Escalation Phase Research Articles

A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

Biologic drugs and allergen immunotherapy: potential allies

Allergen-specific immunotherapy (AIT) is a proven efficacy treatment for allergic rhinitis (AR), asthma, and Hymenoptera venom allergy, but its use in food allergy (FA) is still under investigation. Because some efficacy and safety concerns still remain, biologic drugs, including omalizumab and dupilumab, have been studied as an adjunctive therapy to AIT for these conditions. In this article, the evidence supporting the use of monoclonal antibodies (mAbs) as an add-on therapy to AIT for FA, AR, asthma, and Hymenoptera venom allergy has been reviewed. The review will delve into the mechanisms of action of different mAbs, their efficacy, and how they can be integrated into personalized medicine approaches to treat allergic diseases. Furthermore, future research areas will be considered. Evidence suggests that omalizumab in combination with AIT may be a beneficial option for respiratory allergies or food desensitisation, especially during the escalation or build-up phase, when adverse events are more frequent. Currently, there is a small number of well-structured clinical trials in Hymenoptera venom allergy, and the available data consist mainly of single-case reports that provide information of limited value. Dupilumab has been studied as adjunctive therapy in patients with respiratory and FAs. Clinical trials are ongoing to evaluate the efficacy of dupilumab as monotherapy or as an adjunct to oral immunotherapy (OIT) in peanut allergy. Other studies are investigating the use of dupilumab in patients with multiple FAs and as an adjunct to milk OIT. Overall, mAbs have the potential to improve outcomes in various allergic conditions when used as an add-on to AIT, especially during the build-up phase. Further research is needed to fully understand their optimal dosing and duration of treatment, as well as to identify which patients may benefit the most from these therapies.

Safety and clinical efficacy of sintilimab (anti-PD-1) in pediatric patients with advanced or recurrent malignancies in a phase I study

The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial

Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. Akeso Biopharma. For the Chinese translation of the abstract see Supplementary Materials section.

A first-in-human phase 1 study of nofazinlimab, an anti-PD-1 antibody, in advanced solid tumors and in combination with regorafenib in metastatic colorectal cancer

BackgroundWe assessed nofazinlimab, an anti-PD-1 antibody, in solid tumors and combined with regorafenib in metastatic colorectal cancer (mCRC).MethodsThis phase 1 study comprised nofazinlimab dose escalation (phase 1a) and expansion (phase 1b), and regorafenib dose escalation (80 or 120 mg QD, days 1–21 of 28-day cycles) combined with 300-mg nofazinlimab Q4W (part 2a) to determine safety, efficacy, and RP2D.ResultsIn phase 1a (N = 21), no dose-limiting toxicity occurred from 1 to 10 mg/kg Q3W, with 200 mg Q3W determined as the monotherapy RP2D. In phase 1b (N = 87), 400-mg Q6W and 200-mg Q3W regimens were found comparable. In part 2a (N = 14), both regimens were deemed plausible RP2Ds. Fatigue was the most frequent treatment-emergent adverse event (AE) in this study. Any-grade and grade 3/4 nofazinlimab-related AEs were 71.4% and 14.3%, 56.3% and 5.7%, and 57.1% and 21.4% in phases 1a, 1b, and part 2a, respectively. ORRs were 14.3% and 25.3% in phases 1a and 1b, respectively. In part 2a, no patients had radiological responses.ConclusionsNofazinlimab monotherapy was well tolerated and demonstrated preliminary anti-tumor activity in multiple tumor types. Regorafenib plus nofazinlimab had a manageable safety profile but was not associated with any response in mCRC.Clinical trial registr ationClinicaltrials.gov (NCT03475251).

