Completed Dose Escalation Research Articles

First-in-human study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients (pts) with advanced solid tumors and in combination with fulvestrant in pts with advanced breast cancer.

TPS1128 Background: Oncogenic mutations in PIK3CA occur in ~35% of HR+, HER2– breast cancer (BC) and are frequent in multiple solid tumors. The approval of alpelisib, a non-mutant selective PI3Kα inhibitor, validates PI3Kα as a therapeutic target. However, inhibition of wild-type PI3Kα leads to significant toxicity, including hyperglycemia and rash. RLY-2608, a novel, oral allosteric PI3Kα inhibitor, is designed to overcome these limitations via mutant- and isoform-selective PI3Kα inhibition for greater target coverage, improved tolerability, and anti-tumor activity. ReDiscover (NCT05216432) is the ongoing, first-in-human study to investigate the maximum tolerated dose (MTD), recommended phase 2 doses (RP2Ds), safety, pharmacokinetics (PK), pharmacodynamics (PD) and anti-tumor activity of RLY-2608 monotherapy in pts with PIK3CA-mutant advanced solid tumors; and of RLY-2608 plus fulvestrant with or without ribociclib in pts with PIK3CA-mutant, HR+, HER2– BC. To date RLY-2608 plus fulvestrant has completed dose escalation; 400 and 600 mg BID is being investigated in the combination regimens, based on safety, PK, PD, and anti-tumor activity. Methods: This global, multi-center, dose escalation/expansion study of RLY-2608 monotherapy includes adult pts with advanced solid tumors who are refractory or intolerant to, or have declined, standard therapy. RLY-2608 is also being investigated in combination with fulvestrant and in combination with fulvestrant and ribociclib, each in previously treated pts with HR+, HER2– advanced/metastatic BC. Eligibility criteria include presence of a PIK3CA mutation (blood or tumor) per local assessment, ECOG performance status 0–1, evaluable disease per RECIST 1.1, and no prior treatment with a PI3K pathway inhibitor. RLY-2608 is administered daily in 4-week cycles. Adverse events (AEs) per CTCAE v5, PK, biomarkers (pAKT, mutant ctDNA and insulin pathway markers) and anti-tumor activity are assessed serially. Dose escalation employs a Bayesian Optimal Interval design to identify the MTD. Following dose escalation, expansion cohorts are enrolling patients with select PIK3CA-mutated solid tumors for treatment with RLY-2608 monotherapy and patients with HR+, HER2– metastatic BC for treatment with RLY-2608 plus fulvestrant with or without ribociclib. Primary endpoints are MTD/RP2D and AE profile; key secondary endpoints are PIK3CA genotype in blood and tumor, PK, biomarkers, and overall response rate. All dose expansion cohorts in ReDiscover are now enrolling in the United States and Europe. Clinical trial information: NCT05216432 .

A phase I open-label study of a novel IL-2Rβ/γ cytokine agonist, LTC004, in patients with advanced or metastatic solid tumors.

2652 Background: LTC004, a novel IL-2Rβ/γ cytokine agonist, designed to minimize toxicity with improved potency. It has selective affinity for the receptor IL-2Rβγ subunits, preferentially stimulates CD8+ effector T cells and natural killer cells which are associated with tumor killing, while minimizing the activation of immunosuppressive regulatory T cells. LTC004 has shown significant in vitro and in vivo anti-tumor activity in multiple cell lines and murine models respectively. Methods: This is a first-in-human, multicenter, open-label, dose-escalation and dose-expansion phase I study of LTC004 in advanced solid tumors. Dose escalation part assessed safety and tolerability of intravenous LTC004 with doses ranging from 3.0 to 360 µg/kg. The dose escalation schedule utilized an accelerated titration and Bayesian Optimal Interval (BOIN) design. Eligible pts with advanced solid tumor were required to have received prior standard therapy. LTC004 is administrated intravenously once every 3 weeks. Results: The study completed dose-escalation part (3.0 to 360 µg/kg) as of cutoff date (Jan 10, 2024). 17 pts of multiple tumor types (including non-small cell lung, cervical, colorectal, sarcoma, melanoma, parotid adenocarcinoma, thymic adenocarcinoma, gastric and ovarian cancers) were enrolled and received ≥1 dose of LTC004. At baseline, 12 pts (70.6%) had received ≥2 prior lines therapy, 11 pts (64.7%) had received prior targeted therapy, 10 pts (58.8%) had received prior immune checkpoint inhibitor (ICI) therapy. LTC004 generally well tolerated and no dose-limiting toxicities (DLTs) up to and including 360 µg/kg was observed. The most common TEAEs overall in ≥30% of pts were fever, white blood cell decreased, anemia, AST/ALT increased, neutrophil count decreased, GGT increased, nausea and hypotension. Most of the reported AEs were G1 and G2, all drug related events reversible and responsive to supportive care therapy. Fever can be resolved with standard anti-pyretic treatment or steroids, transient hypotension can be preventable with prophylactic fluid infusion. Of 17 pts enrolled evaluable for efficacy per RECIST v1.1, the ORR were 5.9% (1/17), DCR were 58.8% (10/17). A confirmed PR was achieved in a pMMR/MSS CRC patient with prior therapies including fluoropyrimidines, irinotecan, oxaliplatin, targeted therapy and TKI. The starting dose was 45µg/kg, titration to 90µg/kg after 4 consecutive doses at 45µg/kg Q3W. As of cutoff date, the patient sustained PR for 4.8 months with follow-up ongoing. Conclusions: LTC004 demonstrated encouraging anti-tumor efficacy including cold tumor, and well tolerated in patients with advanced or metastatic solid tumors. The further dose expansion in selected tumor types is ongoing, and evaluations in combination with other agents are being planned. Clinical trial information: NCT05666635 .

