BACKGROUND:Abemaciclib, a potent CDK4 and CDK6 inhibitor, has shown antitumour activity in prostate cancer models and in patients with metastatic castration-resistant prostate cancer (mCRPC) who have been heavily treated. We aimed to evaluate the safety and efficacy of abemaciclib in combination with abiraterone in patients with mCRPC. METHODS:CYCLONE 2 was a randomised, double-blind, placebo-controlled, phase 3 study done in 89 hospitals and academic and private research centres in 12 countries. All study parts had identical eligibility criteria, and used block randomisation with the same stratification factors (previous docetaxel treatment, presence of measurable disease, and type of progression). Participants were adults aged 18 years and older with histologically confirmed adenocarcinoma of the prostate and metastatic disease as documented by bone scans, CT scans, or MRI scans, and radiographic or PSA progression during continuous androgen deprivation therapy. Previous docetaxel for metastatic castration-sensitive prostate cancer was permitted; previous abiraterone, apalutamide, enzalutamide, darolutamide, or CDK4 and CDK6 inhibitors were exclusionary. The trial was conducted in three parts. Part 1 was a four-arm, placebo-controlled safety and dose-finding lead-in to determine the recommended phase 2 dose of abemaciclib with abiraterone. Participants were randomly assigned (2:2:1:1) to receive abiraterone (1000 mg orally once daily) and prednisone or prednisolone (5 mg orally twice daily) with either abemaciclib at 150 mg or 200 mg orally twice daily or with matching placebo (150 mg or 200 mg twice daily). In part 2 and part 3, patients were randomly assigned (1:1) to standard abiraterone and prednisone or prednisolone plus either abemaciclib at the recommended phase 2 dose or matching placebo. Patients, investigators, and sponsor were masked to treatment assignment. The primary outcome, investigator-assessed radiographic progression-free survival, was analysed in the intention-to-treat (participants from all study parts) population. Patients who received at least one dose of abiraterone, abemaciclib, or placebo were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03706365, and is completed. FINDINGS:Between Nov 26, 2018, and July 20, 2022, 515 patients were screened for eligibility, 393 of whom were randomly assigned, 206 patients to abemaciclib plus abiraterone and 187 to placebo plus abiraterone. The median age was 70·0 years (IQR 63·0-76·0). 289 (74%) of 393 patients identified as White, 80 (20%) as Asian, 17 (4%) as Black or African American, and seven (2%) as multiple race or not reported. The highest tested dose of 200 mg abemaciclib administered twice daily was chosen as the recommended phase 2 dose. The median follow-up time was 26·3 months (IQR 22·1-48·2) for the abemaciclib plus abiraterone group and 25·6 months (22·1-40·8) for the placebo plus abiraterone group. The primary endpoint of radiographic progression-free survival was not met: radiographic progression-free survival events were reported in 92 (45%) of 206 patients in the abemaciclib plus abiraterone group and 95 (51%) of 187 patients in the placebo plus abiraterone group (HR 0·83 [95% CI 0·62-1·11]; p=0·21). Median radiographic progression-free survival was 22·0 months (95% CI 19·3-27·5) for abemaciclib plus abiraterone and 20·3 months (16·5-24·4) for placebo plus abiraterone. The most common grade 3 or higher adverse events reported in the abemaciclib plus abiraterone group were anaemia (28 [14%] of 206 vs eight [4%] of 185 in the placebo plus abiraterone group), neutropenia (26 [13%] vs one [1%]), and alanine aminotransferase increase (18 [9%] vs 12 [6%]). Serious adverse events occurred in 91 (44%) of 206 patients in the abemaciclib plus abiraterone group and in 68 (37%) of 185 patients in the placebo plus abiraterone group. There were three treatment-related deaths due to interstitial lung disease in the abemaciclib plus abiraterone group. INTERPRETATION:Dual inhibition of CDK4 and CDK6 and the androgen receptor pathway with abemaciclib plus abiraterone did not improve radiographic progression-free survival compared with abiraterone alone in the CYCLONE 2 study population with mCRPC. Safety of the combination was consistent with the previously reported safety of the individual drugs. Additional research is required to identify effective combination therapies for patients with mCRPC, especially in those presenting with adverse prognostic characteristics. FUNDING:Eli Lilly.