P17.15.A THANK PHASE I TRIAL OF DNX-2440 ONCOLYTIC ADENOVIRUS IN PATIENTS WITH FIRST OR SECOND RECURRENCE OF GLIOBLASTOMA: PRELIMINARY RESULTS

Abstract BACKGROUND Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus DNX-2401, genetically engineered for selective replication and enhanced infectivity in tumor cells, has shown efficacy in adult patients with recurrent glioblastoma (GBM). In order to overcome the immunosuppressive brain-tumor microenvironment and thus enhance its antiglioma effect, DNX-2440 is a new armed virus which contains the same modifications but additionally incorporates OX40 ligand to induce the expression of such molecule in tumor cells and so increase the antitumor immune response. MATERIAL AND METHODS We are conducting a phase I open-label single-center study to investigate the safety and efficacy of a single intratumoral injection of DNX-2440 in patients with first or second recurrence of GBM. This is a dose escalation study, with a 3 + 3 design, evaluating an initial dose of 4x10e9 viral particles (vp) and a target dose of 4x10e10 vp. A single measurable lesion bigger than 10 mm in two perpendicular diameters and smaller than 25 cc is required for inclusion in the study. RESULTS To date 16 patients (6 [37.5%] female, 10 [62.5%] male) have been enrolled and treated with DNX-2401. Median age is 55 years (range, 39-80) and median KPS is 80 (range 70-90). As per protocol, surgery consisted of biopsy in all patients followed by intratumoral injection of DNX-2440. No dose limiting toxicity has been registered during the dose escalation phase (first cohort of 3 patients receiving 4x10e9 vp, and second cohort of 3 patients receiving 4x10e10 vp), and the remainder patients have received the target dose of 4x10e10 vp in the dose expansion cohort. Safety profile is acceptable with no serious adverse events related to DNX-2440 reported to date. Clinical benefit with tumor size reduction and prolonged survival have already been confirmed in 3 patients. Correlative analyses evaluating immune response in blood samples are ongoing. CONCLUSION Our current data suggest that intratumoral injection of DNX-2440 is feasible and safe, and seems to provide a clinical benefit in some patients with recurrent GBM. Furthermore, this trial illustrates the potential of oncolytic virus platforms to reshape the brain-tumor microenvironment and its interesting role in combination strategies with other immune-oncology agents for treating this disease.

A phase 2 trial of CD24Fc for prevention of graft-versus-host disease

AbstractPatients who undergo human leukocyte antigen–matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor–based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD–free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD–free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622.

Efficacy and safety profile of pimicotinib (ABSK021) in tenosynovial giant cell tumor (TGCT): Phase 1b update.