Abstract 7534: Tobemstomig, a novel bispecific checkpoint inhibitory antibody to preferentially block PD-1 and LAG-3 on CD8 TILs over Tregs

Abstract Checkpoint inhibitors targeting PD-1 have shown unprecedented clinical efficacy in several cancer indications and therefore have, revolutionized the standard of care. However, despite this advancement, only ~20-30% of the patients derive durable benefit from such a treatment. One of the suggested reasons for this limited success is the expression/activation of compensatory inhibitory pathways such as LAG-3 on tumor-reactive T cells. Therefore, it is envisioned that simultaneous antagonism of PD-1 and LAG-3 receptors would overcome this adaptive resistance mechanism and allow a more profound reinvigoration of tumor-reactive T cells. LAG-3 is constitutively expressed by regulatory T cells (on Tregs) and it has been reported that its blockade increases Treg suppressive function which could potentially off-sets the benefit of blocking LAG-3 on tumor-reactive CD8 T cells.We therefore developed a 1+1 PD1-LAG3 bispecific antibody, Tobemstomig, with a unique PD-1 binder recognizing a glycoepitope and more than 20 fold higher affinity than the LAG-3 binder which recognizes a novel and differentiated binding epitope (E3). This difference in affinities allows for an avidity driven selectivity gain to PD-1 and LAG-3 double positive T cells over and the following advantages over monospecific and other bispecific aPD-1/-L1 and aLAG-3 antibodies:1.improved targeting to tumor-reactive T cells rather than Tregs due to the selectivity gain and different expression patterns of PD-1 and LAG-3 on these two T cell types, 2.reduced internalization, 3.resistance to drug-shaving by macrophages due to Fc -silencing via P329G LALA,4.increased in vitro T cell effector functions even in the presence of Tregs, 5.in-vivo targeting and expansion of CD8 TILs, including stem-like T cells, and increase in T cell effector functions and6.superior in vivo tumor control/eradication compared to combination of monospecific anti-PD1 and anti-LAG3 antibodies,in several mouse models including Panc02 in syngeneic huPD-1xhuLAG3 dtg mice and BXPC3, WSU, OCI-Ly18 and BC004 in humanized mice Tobemstomig has completed dose escalation and is currently tested in a composite proof of concept Ph2 trial in several solid tumor indications. Citation Format: Laura Codarri-Deak, Patrick Aaron Weber, Valeria Nicolini, Christian Klein, Pablo Umana, Stefan Seeber, Mario Perro, Stephane Leclair. Tobemstomig, a novel bispecific checkpoint inhibitory antibody to preferentially block PD-1 and LAG-3 on CD8 TILs over Tregs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7534.

Abstract 3148: ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers

Abstract Lung cancer has the highest rates of incidence (2.1 million cases/year) and mortality (1.8 million deaths/year) among all cancers worldwide. Approximately 15% of lung cancers are small cell lung cancer (SCLC). SCLC is typically diagnosed at late stages, with approximately 70% of patients having extensive stage disease at time of diagnosis. Unfortunately, these patients have a dismal 5-year survival rate of approximately 3%. In contrast to non-small cell lung cancer (NSCLC), there has been little advancement in the treatment of SCLC, with no biomarker directed therapies available for patients. SEZ6 is overexpressed in most SCLC’s and other neuroendocrine tumor types. This overexpression and limited normal tissue expression suggest SEZ6 would be a good target for the development of an antibody drug conjugate (ADC). Validation of SEZ6 as an ADC target was supported by signs of clinical activity for ABBV-011, a SEZ6-targeting calicheamicin ADC. Preclinical and clinical data suggest an increased therapeutic index for Top1i ADCs relative to calicheamicin ADCs. Furthermore, Top1i inhibition is an effective mechanism of action in SCLC with topotecan approved in 2L, although significant toxicity limits broad utility. As such, we hypothesized that a SEZ6-Top1i ADC would enable effective Top1 inhibition in tumor cells and reduce toxicity relative to ABBV-011 or systemic chemotherapy, driving increased therapeutic benefit. ABBV-706 is an ADC comprised of the same SEZ6 targeting antibody as ABBV-011 conjugated to AbbVie’s topoisomerase-1 (Top1) inhibitor. ABBV-706 is a potent anti-proliferative agent in SEZ6 positive SCLC cell lines, with sub- to low-nanomolar activity. SEZ6 dependence was demonstrated by the correlation of SEZ6 mRNA expression to ABBV-706 growth inhibition. On-target Top1i activity was confirmed in cells treated with ABBV-706 as measured by dose-dependent induction of γ-H2AX, a marker of DNA damage, and G2/M arrest. ABBV-706 possessed superior anti-tumor activity compared to ABBV-011 in a panel of SCLC cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models with a range of SEZ6 expression levels. In addition, ABBV-706 had activity in the setting of resistance to cisplatin/etoposide (1L SoC in SCLC), in combination with cisplatin, and in SEZ6-expressing neuroendocrine liver and cervical PDX models. ABBV-706 has favorable pharmacokinetics and is well-tolerated in cynomolgus monkeys with bone marrow and gastrointestinal tract toxicities common to other Top1 inhibitors. ABBV-706 shows promise as an agent for the treatment of SCLC and other difficult to treat SEZ6 expressing neuroendocrine tumors. ABBV-706 has completed dose escalation, and dose expansion is currently ongoing in a Phase 1 FIH clinical study (NCT05599984). Citation Format: Emily J. Faivre, Marybeth A. Pysz, Eoghainín Ó hAinmhire, Laura Kreckler, Kelly Doyle, Aloma D'Souza, Zhiyong Ding, Trusha Sondkar, Dolonchampa Maji, Fan Zhao, Andrew Phillips. ABBV-706 is a novel SEZ6-targeted topoisomerase 1 inhibitor ADC for SCLC and other neuroendocrine cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3148.