BackgroundThe oral, selective, and potent small molecule cyclin-dependent kinases (CDK) 4/6 inhibitor (CDK4/6i) abemaciclib has demonstrated efficacy in advanced breast cancer and high-risk early breast cancer. This Phase 1b study evaluated the safety, tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapies (Parts A–D), exemestane + everolimus (Part E), or fulvestrant + LY3023414 (a PI3K/mTOR inhibitor; Part G) in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), or trastuzumab (Part F), or trastuzumab + pertuzumab (Part H) in patients with HER2-positive (HER2+) MBC.Patients and methodsThis study enrolled women aged ≥18 years old with either HR+, HER2- (Parts E and G), or HER2+ (Parts F and H) MBC. Additional requirements included measurable disease or non-measurable but evaluable bone disease (Parts E and F), or measurable disease (Parts G and H), an Eastern Cooperative Oncology Group performance status of 0–1, and no prior treatment with CDK4/6i (Parts E, F, and H). Adverse events were graded, and tumor response was assessed.ResultsNineteen patients in Part E received abemaciclib (150 mg, n=15; 200 mg, n=4) with exemestane + everolimus, 24 patients in Part F received abemaciclib (150 mg, n=18; 200 mg, n=6) with trastuzumab, 12 patients in Part G received 150 mg abemaciclib with fulvestrant + LY3023414 (100 mg, n=7; 150 mg, n=5), and four patients in Part H received abemaciclib (100 mg) with trastuzumab + pertuzumab (with prophylactic loperamide). The most common treatment-emergent adverse events (TEAEs) were diarrhea, fatigue, neutropenia, and nausea. Grade ≥3 TEAEs were reported in 16, 18, 10, and 4 patients in Parts E–H, respectively. Abemaciclib had no effect on the pharmacokinetics of the combination study drugs. The objective response rates for patients with measurable disease were 46.2%, 10.0%, 66.7%, and 25.0% in Parts E–H, respectively. A recommended Phase 2 dose was not established for Parts E, G, and H at the dose levels evaluated, and was determined to be 150 mg Q12H in Part F.ConclusionsOverall, our results demonstrate safety profiles consistent with those previously established for abemaciclib and provide preliminary data for these combination therapies in the treatment of HR+, HER2- or HER2+ MBC.

5001 Background: Oncogenic addiction to androgen receptor (AR) signaling drives mCRPC progression, highlighting the unmet need for novel treatment strategies to maximize AR-directed therapy. Preclinical evidence suggests a key role for CDK4/6 in sustained AR signaling, uncontrolled proliferation, and hormonal resistance in prostate cancer. Abemaciclib (ABEMA) is a potent CDK4/6 oral inhibitor that significantly augments the efficacy of endocrine therapy in hormonally driven (ER+) high-risk early-stage and metastatic breast cancer. ABEMA also showed single-agent activity in heavily pretreated mCRPC. Here, we report the primary results of CYCLONE 2, a Phase 3 study of ABEMA plus abiraterone (ABI) in pts with 1L mCRPC. Methods: CYCLONE 2 was a seamless Phase 2/3 adaptive trial with a dose-finding safety lead-in. Randomization to the ABEMA or placebo (PBO) plus ABI and predniso(lo)ne was stratified by prior docetaxel receipt for mHSPC, measurable disease, and radiographic progression at study entry. Primary endpoint was investigator-assessed radiographic progression-free survival (rPFS) per RECIST v1.1 and PCWG3. The study was powered at ~90%, assuming a HR of 0.55 for rPFS, at a cumulative 2-sided alpha level of 0.05. Results: Between Nov 2018 and Jul 2022, 393 pts were randomized. Baseline characteristics were balanced across arms. Primary endpoint of rPFS was not met (HR 0.829; 95% CI, 0.619–1.111; p=0.2123), medians were 21.96 months for the ABEMA plus ABI group vs 20.28 months for the PBO plus ABI group. rPFS by blinded independent central review was consistent with investigator assessment (HR 0.842; 95% CI, 0.611–1.160). OS was a gated secondary endpoint and not inferentially tested (HR 0.927; 95% CI, 0.669–1.285; 38.9% maturity). Other secondary endpoints included time to PSA progression (HR 0.637; 95% CI, 0.474–0.856), time to