A first-in-human phase 1a/b trial of LY3484356, an oral selective estrogen receptor (ER) degrader (SERD) in ER+ advanced breast cancer (aBC) and endometrial endometrioid cancer (EEC): Results from the EMBER study.

1050 Background: Novel degraders and antagonists of ER are under evaluation in aBC, to overcome both ER mediated resistance and the bioavailability and dosing limitations of fulvestrant, the only approved SERD. ER is also overexpressed in ̃80% of EEC and endocrine therapy (ET) is utilized for these patients (pts). LY3484356, a novel, orally bioavailable SERD with pure antagonistic properties results in sustained inhibition of ER-dependent gene transcription and cell growth. Preclinically, LY3484356 shows favorable efficacy and pharmacokinetic (PK) properties, including antitumor activity in ESR1 mutants. Here we present the initial clinical data from EMBER, an ongoing first-in-human phase 1a/b trial of this novel agent. Methods: Phase 1a evaluated LY3484356 dose escalation (i3+3 design) in women with ER+, HER2- aBC (≤3 prior therapies for aBC following protocol amendment; prior ET sensitivity) and ER+ EEC (prior platinum therapy). Premenopausal women received a concomitant GnRH agonist. Key endpoints included determination of the recommended phase 2 dose, safety and tolerability, PK, and objective response rate and clinical benefit rate per RECIST v1.1. Results: As of the data cut (November 9, 2020), 28 pts (n = 24 aBC, n = 4 EEC) were enrolled at doses ranging from 200-1200 mg QD. Median age was 59 years (range, 35-80). Median number of prior therapies for aBC was 2 (range, 1-8; 6 pts enrolled prior to protocol amendment had received ≥4 prior therapies), including prior fulvestrant (46%), a CDK4/6 inhibitor (83%), and chemotherapy (33%). No dose-limiting toxicities were observed. Treatment-emergent adverse events (TEAEs) were mostly grade 1-2, including nausea (32%), fatigue (25%), and diarrhea (18%). The only grade 3 treatment-related AE was diarrhea (n = 1). TEAEs of bradycardia and QTc prolongation were not observed despite intensive central ECG monitoring. Dose-proportional increases in LY3484356 exposures were observed across all evaluated doses and t1/2 was 25-30 hours. At the starting dose level (200 mg QD), unbound LY3484356 exposures exceeded those achieved with fulvestrant. 16 of 28 pts were efficacy evaluable, with the remaining 12 pts ongoing prior to first scan. Among 16 evaluable pts, 11 (8 aBC, 3 EEC) had stable disease (10 pts ongoing), and 5 had progressive disease. RECIST responses were observed after the data cut and will be detailed at the meeting. Plasma ctDNA analysis indicated decreases in mutant allele frequencies, including mutant ESR1 in 9/12 (75%) evaluable pts across all dose levels. Conclusions: LY3484356 QD dosing shows favorable safety and PK properties, along with preliminary efficacy in pts with heavily pretreated ER+ aBC and EEC. Updated data will be presented at the meeting. Clinical trial information: NCT04188548 .

ICEPAC: A phase II multicenter study of avelumab combined with stereotactic ablative body radiotherapy (SABR) in metastatic castration-resistant prostate cancer (mCRPC).

86 Background: Studies investigating immune checkpoint inhibitors (ICI) in mCRPC have produced modest results. Radiation therapy may be synergistic with ICIs. We hypothesised that SABR would enhance anti-tumour activity of PD-L1 inhibitor avelumab in patients (pts) with progressive mCRPC. Methods: This phase II, single arm, multicentre study enrolled mCRPC pts following progression on ≥1 novel androgen receptor-directed therapy. Up to two lines of prior taxane chemotherapy were permitted. Pts received avelumab 10mg/kg IV q2weeks for a total of 24 weeks (12 cycles). A single fraction of 20Gy SABR was administered to 1-2 disease sites within five days prior to first and second doses of avelumab. Primary endpoint was disease control rate (DCR); secondary endpoints were PSA response (PSA50), overall response rate (ORR), radiographic progression-free survival (rPFS), overall survival (OS) and safety. Radiographic disease assessment (CT and bone scintigraphy) was performed after cycles 6 and 12 of avelumab treatment. Following enrolment of 14 pts, a protocol amendment allowed avelumab beyond 12 cycles in pts with disease control at 24 weeks. Results: Thirty-one pts were enrolled, with 30 evaluable for the primary endpoint. Median follow-up was 18 months (mo). Pt characteristics: median age 71 years (IQR 64-75), bone-only disease 42%, visceral disease 16%, prior taxane chemotherapy 84%, treatment with both abiraterone and enzalutamide 13%. Seventy metastatic sites received SABR, most frequently to bone (90%) and soft tissue (29%) disease. Avelumab was given as second-line, third-line and fourth- or greater line systemic therapy in 29%, 42% and 29% of pts, respectively. Median cycles of avelumab administered was 9 (IQR 5-13). DCR (95% CI) was 50% (31-69) and 60% (32-84) in all-comers and soft tissue disease subgroup, respectively. Following protocol amendment, 7/17 pts (41%) received avelumab beyond 12 cycles. Incidence of grade 3-4 treatment-related AEs was 16% (no grade 5 events), with three pts requiring oral/IV corticosteroid therapy. Conclusions: Avelumab with SABR demonstrated durable disease control in treatment-refractory mCRPC with an acceptable toxicity profile. This combination warrants further investigation. Clinical trial information: ACTRN12618000954224. [Table: see text]

Efficacy and Safety of Degludec Compared to Glargine 300 Units/mL in Insulin-Experienced Patients With Type 2 Diabetes: Trial Protocol Amendment (NCT03078478)