11559 Background: TGCT is a rare type of locally aggressive neoplasm that is mainly caused by overexpression of colony-stimulating factor 1 (CSF1) gene. Pimicotinib is an oral, highly potent, and selective small-molecule antagonist of CSF-1R with minimum inhibition of c-Kit and PDGFR, and has been granted Breakthrough Therapy Designation for TGCT by FDA in Jan 2023. Here, we report the updates from 50 mg QD cohort as well as the preliminary data from 25 mg QD cohort in TGCT pts. Methods: The study (NCT04192344) is to evaluate the safety and preliminary antitumor activity of Pimicotinib at 50 mg QD and 25 mg QD in TGCT pts not amenable to surgical resection. Results: As of December 31, 2022, 49 TGCT pts were enrolled, including 37 pts treated with 50 mg QD and 12 pts with 25 mg QD. Median age was 39 y (range: 19-76) and 40.8% were male. The tumor location was mainly in knee (53.1%), hip (18.4%) or ankle (12.2%). Thirty-one pts received at least one prior surgery, and 1 pt received prior exploratory systemic therapy (Anlotinib). Median treatment duration was 7.9 mos (range: 0.4-12.5), and 89.8% remained on treatment. The ORR was 77.4% (24/31, including 2 CR) in 50 mg QD and 40% (4/10, including 1 CR) in 25 mg QD by IRC based on RECIST 1.1. Most responses were achieved within 25 wks and median DOR in both cohorts was not reached. Average improvement of flexion range of knee at wk 13 from baseline was 30.2 degrees (n = 13, range: 2, 105) in 50 mg QD and 4.8 degrees (n = 5, range: -12, 24) in 25 mg QD. Proportion of responders based on BPI-30 at wk 25 was 66.7% (16/24) in 50 mg QD and 60% (3/5) in 25 mg QD, along with a similar trend of stiffness. Most TEAEs were Gr 1 or 2. Four Gr 3/4 TEAEs were reported (2 drug-related), including 1 Gr 3 serious TEAE. Most common TEAEs (≥20%) include LDH increase (75.5%), CPK increase (67.3%), α-HBDH increase (63.3%), AST increase (42.9%), amylase increase (26.5%), ALT increase (24.5%), pruritus (20.4%) and rash (20.4%). No hair color changes or serious liver injuries were reported. CPK and transaminase elevations were asymptomatic, on-target and quickly recovered after drug interruptions. nder steady-state, 50 mg QD resulted in ~ 2-fold higher Cmax and Ctrough compared to 25 mg QD, in sync with findings from escalation phase. Significant PD changes were observed in both cohorts, such as increase in plasma CSF-1 levels, decrease in non-classical monocytes and C-terminal telopeptide(CTx). Changes from baselines in both CSF-1 and CTx showed a correlation with pimocetinib plasma concentrations. Conclusions: Pimicotinib has demonstrated a significant antitumor activity, favorable safety, and PK profiles at both 50 mg QD and 25 mg QD with no apparent hepatotoxicity. The changes in PD biomarkers indicate significant CSF-1R inhibition in TGCT pts. Updated data from 50 mg QD cohort showed higher ORR and continuous improvement over a longer treatment time, which supports the further evaluation of Pimicotinib in a phase 3 study. Clinical trial information: NCT04192344 .

A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumors: Safety and efficacy in patients with dedifferentiated liposarcoma (DDLPS).

11554 Background: Inactivation of p53 is a key mechanism which promotes tumor survival and proliferation. p53 inactivation can be due to mutations in TP53 or downregulation of wild-type (wt) p53 by the key negative regulator mouse double-minute 2 (MDM2). BI 907828 is a highly potent MDM2–p53 antagonist which has demonstrated preclinical antitumor activity, particularly in TP53-wt MDM2-amplified DDLPS models. In this phase I study (NCT03449381), BI 907828 monotherapy is being evaluated in pts with advanced solid tumors, including DDLPS. During dose escalation (phase Ia), BI 907828 had a manageable safety profile and the selected recommended dose for expansion (RDE) was 45 mg q3w. Here we report safety data in all pts who received the RDE of 45 mg q3w and present efficacy data in the subgroup of pts with DDLPS. Methods: In Phase Ia, pts received one of two BI 907828 dosing schedules: Arm A, day 1 of 21-day cycles (q3w); Arm B, days 1 and 8 of 28-day cycles. During Phase Ib (dose expansion), pts were enrolled to Cohort 1 ( TP53wt, MDM2-amplified sarcoma) or Cohort 2 (other TP53wt, MDM2-amplified solid tumors). Here we focus on Cohort 1 (received BI 907828 45 mg q3w). The primary endpoint (phase Ib) was progression-free survival (PFS). Secondary endpoints/objectives included overall response rate (ORR) and grade ≥3 treatment-related AEs (TRAEs). Results: As of December 22, 2022, a total of 137 pts had been enrolled; 72 (52.6%) were male, 77 (56.2%)/59 (43.1%) had ECOG PS 0/1, and the median number of prior systemic therapies was 2 (range, 0–11). In the 73 pts who received the RDE of 45 mg q3w, the most common any-grade TRAEs were nausea (74.0%) and fatigue (61.6%). 33 (45.2%) pts had grade ≥3 TRAEs; the most common were thrombocytopenia (23.3%), neutropenia (21.9%), anemia (11.0%), and leukopenia (11.0%). 22 (30.1%) pts had TRAEs leading to dose reductions and 6 (8.2%) had TRAEs leading to treatment discontinuation. 20 pts (27.4%) had serious AEs; the most common were nausea, pulmonary embolism (each 4.1%), sepsis, small intestine obstruction, vomiting, thrombocytopenia, and pyrexia (each 2.7%). 50/73 pts who received 45 mg q3w had advanced DDLPS; all had MDM2-amplified disease. Of the 42 evaluable DDLPS pts, 8 achieved a confirmed PR (ORR 19.0%; locally assessed) and a further 29 achieved a best response of stable disease (including 2 with unconfirmed PR), giving a disease control rate of 88.1%. Preliminary median PFS was 8.1 months. Conclusions: BI 907828 demonstrated a manageable safety profile overall and encouraging preliminary efficacy was seen in pts with advanced MDM2-amplified DDLPS; Phase Ib is ongoing. BI 907828 is also being evaluated versus doxorubicin as first-line treatment for pts with advanced DDLPS in the ongoing Phase II/III Brightline-1 study (NCT05218499), for which the FDA has granted a Fast Track Designation. Clinical trial information: NCT03449381 .