symptomatic progression (HR 0.768; 95% CI, 0.522–1.131), and time to worst pain progression (HR 0.935; 95% CI 0.665–1.314). The most common grade ≥3 adverse events (AEs) reported in the ABEMA plus ABI group were anemia (13.6% vs 4.3% in the PBO plus ABI group), neutropenia (12.6% vs 0.5%) and ALT increased (8.7% vs 6.5%). Discontinuations of all study treatments due to AEs were 13.1% vs 4.3% in ABEMA plus ABI vs PBO plus ABI groups, while discontinuations of ABEMA or PBO alone due to AEs were 5.8% vs 1.6%, respectively. Conclusions: In patients with mCRPC, adding abemaciclib to abiraterone did not significantly increase rPFS. While no OS detriment was observed, secondary endpoints were not meaningfully improved. Overall, the combination was well tolerated, and safety was consistent with the known profiles of the individual medicines. Clinical trial information: NCT03706365 Clinical trial information: NCT03706365 .

TPS289 Background: Landmark trials have established a survival benefit for novel hormonal agents (NHA) added to androgen deprivation therapy (ADT) for mHSPC. Yet, there is a significant medical need to expand therapeutic options, especially for pts with high-risk mHSPC who experience poorer outcomes. Abemaciclib is an oral selective inhibitor of cyclin-dependent kinase 4 and 6 (CDK4 & 6) dosed on a continuous schedule, approved for the treatment of node-positive high-risk early-stage and advanced or metastatic HR+, HER2- breast cancer. Analogous to the estrogen receptor signaling pathway in breast cancer, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation, and upregulation of cyclin D1 is a potential mechanism of resistance to NHA therapy. In preclinical models, abemaciclib induces cell cycle arrest and inhibition of prostate tumor growth. Methods: CYCLONE 3 (NCT05288166) is a global, randomized, double-blind, placebo-controlled study evaluating the addition of abemaciclib to abiraterone+prednisone (AP) in pts with high-risk mHSPC. Approximately 900 pts with high-risk mHSPC defined by ≥4 bone metastasis and/or visceral disease will be randomised in a 1:1 ratio to the AP + abemaciclib or AP + placebo arm. Up to 3 months of ADT prior to randomization is permitted; prior D for mHSPC will be excluded per planned protocol amendment. Pts who have not undergone orchiectomy will continue ADT. Stratification factors are de novo mHSPC and visceral metastases. Primary endpoint is investigator-assessed radiographic progression-free survival (rPFS). Key secondary endpoints include rPFS assessed by blinded independent central review, castration-resistant prostate cancer-free survival, overall survival, time to pain progression, safety and pharmacokinetics. Enrollment is open at approximately 270 sites across 25 countries. Clinical trial information: NCT05288166 .

TPS198 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase 2/3, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) in pts with mCRPC. CYCLONE 2 is an adaptive study which is designed in three parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase 2 dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to AA+P with abemaciclib at the RP2D or placebo. The study expands to enroll an additional 170 pts in Part 3 if prespecified expansion criteria are met at a planned adaptive interim analysis performed by an independent data monitoring committee (IDMC). Pts with mCRPC evidenced by radiographic and/or PSA progression during continuous ADT are eligible. Prior docetaxel for mHSPC is permitted. Systemic anti-cancer therapy for mCRPC and prior novel hormonal agents are exclusionary. The primary objective is radiographic progression free survival (rPFS; per RECIST1.1 for soft tissue and PCWG3 for bone). Secondary objectives include safety, objective response rate, duration of response, time to symptomatic and PSA progression, overall survival, and pharmacokinetics. Status: Enrollment in Part 1 & 2 is completed. Based on the recommendation from the IDMC, Part 3 was opened in June 2021 and enrolls pts from about 112 sites across 12 countries. Clinical trial information: NCT03706365.

BackgroundCyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and MethodsWomen ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0–1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.ResultsSixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.ConclusionsAbemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT02057133

TPS5086 Background: In cancer cells, the cyclin-dependent kinases 4 and 6 (CDK4 & 6)/retinoblastoma protein (Rb) pathway is commonly altered, resulting in uncontrolled cell cycle entry and proliferation. CDK4 & 6 inhibitors represent a major advance in the management of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (ABC or MBC, respectively). Abemaciclib is an oral selective inhibitor of CDK4 & 6 administered on a continuous dosing schedule, approved in combination with endocrine therapy for HR+, HER2- ABC or MBC. In addition, abemaciclib is also approved by the FDA as monotherapy for HR+, HER2- ABC or MBC following endocrine therapy and prior chemotherapy in the metastatic setting. Similar to the estrogen receptor signaling pathway in breast cancer cells, there is evidence that the androgen receptor axis activates CDK4 & 6 to sustain prostate cancer cell proliferation and survival. Preclinical studies in prostate cancer cell lines and xenograft models showed that abemaciclib exhibits single agent activity by inducing cell cycle arrest and tumor growth inhibition. Clinical activity of abemaciclib in combination with abiraterone and prednisone is investigated in a randomized phase 2 study in the first-line mCRPC setting (CYCLONE 2, NCT03706365). Despite recent advances, management of heavily pretreated mCRPC remains a major clinical challenge. Herein, we hypothesize that mCRPC patients whose disease progressed after novel hormonal agents (NHA) and taxane therapies may derive therapeutic benefit from single agent abemaciclib. Methods: CYCLONE 1 is a phase 2, single-arm, multicenter study to assess the safety and efficacy of abemaciclib monotherapy in 40 patients with mCRPC progressing after ≥1 NHA and 2 taxane regimens. Patients will be enrolled at time of prostate specific antigen (PSA) or radiographic progression per PCWG3 criteria and have at least 1 measurable lesion per RECIST 1.1. Metastatic tumor tissue (fresh biopsy or archival material <12 weeks) is required at baseline for biomarker analysis. Patients will receive abemaciclib 200 mg twice daily until unacceptable adverse events or disease progression. The primary objective is investigator-assessed objective response rate (ORR). Key secondary objectives include safety, radiographic progression-free survival, overall survival, PSA response rate, time to PSA progression, time to symptomatic progression, Ki-67 expression, patient-reported outcomes, and pharmacokinetics. Assuming an ORR of 15%, the study has over 73% power to observe a response rate of at least 12.5%. Accrual began in January 2021. Clinical trial information: NCT04408924.

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0–1, and disease progression after one to four prior treatment regimens were enrolled. Primary objective was to determine maximum tolerated dose (MTD); secondary objectives included evaluation of the tolerability and safety profile and pharmacokinetics of LY3295668. All patients received twice-daily (BID) oral LY3295668 in 21-day cycles in an ascending-dose schedule. Results Twelve patients were enrolled in phase 1 (25 mg, n = 8; 50 mg, n = 2; 75 mg, n = 2) and one patient was enrolled after. Overall, four patients experienced dose-limiting toxicities (DLTs) within the first cycle (75 mg: Grade 3 diarrhea [one patient], Grade 4 mucositis and Grade 3 corneal deposits [one patient]; 50 mg: mucositis and diarrhea [both Grade 3, one patient]; 25 mg: Grade 3 mucositis [one patient]). Patients exhibiting DLTs had the highest model-predicted exposures at steady state. Mucositis was the most common adverse event (67%), followed by diarrhea, fatigue, alopecia, anorexia, constipation, and nausea. Nine patients had best response of stable disease; the disease control rate was 69%. Conclusions MTD of LY3295668 was 25 mg BID. LY3295668 had a manageable toxicity profile and demonstrated activity in some patients with locally advanced or metastatic solid tumors. Trial registration ClinicalTrials.gov, NCT03092934. Registered March 22, 2017. https://clinicaltrials.gov/ct2/show/NCT03092934 .