Results from the Completed Dose Escalation Portion of the Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC®) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM)

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Fractionated Gemtuzumab Ozogamicin Followed By Non-Engraftment Donor Leukocyte Infusions for Relapsed/Refractory Acute Myeloid Leukemia

Background: Previous studies have shown durable AML patient responses following donor lymphocyte infusions (DLI) in the absence of engraftment in both the frontline and relapsed setting (Dey et al, BJH 2005, Colvin et al, BBMT 2009, Ai et al, Blood 2010). Herein we report results from the completed dose-escalation phase from our trial of fractionated dosing of gemtuzumab ozogamicin (GO) followed by non-engraftment mismatched allogeneic donor cells infusion in patients with relapsed/refractory (R/R) AML. In this trial, instead of engraftment, it is postulated that donor cells serve as a potent immune stimulator. Study Design and Methods: In this phase I/II study, GO 6-9mg/m 2 total dose was administered as a fractionated 2-3mg/m 2 dose (capped at 4.5mg) on days 1, 4, and 7, followed by infusion of HLA-mismatched (0-3/6 antigens) related donor cells on day 8 [NCT03374332]. The dose-escalation phase 1 cohort used a 3+3 design combining GO with donor leucocyte infusion (DLI) at dose 1-2x10 7 CD3+ cells/kg (Dose Level 1) or 1-2x10 8 CD3+ cells/kg (Dose Level 2). Patients enrolled in the phase II portion were treated at the maximum tolerated dose (MTD) level. Lab correlative studies were drawn pre and post DLI to assess immune effector cells and leukemic blast surface expression as well as cytokine release profiles. Patients 18 years of age and older with histologically confirmed R/R AML who had recurrence or progression after at least 1 prior standard treatment were eligible. Enrollees must have had no active systemic infections and adequate lung, liver, cardiac, and renal function with an ECOG PS 0-1. Patients in CR or CRi after initial treatment could receive up to 2 additional treatments with GO+DLI. Results: Eleven patients (7 men and 4 women) were enrolled into the study. The median age was 72 years (54-81 years) and patients had received 1-4 previous lines of treatment. All patients were refractory to hypomethylating agents and venetoclax. No patient was a candidate for allogeneic stem cell transplant at the time of study enrollment. Ten patients received 3/6 and one patient received 1/6 HLA mismatched donor cells from a first- or second-degree relative. The MTD was determined to be 2x10 8 CD3+ cells/kg. Three patients were enrolled on dose level 1 and eight patients were enrolled on dose level 2. Treatment was well tolerated with minimal Grade 3 or 4 non-hematologic adverse events attributable to the study ( Table 1). One patient at dose level 2 developed septic shock and died prior to DLI while another patient at dose level 2 developed cryptococcal fungemia and died within one week of DLI. No donor experienced a Grade 3 or 4 adverse event. All patients had fever post DLI that fit criteria for Grade 1 or 2 CRS while one patient developed Grade 3 CR. Two patients with Grade 2 CRS and one patient with Grade 3 CRS received tociluzimab. One patient attained a CR after one cycle of GO+DLI. All other patients had progressive disease. Ultimately the study was stopped early due to futility. Median IL-6 and IL-8 levels were higher in the first 3 patients at dose level 2 (605.5pg/mL and 218.5 pg/mL) compared to the three patients in dose level 1 (79pg/mL and 57.8 pg/mL) but the difference was not statistically significant. IL-10 levels were significantly higher in dose level 2 than dose level 1(125 vs 14.8 pg/mL, p=0.05) Conclusions: The MTD of DLI in combination with GO for relapsed/refractory AML patients is 2x10 8 CD3+ cells/kg. Treatment in an older relapsed/refractory population was well tolerated. Patients reliably developed fevers post DLI with Grade1 or 2 CRS. However, there was no evidence that fever development corresponded to a clinical benefit or that the addition of non-engraftment DLI augmented the effect of single agent gemtuzumab. Additional analysis of cytokine release profiles for the remaining patients as well as immune checkpoint inhibition on leukemic blasts for all patients will be presented at the meeting.

15-month safety and efficacy data after intraperitoneal treatment with 224Radium-labelled microparticles after CRS-HIPEC for peritoneal metastasis from colorectal cancer.