Background: A head-to-head trial (NCT03078478) between insulin degludec and insulin glargine U300 with the primary objective of comparing the risk of hypoglycemia is being conducted. During trial conduct, safety concerns related to the glycemic data collection system led to a postinitiation protocol amendment, described here. Methods: This randomized (1:1), open-label, treat-to-target, multinational trial was initiated in March 2017 with a planned treatment period of 52 weeks (16 weeks titration + 36 weeks maintenance). Overall, ~1600 insulin-experienced patients at risk of developing hypoglycemia based on predefined risk factors were included. The protocol amendment implemented in February 2018 resulted in assuring patient safety and an extension of the total treatment period up to 88 weeks (16 weeks titration + variable maintenance 1 + 36 weeks maintenance 2). The original glycemic data collection system (MyGlucoHealth blood glucose meter + electronic diary) was discontinued because of safety concerns and replaced with an Abbott blood glucose meter and paper diary to collect self-measured blood glucose and hypoglycemic episodes. The primary endpoint of number of severe or blood-glucose confirmed symptomatic hypoglycemic episodes will be evaluated with the same analysis duration and statistical methods as the original protocol. Only relevant changes were implemented to maintain patient safety while permitting evaluation of the scientific objectives of the trial. Conclusions: These observations highlight the importance of safety surveillance during trial conduct despite the use of currently marketed glucose monitoring devices. The prompt protocol amendment and ensuing actions ensured that the scientific integrity of the trial was not compromised.

Non-superiority of lumen-apposing metal stents over plastic stents for drainage of walled-off necrosis in a randomised trial

ObjectiveAlthough lumen-apposing metal stents (LAMS) are increasingly used for drainage of walled-off necrosis (WON), their advantage over plastic stents is unclear. We compared efficacy of LAMS and plastic stents for WON drainage.DesignPatients with WON were randomised to endoscopic ultrasound-guided drainage using LAMS or plastic stents. Primary outcome was comparing total number of procedures to achieve treatment success defined as symptom relief in conjunction with WON resolution on CT at 6 months. Secondary outcomes were treatment success, procedure duration, clinical/stent-related adverse events, readmissions, length of hospital stay (LOS) and costs.Results60 patients underwent LAMS (n=31) or plastic stent (n=29) placement. There was no significant difference in total number of procedures performed (median 2 (range 2–7) LAMS vs 3 (range 2–7) plastic, p=0.192), treatment success, clinical adverse events, readmissions, LOS and overall treatment costs between cohorts. Although procedure duration was shorter (15 vs 40 min, p<0.001), stent-related adverse events (32.3% vs 6.9%, p=0.01) and procedure costs (US$12 155 vs US$6609, p<0.001) were higher with LAMS. Significant stent-related adverse events were observed ≥3 weeks postintervention in LAMS cohort. Interim audit resulted in protocol amendment where CT scan was obtained at 3 weeks postintervention followed by LAMS removal if WON had resolved. After protocol amendment, there was no significant difference in adverse events between cohorts.ConclusionExcept for procedure duration, there was no significant difference in treatment outcomes between LAMS and plastic stents. To minimise adverse events with LAMS, patients should undergo follow-up imaging and stent removal at 3 weeks if WON has resolved.Trial registration numberNCT02685865.

Frontline hyper-CVAD plus ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Updated results of a phase II study.

7013 Background: The combination of chemotherapy plus a TKI is highly effective in Ph+ ALL. In this phase II study, we evaluated the safety and efficacy of HCVAD in combination with the third-generation pan- BCR-ABL inhibitor, ponatinib. Methods: Patients (pts) with newly diagnosed Ph+ ALL received 8 cycles of HCVAD alternating with high dose MTX/Ara-C every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1. Initially ponatinib 45 mg daily was given indefinitely beginning at cycle 2. Due to concern for vascular events, a protocol amendment was made in which, beginning in cycle 2, pts in CR received 30mg daily and pts in CMR received 15mg daily. Rituximab and IT chemotherapy were given with the first 4 courses. After 8 cycles of HCVAD, pts in CR received maintenance with ponatinib, vincristine and prednisone for 2 years followed by indefinite ponatinib. Results: 64 pts have been treated, 10 of whom had received prior treatment with another regimen (8 in CR, 2 not in CR). Median age was 48 years (range, 21-80) and median follow-up was 33 months (range, 2-62). Median cycles received was 6 (range, 2-8). 63 pts (98%) achieved CR after 1 cycle; 1 pt achieved CRp. CCyR was achieved in 98%, MMR in 97% and CMR in 77%. Median time to CMR was 10 weeks (range, 2-96). Median times to platelet and ANC recovery in cycle 1 were 22 and 18 days, respectively, and for subsequent cycles were 22 and 16 days, respectively. Grade ≥3 pancreatitis was observed in 12 pts (19%), thrombotic events in 4 (6%) and MI in 3 (5%). 8 pts have died, with 2 deaths attributed to ponatinib (both from MI). No grade ≥3 vascular events occurred after the protocol amendment. 38 pts continue to receive treatment (7 in consolidation, 14 in maintenance and 17 post-maintenance). 10 pts (16%) underwent allogeneic SCT in CR1. 7 pts have relapsed, 3 of whom were still receiving ponatinib. The 3-year continued remission and OS rates were 79% and 76%, respectively. In a landmark analysis at 4 months, CR duration and OS did not differ significantly in pts with or without allogeneic SCT. Conclusions: HCVAD plus ponatinib is highly effective in pts with newly diagnosed Ph+ ALL, resulting in high rates of CMR and promising long-term survival. Clinical trial information: NCT01424982.