BackgroundDeregulated Notch signaling is implicated in T‐cell acute lymphoblastic leukemia (T‐ALL)/T‐cell lymphoblastic lymphoma (T‐LBL). Crenigacestat (LY3039478) prevents cleavage of Notch proteins and may benefit patients with relapsed/refractory T‐ALL/T‐LBL.MethodsJJCB was a multicenter, nonrandomized, open‐label, dose‐escalation, phase 1 study in adult patients with relapsed/refractory T‐ALL/T‐LBL. Eligible patients received Crenigacestat orally 3 times per week plus dexamethasone at 24 mg twice daily on days 1 to 5 every other week in a 28‐day cycle. The starting level of Crenigacestat was 50 mg, and dose escalation was performed with a modified 3+3 scheme for the estimation of dose‐limiting toxicity (DLT) at the recommended dose level.ResultsIn total, 36 patients with T‐ALL (n = 31 [86.1%]) or T‐LBL (n = 5 [13.9%]) were treated with Crenigacestat and dexamethasone. Six patients (16.7%) experienced DLTs: 2 of 12 (16.7%) in the 75‐mg cohort (grade 4 gastrointestinal hemorrhage and grade 3 nausea, vomiting, and diarrhea), 1 of 15 (6.7%) in the 100‐mg cohort (grade 3 diarrhea), and 3 of 3 (100%) in the 125‐mg cohort (grade 3 diarrhea, nausea, and vomiting). The maximum tolerated dosewas 75 mg plus 24 mg of dexamethasone daily on days 1 to 5. Twenty‐eight patients (77.8%) experienced 1 or more treatment‐emergent adverse events related to the study treatment. The best overall response was a confirmed response, with 1 patient (2.8%) having a duration of response of 10.51 months. Six patients (16.7%) achieved stable disease, and 12 patients (33.3%) experienced progressive disease. The remaining 17 patients (47.2%) were not evaluable. The median event‐free survival was 1.18 months (95% confidence interval, 0.76‐2.14 months) among all groups. A pharmacodynamic analysis showed decreased plasma amyloid β levels.ConclusionsCrenigacestat demonstrated limited clinical activity at the recommended dose in adult patients with relapsed/refractory T‐ALL/T‐LBL.

TPS10561 Background: Aurora kinase A (AurA) has been implicated in high-risk neuroblastoma, including roles stabilizing and increasing expression of MYCN protein. AurA impacts the function of MYCN in mediating transcription in a cell cycle dependent manner, suggesting that neuroblastoma and other MYC/MYCN-driven tumors may be sensitive to AurA inhibition. LY3295668 is a selective AurA inhibitor. The lack of AurB inhibitory activity is hypothesized to minimize on-target hematologic toxicity associated with AurB inhibition. The molecule’s selectivity is intended to allow for continuous dosing at exposures associated with > 90% target inhibition at trough. In an analysis of LY3295668 antiproliferative effects in 560 cancer cell lines, neuroblastoma was among the most sensitive histologies tested. This screen also separately evaluated genomic predictors of response to LY3295668, with MYC/ MYCN amplification identified as among the strongest predictors of sensitivity to this agent. LY3295668 is currently being evaluated in early phase adult trials. The current trial (J10-MC-JZHD) was uniquely designed to hasten time to first-in-child oncology development for a rare unmet need of relapsed/refractory neuroblastoma patients. Methods: Study J1O-MC-JZHD (NCT04106219) is a multicenter, dual collaboration (NANT and ITCC), randomized, open-label, Phase 1 study of oral LY3295668 in children with relapsed/refractory neuroblastoma. A rolling 6 design will be followed for dose escalation in both a monotherapy cohort and a combination cohort testing LY3295668 together with cyclophosphamide and topotecan. The starting monotherapy dose will be equivalent to 80% of the adult maximum tolerated dose. Key eligibility criteria include recurrent/refractory neuroblastoma not amenable to curative treatment, age 2-21 years, mandatory archival tissue submission, ability to swallow capsules, and adequate hematologic and organ function. LY3295668 is administered in capsule form orally BID continuously. Primary objectives include assessments of safety and tolerability of study drug to identify RP2D as monotherapy and combination, and assess antitumor activity. Secondary objectives include assessment of the pharmacokinetic profile as monotherapy and in combination, and assessment of the relationship between study drug exposure and efficacy. Following determination of the RP2Ds, an expansion phase will randomize patients to monotherapy or to the combination arm. Enrollment began 16 Dec 2019 and is ongoing. Clinical trial information: NCT04106219.