Osemitamab in combination with capecitabine and oxaliplatin (CAPOX) as a first line treatment of advanced G/GEJ cancer: Updated data of cohort C from a phase I/IIa, multi-center study (TranStar102/TST001-1002).

4046 Background: Adding a claudin18.2 antibody to a chemotherapy is a clinically validated approach for patients with high CLDN18.2 expressing tumors. TST001 is a best in class differentiated antibody whose improved CLDN18.2 affinity and enhanced antibody-dependent cellular cytotoxicity, leads to anti-tumor activity in low to medium CLDN18.2 expressors gastric cancer cells. Pre-clinical studies also showed that TST001 has stronger tumor regression effects than the IMAB362-analog at the same dose. Methods: The efficacy and safety of osemitamab with CAPOX as 1st line treatment with G/GEJ cancer was explored in a dose escalation and expansion phase 1/2 study in China (Cohort C, NCT04495296). Positive claudin18.2 expression (membranous staining ≥1+ intensity in≥10% of tumor cells) as assessed centrally using the LDT assay was required in the expansion phase only. Results: As of Dec 31, 2022, 64 patients were dosed with osemitamab in combination with CAPOX, 15 patients received osemitamab at doses ranging from 1 to 8 mg/kg Q3W in the dose escalation and 49 patients at 6 mg/kg in the dose expansion. The median follow up was 151 days. Patient characteristics were typical of 1st line G/GEJ cancer, with relatively higher percentage of peritoneal disease (48.4%). Nausea (65.4%), vomiting (46.2%) and hypoalbuminemia (65.4%) were the most common adverse events related to TST001 at dose of 6mg/kg in 52 patients (3 patients in dose escalation and 49 patients in dose expansion), most of them were grade 1 or 2 (only one patient experienced grade 3 nausea and vomiting, and one experienced grade 3 hypoalbuminemia). In the expansion cohort, 40 of the 45 patients with measurable lesions had at least one post-treatment tumor assessment. 27 achieved partial response (PR) of which 21 were confirmed. There was no obvious trend in improved efficacy with higher level of CLDN18.2 expression based on overall response rate (ORR). Progression free survival (PFS) and duration of response (DOR) were still immature. Conclusions: TST001 in combination with CAPOX as first-line treatment for the patients with G/GEJ cancer is safe and encouraging anti-tumor activities have been observed regardless of the CLDN18.2 expression levels above 1+ intensity in >=10% tumor cells per central LDT assay. Updated ORR, mPFS and mDOR will be presented at the time of the congress. Clinical trial information: NCT04495296 .

Preclinical and early clinical data of ZN-1041 in combination with trastuzumab deruxtecan to treat breast cancer with or without CNS metastases.

