue (17%). Sixteen patients required dose duction of adavosertib to 250 mg, and 7 further to 200 mg. Biomarker analysis is ongoing to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in patients with refractory solid tumors harboring CCNE1 amplification, especially in high-grade serous ovarian cancer. Further exploration of adavosertib in CCNE1 amplified high grade serous ovarian cancer is warranted. Citation Format: Siqing Fu, Shuyang Yao, Yuan Yuan, Rebecca A. Previs, Anthony D. Elias, Richard Carvajal, Thomas J. George, Ying Yuan, Yuko Yamamura, Shannon Westin, Yan Xing, Ecaterina E. Ileana Dumbrava, Daniel D. Karp, Sarina A. Piha-Paul, Apostolia M. Tsimberidou, Jordi Rodon, Naoko Takebe, Charles Kunos, Karen Lu, Khanda Keyomarsi, Funda Meric-Bernstam. Phase II trial of the Wee1 inhibitor adavosertib in advanced refractory solid tumors with CCNE1 amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 974.