Background Crenigacestat is a potent Notch inhibitor that decreases Notch signaling and its downstream biological effects. Here, we report the results from Part F of study 16F-MC-JJCA designed to evaluate the safety, pharmacokinetics (PK), and antitumor activity of crenigacestat with prednisone in advanced or metastatic cancer. The combination was planned to mitigate gastrointestinal toxicities. Methods Eligible patients (Study Part F) received crenigacestat loading dose (75 mg, escalating to 150 mg) administered thrice weekly (TIW) (F1) or twice weekly (BIW) (F2) for 2 weeks during Cycle 1, followed by 50 mg TIW from week 3 onwards. Prednisone was co-administered for 2 weeks in Cycle 1. Results Twenty-eight patients were enrolled; 11 in F1 (median age, 63 years), 17 in F2 (median age, 50 years). Dose-limiting toxicities were Grade 3 increased serum amylase and Grade 2 fatigue in F1, and Grade 4 hypophosphatemia and Grade 3 rash maculo-papular in F2. The maximum tolerated dose was 75 mg in F1 and 100 mg in F2. Best overall response was stable disease (F1, 6 [54.5%] patients; F2, 11 [64.7%] patients). Pharmacokinetic was dose proportional. Prednisone did not modify PK of crenigacestat, and both F1 and F2 achieved pharmacodynamics effects on evaluable tumor tissue samples. Conclusions This study demonstrated the potential use of prednisone to reduce gastrointestinal (GI) toxicities of a Notch inhibitor without affecting its PK. The safety profile observed was consistent with Notch pathway inhibitors, and the maximum tolerated dose was 75 mg TIW and 100 mg BIW in F1 and F2, respectively. ClinicalTrials.gov: NCT01695005.