1041 Background: While treatment options for advanced HER2+ breast cancer have improved, HER2+ breast cancer brain metastases (BCBM) remain a clinical challenge warranting the development of additional, brain permeable HER2-targeted therapies. ZN-1041 is a brain permeable, selective HER2-targeted oral tyrosine kinase inhibitor. Preclinical studies have demonstrated efficacy and safety of ZN-1041 warranting clinical development alone and in combination with approved monoclonal antibodies or antibody drug conjugates for patients (pts) with HER2+ BCBM. Methods: Anti-tumor activity of ZN-1041 alone or in combination with trastuzumab emtansine (TDM1), trastuzumab deruxtecan (TDXd), or trastuzumab (H) plus pertuzumab (P) was evaluated in BT474 BM orthotopic xenograft models. ZN-A-1041-101-US (NCT05593094) is an on-going phase 1, multicenter, open-label study. The study comprises dose escalation of ZN-1041 monotherapy (Phase 1a) in pts with HER2+ solid tumors with or without BM, dose escalation (Phase 1b) and expansion (phase 1c) of ZN-1041 in combination with TDM1 (Arm 1), TDXd (Arm 2), or HP as maintenance therapy (Arm 3) in pts with HER2+ mBC with or without BM. The primary objectives were safety, tolerability and recommended phase 2 dose. The secondary objective includes pharmacokinetics (PK) and preliminary efficacy per RECIST 1.1. Results: Preclinically, ZN-1041 alone or combined with TDM1, TDXd or HP demonstrated significant improvement in intracranial tumor growth inhibition compared to TDM1, TDXd, or HP alone. As of data cutoff, Phase 1a (n = 7 pts) and Arm 2 of Phase 1b (n = 3 pts) were completed. Among 10 pts enrolled, 8 pts had received prior HER2 TKI. In Phase 1a, ZN-1041 was well tolerated with no dose-limiting toxicities (DLTs) or drug discontinuation due to toxicity up to a dose of 800 mg BID. Adverse reactions were mainly grade 1. The most common treatment related adverse reactions (TRAEs≥15%) were grade 1 nausea (43%) and vomiting (29%), with no ≥ grade 2 diarrhea reported. PK exposure was increased with dose escalation. In Phase 1a, one pt with mBC (without BM) achieved a confirmed partial response (PR) at 400 mg BID dose for > 15 months; one with gastric cancer achieved stable disease at the first dose level of 50mg BID for nearly 1 year. In Phase 1b, pts who had previously progressed on TDXd and/or TKI were enrolled and received ZN-1041 at a dose of 800 mg BID in combination with TDXd. Combination therapy was well tolerated with no DLTs reported. One pt with BCBM who was previously on tucatinib and TDXd had a confirmed PR. Conclusions: Safety and tolerability was observed for ZN-1041 with maximum tolerated dose 800 mg BID as monotherapy and combined with TDXd in pts with advanced HER2+ malignancies. Encouraging efficacy was observed in treatment-refractory settings. Additional safety and efficacy data of ZN-1041 in combination with TDM1, TDXd or HP are warranted. Clinical trial information: NCT05593094 .

Phase 1 study of ziftomenib (KO-539) in combination with venetoclax or venetoclax/azacitidine or standard induction cytarabine/daunorubicin (7+3) chemotherapy for the treatment of patients with acute myeloid leukemia.

TPS7079 Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML ( KMT2A-r and NPM1-m) and zifto/ven in R/R AML ( NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336 .

BELLWAVE-003: A phase 2 dose escalation, confirmation, and cohort expansion study of nemtabrutinib in hematologic malignancies.