3518 Background: Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis. Improved survival can be achieved by extensive cytoreductive surgery (CRS), frequently used together with hyperthermic intraperitoneal chemotherapy (HIPEC), with median time to recurrence around 12 months. Radspherin is a novel treatment principle based on the delivery of short range and cytotoxic alpha particles emitted during the decay of 224Ra. Alpha particles have high linear energy transfer and a radiation range less than 100 µm (3-10 cell diameters), generating highly localized and effective radiation with non-repairable double-strand DNA breaks in affected cells. Our hypothesis is that Radspherin produces an alpha-particle radiation field exclusively to the surfaces and liquid volumes of the peritoneum, delivering lethal doses to remaining micrometastasis in the peritoneal linings and eradicate free-floating tumor cells after surgical resection, thus assumingly prolonging time to recurrence and potentially overall survival. Methods: A phase 1/2a study (EudraCT 2018-002803-33) is ongoing to evaluate safety, tolerability and signal of efficacy of Radspherin injected intraperitoneally two days after CRS-HIPEC. After completion of dose escalation (1-2-4-7 MBq), an activity-dose of 7 MBq was recommended. Assessment of safety and efficacy (diagnostic imaging) was performed every three months. Safety data and progression-free survival (PFS) at 15 months are presented. Results: Twenty-three patients (pts) were enrolled across cohorts (safety population), of these 12 pts received the recommended dose of 7MBq, 9 pts single dose and 3 pts split dose (3,5 MBq x2). Twelve pts had synchronous PM and 11 metachronous PM. Median age was 64 years (28-78), 70 % were female and median peritoneal cancer index was 7 (3-19). To date, 271 adverse events (AE) were reported, whereof only 7 (all grade 1-2) were deemed related to Radspherin. Fourteen serious adverse events (SAEs) in 8 pts have been reported, none considered related to Radspherin. At 15 months, 9 out of 23 pts (39 %) had recurred, whereof 4 pts recurred in the peritoneum. In the expansion cohort (7MBq), 3 out of 12 pts (25 %) had recurred and none of these pts had peritoneal recurrences. Median PFS was not reached in the two populations. Conclusions: Radspherin was well tolerated with no related SAEs reported. At 15 months median PFS has not been reached and none of the patients at recommended dose had peritoneal recurrences. The results are encouraging and warrant further exploration of Radspherin as a novel treatment principle in clinical trials. Clinical trial information: NCT03732781 .

Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.

2536 Background: PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. We had completed dose escalation from 1mg/kg to 45mg/kg and had not found DLT/MTD. In a Phase Ib dose expansion and Phase IIa studies we are evaluating the safety and preliminary anti-tumor activity of PM8002 as a monotherapy. Here, we provide an update of PM8002 Phase Ib/IIa results. Methods: During Phase Ib dose-expansion and Phase IIa studies, the majority of patients received PM8002 at 20mg/kg Q2W or 30mg/kg Q3W as a monotherapy (recommended phase II doses). The primary endpoint was ORR with secondary endpoints/objectives including safety. Results: As of Feb 3, 2023, 263 patients of advanced solid tumor with prior 0 to 4 line systematic treatment had been enrolled (1mg/kg Q2W [n=1], 10mg/kg Q2W [n =1], 20mg/kg Q2W [n=190], 20mg/kg Q3W [n=4], 30mg/kg Q2W [n=4], 30mg/kg Q3W [n=52], and 45mg/kg Q3W [n=11]). The median duration of exposure was 10.6 weeks (range, 0.1—51.0). Of the 263 enrolled patients, 211 had completed their first evaluation for efficacy. The overall ORR, regardless of tumor type, was 15.2% (32/211) with 32 PRs (20 confirmed PRs), and the DCR was 75.4% (159/211) per RECIST 1.1. Twenty-five patients with cervical cancer had an ORR of 28% (7/25). Twenty-six patients with renal cell carcinoma had an ORR of 26.9% (7/26). Twenty-six patients with platinum-resistant ovarian cancer had an ORR of 15.4% (4/26), and 27 patients with NSCLC (with EGFR mutations) had an ORR of 18.5% (5/27). Any-grade TRAEs occurred in 68.8% patients (181/263), with 18.3% Grade ≥3 (48/263). The most common TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), Aspartate aminotransferase (9.9%), Alanine aminotransferase increased (9.5%), Hypoalbuminemia (8.7%), and increased gamma-glutamyl transferase levels (6.8%). Thirty-six patients (13.7%) discontinued PM8002 due to TRAEs. No death-related cases occurred, and most patients remain on treatment. Conclusions: PM8002 showed encouraging antitumor activity and good safety in patients with advanced solid tumors. Phase 1b/IIa of PM8002 as a monotherapy and Phase II combination trials of PM8002 with chemotherapy are ongoing for multiple indications. Clinical trial information: ChiCTR2000040552.

A phase 2 expansion study of ARV-766, a PROTACandrogen receptor (AR) degrader, in metastatic castration-resistant prostate cancer (mCRPC).