TPS5591 Background: Despite recent advances, nearly all patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) experience disease progression and cancer-specific mortality. Persistent or reactivated androgen receptor (AR) signaling and/or activation of pathways in cross-talk with AR signaling are key drivers of mCRPC progression. Evidence suggests that AR signaling promotes translation of D-type cyclins resulting in cyclin-dependent kinase 4 and 6 (CDK4&6) activation and cell cycle progression. Abemaciclib is an oral selective inhibitor of CDK4&6 dosed on a continuous schedule, that is FDA-approved in combination with endocrine therapy or as monotherapy to treat HR+, HER2- metastatic breast cancer pts. Preclinical studies with prostate cancer cell lines and xenograft models showed that abemaciclib induces cell cycle arrest and tumor growth inhibition. The hypothesis is that addition of abemaciclib to AR targeted therapy may be an effective treatment for mCRPC pts. Methods: CYCLONE 2 (NCT03706365) is a phase II, randomized, double-blind, multicenter, placebo-controlled study to assess the safety and efficacy of abemaciclib in combination with abiraterone acetate plus prednisone (AA+P) as first-line treatment of pts with mCRPC. The study is designed in two parts. Part 1 is a 30-patient safety lead-in to determine the recommended phase II dose (RP2D; 150 mg or 200 mg, twice daily) of abemaciclib in combination with AA (1000 mg, once daily) + P (5 mg, twice daily). In part 2, 150 pts are randomized 1:1 to abemaciclib at the RP2D with AA+P or placebo with AA+P. Pts who received prior AA+P, enzalutamide, apalutamide, darolutamide, radiopharmaceuticals, or sipuleucel-T are excluded. Prior docetaxel for metastatic hormone-sensitive prostate cancer, but not for mCRPC, is allowed. Pts must have progressive mCRPC (by PSA and/or imaging) and an accessible metastatic lesion for tumor biopsy. The co-primary objectives are radiographic PFS (per RECIST1.1 for soft tissue and PCWG3 for bone) and time to PSA progression. Secondary objectives include safety, objective response rate, duration of response, OS, time to symptomatic progression, and pharmacokinetics. Assuming hazard ratios of 0.64 (rPFS) and 0.6 (PSA progression), the study is powered to 80% and 85%, respectively, to test the superiority of abemaciclib plus AA+P vs. placebo plus AA+P at one-sided α=0.1 using stratified log-rank tests. Part 1 is completed and part 2 is enrolling in 70 sites worldwide. Clinical trial information: NCT03706365 .

Background: LY3295668 erbumine (AK-01) is a selective, reversible, ATP-competitive small molecule inhibitor of aurora kinase A (AurA). LY3295668 erbumine treatment in xenograft and patient-derived xenograft models resulted in tumor growth arrest or regression of several tumor types with an acceptable safety profile. This study evaluated dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and safety of LY3295668 erbumine monotherapy in patients with locally advanced or metastatic solid tumors.Methods: This ongoing phase I/II, open-label, multicenter study enrolled patients with locally advanced or metastatic solid tumors, ECOG PS 0-1, estimated life expectancy ≥ 12 weeks, adequate organ function, disease progression after 1 - 4 regimens for locally advanced or metastatic disease and no history of clinically significant cardiac disease. The primary objective was to determine MTD; secondary objectives included evaluation of tolerability and overall safety profile of LY3295668 erbumine. All patients received oral, twice daily (BID) doses of LY3295668 erbumine in cycles of 21 days in a multiple ascending dose schedule. Adverse events (AEs) were graded per NCI CTCAE v4.03.Results: Twelve patients median age of 60 (range 39-74, 5 male and 7 female) were enrolled in the phase I study at the following dose levels: 25 mg (n=8); 50 mg (n=2); 75 mg (n=2). One patient in the 25 mg cohort experienced a DLT of grade (G) 3 mucositis. One patient in the 50 mg cohort experienced a DLT of G3 mucositis and G3 diarrhea. Both patients in the 75 mg cohort experienced DLTs (1=G3 mucositis, 1=G4 mucositis and G3 corneal deposits). The treatment-related AEs (TRAEs) observed in each cohort were as follows: in the 25 mg treatment group, six patients experienced various G1/2 TRAEs with only mucositis reported in > one patient (n=2); G3 TRAEs were anemia (n=1) and mucositis (n=1). In the two patients receiving 50 mg, G3 TRAEs were: mucositis (n=1), diarrhea (n=1), and upper chest rash (n=1). In the two patients receiving 75 mg, G3/4 TRAEs were: mucositis (n=2), corneal deposits (n=1), neutropenia (n=1) and diarrhea (n=1). There were no treatment-related deaths. During this study, three patients died due to disease progression: one patient died < 30 days and two patients died > 30 days after the last treatment dose. At the time of data lock, two of the eight patients in the 25 mg BID phase I cohort remained on treatment for ≥ 8 months. In addition to the 12 patients in phase I, one patient was enrolled in phase II after the MTD was determined, totaling 13 patients who received treatment in the entire study.Conclusion: The MTD of LY3295668 erbumine was determined to be 25 mg BID and found to be well tolerated in patients with locally advanced or metastatic solid tumors.Trial Registration: NCT03092934Citation Format: Quincy Chu, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, John R. Stille, Jill D. Kremer, Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Andrew Lithio, Patricia S. Smith, Gerald Batist. A Phase I/II study of aurora kinase A inhibitor, LY3295668 erbumine (AK-01): Safety as monotherapy in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT083.