TPS290 Background: Patients with mCRPC inevitably develop resistance to available therapies and lack curative options. In patients treated with novel hormonal agents (NHAs), mutations can develop in the ligand-binding domain (LBD) of the AR gene, some of which are associated with resistance to current therapies and disease progression. ARV-766 is a novel, potent, orally bioavailable proteolysis targeting chimera (PROTAC) protein degrader that degrades not only wild-type AR but also clinically relevant AR LBD mutants, including the most prevalent AR L702H, H875Y, and T878A mutations. Here we describe a phase 2 expansion study to evaluate the clinical activity and safety of ARV-766 in men with mCRPC who have experienced disease progression on prior NHA therapy. Methods: This phase 2 cohort expansion is part of an open-label, first-in-human, phase 1/2 clinical trial of ARV-766 in men (aged ≥18 years) with histologically, pathologically, or cytologically confirmed mCRPC and Eastern Cooperative Oncology Group performance status score of 0 or 1. Ongoing androgen deprivation therapy with a gonadotropin-releasing hormone analog or inhibitor or orchiectomy is required. Patients enrolled in the cohort expansion must have received 1–3 prior NHAs (eg, abiraterone or enzalutamide) and ≤2 prior chemotherapy regimens. Following completion of dose escalation in the phase 1 portion of the study, which is evaluating the safety and tolerability of ARV-766, 2 doses (100 mg and 300 mg administered orally once daily in 28-day cycles) were selected for the phase 2 cohort expansion. The primary objectives of the cohort expansion study are to evaluate the antitumor activity of ARV-766 based on the overall response rate (per Response Evaluation Criteria in Solid Tumors) and the rates of prostate-specific antigen (PSA) declines of 30% (PSA30) and 50% (PSA50). Enrollment in the phase 2 expansion study is ongoing. Clinical trial information: NCT05067140 .

Anti-CD73 antibody activates human B cells, enhances humoral responses and induces redistribution of B cells in patients with cancer

BackgroundCD73 is widely expressed on immune cells playing a critical role in immunomodulatory functions including cell adhesion and migration, as a costimulatory molecule for T cells and in production of...

Abstract CT002: BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors

Abstract Background: BNT211 comprises two drug products, a chimeric antigen receptor (CAR)-T cell product candidate that targets the tumor specific antigen claudin 6 (CLDN6) and a CAR-T cell-Amplifying RNA Vaccine (CARVac). In mice, CARVac mediates expansion of adoptively transferred CAR-T cells, improving their persistence and functionality. BNT211 aims to establish CAR-T cell therapy for CLDN6-positive solid tumors. Methods: This first-in-human, open label, multi-center trial involves a bifurcated 3+3 design with CLDN6 CAR-T cell dose escalations for both monotherapy (Part 1) and combination with CARVac (Part 2) following lymphodepletion. In Part 2, CARVac is applied q2/3w up to 100 days post CAR-T cell transfer, including a one-step intra-patient dose escalation followed by q6w maintenance dosing. Patients with CLDN6-positive relapsed or refractory solid tumors without further standard treatment options and ECOG 0-1 are eligible for recruitment. Results: As of 19th Jan 2022, 16 patients have been treated, with CAR-T cell transfer performed at dose levels (DLs) 1 and 2 for parts 1 and 2. In total, 37 ≥G3 AEs related to the drug product (mainly cytopenia, or transaminase and lipase elevations without clinical correlates) and 2 DLTs (G4 cytopenia at DL2, part 1 and G4 hemophagocytic lymphohistiocytosis at DL2, part 2) were reported (all resolved). Pronounced cytopenia occurred in patients with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplantation. For these patients a lymphodepletion-free/reduced cohort was recently opened. Analysis of CAR-T cell frequency in peripheral blood revealed robust engraftment in all patients, with peak engraftment around day 17. Manageable cytokine release syndrome (G1-2) without any signs of neurotoxicity was observed in 8 patients. Administration of CARVac resulted in transient flu-like symptoms resolving within 24 h. Preliminary efficacy data of 12 evaluable patients 6 weeks after infusion showed 5 patients with PRs (with 39-49% shrinkage of target lesions), 6 with SD and 1 patient with PD (ORR 42%; DCR 92%), with responses seen in testicular and ovarian cancer patients. At 12 weeks, 5 of the 6 patients with PRs showed deepening of responses (50-73% shrinkage). In addition, one testicular cancer patient was treated with a 50% lymphodepletion regime and showed PR after 6 weeks. Conclusions: CLDN6 CAR-T cells ± CARVac show an acceptable safety profile at doses tested and encouraging signs of clinical activity. Data from the completed dose escalation phase will be presented. Acknowledgements: BNT211-01 is funded by BioNTech Cell & Gene Therapies GmbH. Trial registration: Clinicaltrials.gov: NCT04503278. Ethics approval: Ethics & Institutional Review Board approvals were obtained from the respective participating countries prior to initiation of the trial. Citation Format: John BAG Haanen, Andreas Mackensen, Christian Koenecke, Winfried Alsdorf, Eva Wagner-Drouet, Daniel Heudobler, Peter Borchmann, Carsten Bokemeyer, Sebastian Klobuch, Alexander Desuki, Florian Lüke, Erol Wiegert, Catrine Schulz, Benjamin Rengstl, Liane Preussner, Özlem Türeci, Ugur Sahin. BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT002.

Open-label, dose-escalation, and expansion trial of CA-4948 in combination with ibrutinib in patients with relapsed or refractory hematologic malignancies.

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

A phase 1 multiple-ascending dose study to evaluate the safety and tolerability of XmAb23104 (PD-1 x ICOS) in subjects with selected advanced solid tumors (DUET-3).