Background: The aurora kinase family plays a vital regulatory role in mitotic and meiotic events, with aurora kinase A (AurA) critical to centrosome maturation, mitotic spindle formation and checkpoint activation. LY3295668 erbumine (AK-01) is an inhibitor of AurA with 1000-fold selectivity for inhibition of AurA over aurora kinase B (AurB). Pharmacokinetic-pharmacodynamic (PK-PD) nonclinical models have shown that 90% inhibition of AurA phosphorylation (pAurA) over an extended period (≥ 16 hours per day) was required to yield efficacy in H446 (small cell lung cancer) xenograft models. Nonclinical plasma LY3295668 concentrations associated with 90% pAurA inhibition (IC90) were estimated previously using a direct sigmoidal relationship between PK and pAurA. In this first-in-man study, PK of LY3295668 in patients with advanced/metastatic cancer were evaluated. Human PK profiles were simulated subsequently and compared to pAurA IC90 to estimate a human efficacious dose range. Methods: LY3295668 erbumine was administered to 13 patients with locally advanced or metastatic solid tumors over a dose range of 25 to 75 mg given twice daily (BID). In the first cycle, serial plasma PK samples were collected up to 8 hours on Day 1 and Day 15. Additional trough samples were obtained prior to dosing on Day 2, on Day 8 and at discontinuation if applicable. PK parameter estimations were performed using non-linear mixed effects models in NONMEM v7.3. Results: The population PK model was developed using 146 plasma concentrations collected from 13 patients. A 2-compartment PK model with first order absorption best described the disposition of LY3295668. Following oral administration, LY3295668 was rapidly absorbed with peak concentrations occurring within 1 to 2 hours. The estimated elimination half-life was approximately 21 hours; therefore, steady state was attained within 4 to 5 days of dosing. Simulations of plasma concentration-time profiles showed that at the maximum tolerated dose (MTD) of 25 mg BID, 90% of patients are expected to achieve steady-state plasma concentrations greater than the pAurA IC90 for the entire day. Patients with dose limiting toxicities (DLTs) had the highest model-predicted exposures amongst the 13 patients. Conclusion: At the MTD of 25 mg BID, steady state LY3295668 plasma concentrations are maintained above the pAurA IC90 for the entire dosing interval, exceeding the minimum requirements for efficacy associated with non-clinical xenograft models. Trial Registration: NCT03092934 Citation Format: Eunice Yuen, Yu-Hua Hui, Amparo de la Peña, Sonya C. Tate, John R. Stille, Andrew Lithio, Patricia S. Smith, Quincy Chu, Gerald Batist, Nathaniel Bouganim, Caroline Fortier, Sara Zaknoen, Jill Kremer. Population pharmacokinetics of an aurora kinase A inhibitor, LY3295668 erbumine (AK-01), in patients with locally advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT019.

The k ‐means algorithm is arguably the most popular nonparametric clustering method but cannot generally be applied to datasets with incomplete records. The usual practice then is to either impute missing values under an assumed missing‐completely‐at‐random mechanism or to ignore the incomplete records, and apply the algorithm on the resulting dataset. We develop an efficient version of the k ‐means algorithm that allows for clustering in the presence of incomplete records. Our extension is called k m ‐means and reduces to the k ‐means algorithm when all records are complete. We also provide initialization strategies for our algorithm and methods to estimate the number of groups in the dataset. Illustrations and simulations demonstrate the efficacy of our approach in a variety of settings and patterns of missing data. Our methods are also applied to the analysis of activation images obtained from a functional magnetic resonance imaging experiment.