2604 Background: XmAb23104 is a bispecific antibody targeting T cells that simultaneously express PD-1, an immune checkpoint, and ICOS, a costimulatory molecule expressed after T cell activation. DUET-3 is a Phase 1, first-in-human, dose-escalation and expansion study in subjects with advanced solid tumors, designed to assess safety, tolerability and to identify the maximum tolerated dose (MTD) of XmAb23104. Secondary objectives are to assess pharmacokinetics (PK), immunogenicity, and preliminary anti-tumor activity. We report preliminary data from the completed dose-escalation phase. Methods: A 3+3 monotherapy dose escalation with 9 dose levels from 0.002 to 15 mg/kg has been completed. Subjects with measurable disease who progressed on prior standard therapy were eligible. A minimum 6-week washout from prior pembrolizumab was required. XmAb23104 was administered biweekly and RECIST 1.1 assessment was performed every 8 weeks. Results: Sixty-two subjects were treated in escalation at doses up to 15 mg/kg; no dose-limiting toxicities were observed and an MTD was not reached. These subjects had advanced disease, 92% were Stage IV at screening, the median number of prior therapies was 3, and 37% had previous checkpoint therapy. Thirty-seven subjects (59.7%) experienced a treatment-related adverse event (TRAE); the most common were diarrhea (9.7%), decreased appetite (9.7%), and fatigue (9.7%). The majority of TRAEs were Grades 1 or 2, with 6 subjects (9.7%) having a Grade 3 or higher TRAE. Thirteen immunotherapy-related adverse events (irAEs) occurred in 8 subjects; no individual irAE occurred in more than 1 subject. Most irAEs were mild (Grades 1 and 2) with 1 Grade 3 pruritus and 1 asymptomatic Grade 4 lipase elevation. Partial responses were observed in 3 subjects (sarcoma; prior PD-1 head and neck squamous cell carcinoma [HNSCC] and renal cell carcinoma [RCC]), and stable disease > 12 months was observed in 2 subjects with colorectal cancer (CRC; 1 MSS and 1 MSI-H). A dose of 10 mg/kg was selected after consideration of PK, safety, and clinical activity data in consultation with the investigators and continues to be evaluated in the expansion part of the study. Conclusions: The dose escalation part of this study indicates XmAb23104 was generally well tolerated at doses up to 15 mg/kg and has shown clinical activity in subjects with advanced solid tumors. CTLA4 blockade has been found to increase the frequency of ICOS-expressing T cells in prostate cancer, bladder cancer, melanoma, and hepatocellular cancer (Chen, 2009; Liakou, 2008; Wei, 2017) and may be applicable to other immunogenic tumor types. XmAb23104 is currently being studied alone or in combination with ipilimumab in expansion in non-squamous non-small cell lung carcinoma, melanoma, CRC, undifferentiated pleomorphic sarcoma, HNSCC, and RCC. Clinical trial information: NCT03752398.

A Phase 1 Dose-Escalation Study of the Oral CDK Inhibitor Voruciclib in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia (AML): Preliminary Results of the Completed Dose Escalation Stage in AML

A Phase 1 Dose-Escalation Study of the Oral CDK Inhibitor Voruciclib in Patients with Relapsed/Refractory B-Cell Malignancies or Acute Myeloid Leukemia (AML): Preliminary Results of the Completed Dose Escalation Stage in AML

1010P Intratumorally administered CV8102 in patients with advanced solid tumors: Preliminary results from completed dose escalation in study 008

CV8102 is a non-coding, non-capped RNA complexed with a carrier peptide activating the innate (via TLR7/8, RIG-I) and adaptive immune system. An ongoing phase I trial (CV-8102-008) is investigating it. CV8102 either as a single agent or in combination with systemic anti-PD-1 antibodies in patients with advanced cutaneous melanoma (cMEL), squamous cell carcinoma of the skin (cSCC) or head and neck (hnSCC) and adenoid cystic carcinoma (ACC). The dose escalation part of this study has been completed, and preliminary results from this part are reported here. Study CV-8102-008 is an open-label, cohort-based, dose escalation and expansion phase I study. Eight intratumoral injections of CV8102 are being administered initially over a 12-week period. Primary objective of the dose-escalation part is to determine the maximum tolerated dose and recommended phase II dose. As of February 5, 2021, 33 patients have been treated with CV8102 as a single agent (25-900 μg) and 25 patients have received CV8102 (25-900 μg) in combination with anti-PD-1 antibodies. At CV8102 dose levels of 25 μg 600 μg no dose limiting toxicities were reported in the single agent and anti PD-1 combination cohorts. At the 900 μg dose level (single agent) 1 out of 6 patients experienced a dose limiting toxicity (transient G3 transaminase increase in the context of G2 CRS) after the second injection of CV8102. Based on recommendation of the DMC, a dose of 600 μg was determined as recommended phase II dose for both, monotherapy and combination therapy. Overall, most frequent treatment emergent adverse events were mild to moderate fatigue, fever, headache or chills. Regression of injected and distant noninjected lesions was observed in several patients in the single agent (including 1 CR and 2 PRs) and the anti-PD-1 combination cohorts (including 1 PR per RECIST 1.1.). Updated safety and efficacy results will be presented. CV8102 showed an acceptable safety profile and preliminary evidence of clinical efficacy as single agent and in combination with anti-PD-1-antibodies.

A Phase I, Open Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma

A Phase I, Open Label, Multicenter Trial of Oral Azacitidine (CC-486) Plus R-CHOP in Patients with High-Risk, Previously Untreated Diffuse Large B-Cell Lymphoma, Grade 3B Follicular Lymphoma, or Transformed Lymphoma

Phase 1 trial of seclidemstat (SP-2577) in patients with relapsed/refractory Ewing sarcoma.

11514 Background: Ewing sarcoma (ES), a rare bone and soft tissue sarcoma mainly of adolescents and young adults, is characterized by a chromosomal translocation resulting in a fusion oncoprotein. Lysine specific demethylase 1 (LSD1) has been shown to associate with the fusion oncoprotein and promote oncogenic transcriptional activity making LSD1 an attractive target for ES treatment. Seclidemstat is a novel, selective, reversible oral LSD1 inhibitor capable of inhibiting both LSD1’s catalytic and scaffolding functions. This is the first report of an LSD1 inhibitor in a Phase 1 trial focused exclusively on ES. Methods: SALA-002-EW16 is a Phase 1 trial of single agent seclidemstat in patients (pts) with relapsed or refractory (R/R) ES. This report describes the completed monotherapy dose escalation. Pts > 12 years received oral SP-2577 twice daily in 28-day cycles under fasting conditions at the assigned dose level. The primary objective was safety and tolerability. Secondary objectives include to determine maximum-tolerated dose (MTD), recommended Phase 2 dose (RP2D), preliminary efficacy, pharmacokinetics, and pharmacodynamics. Results: As of December 30, 2020, 27 pts with R/R ES were enrolled. Pts received escalating doses of SP-2577 at 75 (n = 1), 150 (n = 2), 300 (n = 4), 600 (n = 6), 900 (n = 8), or 1200 mg PO BID (n = 6). The median age was 25 years (range 15–68), 63% were male, and pts had received a median of 3 (range 2–12) prior systemic therapies. There were no treatment-related deaths. The most common ( > 5%) grade 3 treatment-related adverse events (TRAEs) were vomiting (15%), abdominal pain (11%), and hypokalemia (11%). One pt (4%) with grade 3 pancreatitis reported a grade 4 AE of elevated lipase. All remaining grade 3 TRAEs, including hematological TRAEs, were reported in only one pt each. Four pts discontinued study for an AE (weight loss, pancreatitis, vomiting, abdominal pain). Three pts had a dose reduction. The first cycle dose-limiting toxicities were gastrointestinal-related AEs observed in 2 pts at 1200 mg BID. Thus, the MTD/RP2D was established as 900 mg BID. Peak plasma concentrations occurred at a median of 4 hours (h) post-dose and median terminal half-life was 6 h; exposure was dose proportional through 900 mg BID. One pt at 600 mg BID achieved a reduction in target lesions starting at end of C2 with further target lesion tumor shrinkage through end of C4 and C6 (maximum 76% tumor shrinkage) with coincident new non-target lesion appearance at end of C2. Of pts evaluable for response at the end of C2 (12 pts), two additional pts (16.7%) at 600 mg BID and 900 mg BID had overall stable disease. Conclusions: Seclidemstat has a manageable safety profile with proof-of-concept preliminary activity in heavily pretreated pts with relapsed/refractory ES. These data support the planned Phase 2 expansion of seclidemstat as single agent and in combination with chemotherapy in ES and other sarcomas that share similar translocations. Clinical trial information: NCT03600649.

The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alström syndrome: Phase 3 trial design

BackgroundA phase 2 trial has suggested that treatment with the melanocortin-4 receptor (MC4R) agonist setmelanotide is associated with a decrease in hunger and weight-related outcomes in participants with Bardet-Biedl syndrome (BBS) and Alström syndrome. Here, we present the study design of an ongoing, randomized, double-blind, placebo-controlled, phase 3 trial to assess the long-term efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS or Alström syndrome (ClinicalTrials.gov identifier: NCT03746522). MethodsIt was initially planned that ~30 participants aged ≥6 years with a clinical diagnosis of BBS or Alström syndrome would be enrolled. Participants with obesity as defined by a body mass index ≥30 kg/m2 (in those aged ≥16 years) or a weight >97th percentile (in those aged 6–15 years) are included. Participants are initially randomized in a 1:1 ratio to receive setmelanotide or placebo for 14 weeks (period 1). Following period 1, all participants receive 38 weeks of open-label treatment with setmelanotide (period 2). In each treatment period, setmelanotide is administered at 3 mg once a day following completion of dose escalation. The primary endpoint is the proportion of participants aged ≥12 years achieving a clinically meaningful reduction from baseline (≥10%) in body weight after ~52 weeks (eg, following period 2). Safety and tolerability are assessed by frequency of adverse events. ConclusionsThis pivotal trial is designed to evaluate the efficacy and safety of setmelanotide for the treatment of obesity and hyperphagia in individuals with BBS and Alström syndrome. Submission categoryStudy Design, Statistical Design, Study Protocols.

Abstract PS11-26: A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer

Abstract Background: Targeting the estrogen receptor (ER) has proven to be one of the most successful strategies in treating HR+ (ER+ and PR+) and HER2- breast cancer. Selective estrogen receptor degraders (SERD) can be used as single agents or in combination with CDK4/6 inhibitors such as palbociclib. Fulvestrant is currently the only approved agent in its class and is limited by poor oral bioavailability necessitating monthly intramuscular injections. D-0502 is an orally bioavailable SERD with potent activity in various HR+ and HER2- breast cancer cell lines and xenograft models. Its combination with palbociclib in both MCF-7 xenograft models and ESR-1 mutated (Y537S) patient derived breast cancer xenograft models resulted in further tumor growth inhibition or regression. Drug metabolism and pharmacokinetic studies both in vitro and in vivo demonstrated that D-0502 exhibits favorable PK profiles suitable for clinical development. Methods: A first-in-human phase 1 study was conducted to evaluate D-0502 in women with advanced or metastatic HR+, HER2- breast cancer (MBC) (NCT03471663). The primary objective is to characterize the safety and tolerability of D-0502 and D-0502 in combination with palbociclib, to identify an MTD and/or RP2D. The secondary objectives are to evaluate the PK properties and the preliminary anti-tumor activities. Patients received D-0502 orally once daily in 28-day cycles. The study has completed dose escalation (phase 1a), and dose expansion and combination studies (phase 1b) are ongoing. In phase Ia, patients were enrolled and evaluated using conventional 3+3 dose-escalation to identify the MTD of D-0502 as a single agent. The phase 1b was divided into 2 stages. In Stage 1, D-0502 was evaluated with palbociclib at a dose below the MTD first before escalating to the MTD. Stage 1 also included patients in China treated at a dose below and at the MTD as single agent as well as in combination with palbociclib. Stage 2 will further evaluate the MTD for both single agent and combination of D-0502 with palbociclib. Results: At the time of this abstract submission, phase 1a dose escalation is completed, R2PD has been identified, and no DLTs were observed. PK analysis of D-0502 indicates a dose proportional increase in exposure as the dose increases, and the exposure has exceeded the potential therapeutic exposure level based on preclinical studies. The Phase Ib Stage 1 portion has also completed enrollment and the study is currently enrolling patients into phase Ib Stage 2. D-0502 as a single agent or in combination has been well tolerated with radiological tumor response and clinical benefit response (CBR) observed. Safety, PK and preliminary efficacy data will be reported at the meeting presentation. Conclusion: A first-in-human phase 1 study of D-0502 has been initiated in women with advanced or metastatic HR-positive and HER2-negative breast cancer. D-0502 has been well tolerated and achieved significant exposure and preliminary clinical activity in patients. Further results will be presented at the meeting. Citation Format: Cynthia Osborne, Donald A Richards, Sharon T Wilks, Sami Diab, Dejan Juric, Kate Lathrop, Andrea Silber, William Edenfield, Amardeep Aulakh, Ben Cho, Binghe Xu, Tao Sun, Quchang Ouyang, Yanxia Shi, Kathryn Stazzone, Zhe Shi, Ling Zhang, Yaolin Wang, Erika P Hamilton. A phase 1 study of D-0502, an orally bioavailable SERD, for advanced or metastatic HR-positive and HER2-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-26.

Combination Hydralazine and Isosorbide Dinitrate in Dialysis-Dependent ESRD (HIDE): A Randomized, Placebo-Controlled, Pilot Trial.

Combination therapy with isosorbide dinitrate (ISD) and hydralazine (HY) reduces heart failure mortality. The safety and tolerability in individuals requiring maintenance hemodialysis (HD) is unknown. Single-center, randomized, placebo-controlled, double-blind pilot trial to explore safety and tolerability of ISD/HY in maintenance HD. Participants were randomized to placebo or combination ISD/HY. Dose was escalated over 3 weeks from ISD 10 mg/HY 10 mg to ISD 40 mg/HY 75 mg three times per day with the maximum tolerated dose maintained for the subsequent 21 weeks. Primary endpoints included adverse events, adverse events precluding further treatment with study medication, serious hypotension (i.e., requiring hospitalization or emergency room visit), and recurrent intra-dialytic hypotension. Efficacy signals included change in mitral annular E' velocity by tissue Doppler echocardiography and change in left ventricular coronary flow reserve on positron emission tomography. A total of 17 individuals were randomized to ISD/HY (N=7) or placebo (N=10). All participants assigned to ISD/HY completed dose escalation to 40/75 mg, but dose reductions were required in two participants. No participants discontinued therapy. There were no serious hypotension events. Recurrent intradialytic hypotension was less frequent with ISD/HY (0.47 events/patient-year) than placebo (1.83 events/patient-year, P=0.04). In contrast, nausea (ISD/HY, 1.90 events/patient-year; placebo, 0.50 events/patient-year, P=0.03) was significantly more frequent, and headache and diarrhea were numerically but not significantly more frequent with ISD/HY. Adverse events were more frequent with ISD/HY (11.4 events/patient-year) than placebo (6.31 events/patient-year). We did not detect between-group differences in the change in E' (P=0.34); ISD/HY showed a mean increase of 0.6 cm/s (SD 1.1), and placebo showed a mean decrease of 0.04 cm/s (SD 0.9). Changes in coronary flow reserve were minimal, -0.3 (0.2) with ISD/HY and -0.03 (0.5) in the placebo group, P=0.19. ISD/HY appears to be well tolerated in patients being treated with maintenance HD, but headache and gastrointestinal side effects occur more frequently with ISD/HY compared with placebo.