TPS7593 Background: Bruton tyrosine kinase (BTK) inhibitors (BTKi) have transformed the treatment of several hematologic malignancies. However, acquired resistance, commonly associated with BTK C481S mutations, can develop. Nemtabrutinib (MK-1026, formerly ARQ 531) is a noncovalent, competitive inhibitor of both wild type and C481S-mutant BTK that has shown promising antitumor activity at 65 mg once daily (QD) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BELLWAVE-003 (NCT04728893) is an open-label, phase 2 study investigating the safety and efficacy of nemtabrutinib in patients (pts) with R/R B-cell malignancies. Methods: BELLWAVE-003 includes a dose escalation and confirmation phase (part 1) and a cohort expansion phase (part 2). Enrollment of 450 pts is planned. Part 1 will enroll approximately 30 pts, with a minimum of 6 and maximum of 20 per dose level. Part 2 will enroll approximately 420 pts. All pts must be ≥18 years and have an ECOG performance status of 0 to 2. Part 1 will enroll pts with CLL/SLL that was R/R after ≥2 prior therapies. Part 2 will enroll pts in 8 cohorts: CLL/SLL that is R/R to a covalent irreversible BTKi and a BCL2 inhibitor, and, for pts with CLL, R/R to or ineligible for a PI3K inhibitor (cohort A); R/R CLL/SLL that is BTKi–naive (cohort B); del17p or TP53-mutant R/R CLL/SLL (cohort C); R/R Richter transformation (cohort D); R/R mantle cell lymphoma, including prior covalent BTKi (cohort E); R/R marginal zone lymphoma, including prior covalent BTKi (cohort F); R/R follicular lymphoma (cohort G); and R/R Waldenström’s macroglobulinemia, including prior covalent BTKi (cohort H). Initially, pts received nemtabrutinib 80 mg QD orally at dose level 1. Data from BELLWAVE-001 and BELLWAVE-003 subsequently established nemtabrutinib 65 mg QD as the recommended phase 2 dose (RP2D) for future pt enrollment. Treatment will continue until unacceptable toxicity, disease progression, or withdrawal. Adverse events will be monitored throughout and graded using NCI CTCAE version 5.0. Hematologic toxicities in pts with CLL will be assessed using iwCLL 2018 criteria. CT/MRI and/or PET will be performed every 12 weeks, unless needed more frequently. For part 1, the primary end points are safety and tolerability and establishing the RP2D; secondary end points are pharmacokinetics (PK), ORR, and DOR. For part 2, the primary end point is ORR; secondary end points are safety and tolerability, PK, and DOR; and exploratory end points include PFS, OS, and health-related quality of life. Safety and efficacy will be assessed in all pts who receive ≥1 dose of study drug. Pts receiving nemtabrutinib 80 mg and 65 mg QD will be analyzed separately. Safety will be summarized descriptively. ORR and 95% CI will be estimated using an exact binomial method. DOR, PFS, and OS will be estimated using the Kaplan-Meier method. Enrollment for this study is ongoing. Clinical trial information: NCT04728893 .

Preclinical and early clinical data of ZN-1041, a best-in-class BBB penetrable HER2 inhibitor to treat breast cancer with CNS metastases.

1040 Background: HER2+ breast cancer brain metastases (BCBM) is an aggressive malignancy with high prevalence and limited treatment options. ZN-1041 is a best-in-class HER2 inhibitor designed to be delivered across the blood-brain barrier (BBB) with high selectivity and broader safety margin to treat HER2+ BCBM. Methods: Brain penetration of ZN-1041 and other approved HER2 tyrosine kinase inhibitors (TKI) were evaluated. Anti-tumor activity of ZN-1041 alone or in combination were evaluated in xenograft models. ZN-A-1041-101 (NCT04487236) is an on-going phase 1, multicenter, open-label study. The study comprises first-in-human dose escalation of ZN-1041 monotherapy (phase 1a) in HER2+ solid tumor patients (pts) with or without BM, dose escalation (phase 1b) and expansion (phase 1c) of ZN-1041 in combination with capecitabine and trastuzumab in pts with HER2+ BCBM (including active BM). The primary objective was safety and tolerability. The secondary objective includes pharmacokinetics and anti-tumor response including ORR per RECIST 1.1 and intracranial ORR (iORR) per RANO-BM. Results: Unlike currently approved HER2 TKIs which are strong human efflux transporter P-gp and BCRP substrates, ZN-1041 is not a substrate of either and has high BBB permeability, therefore predicted to have good BBB penetration. ZN-1041 alone demonstrated dose-dependent and significant anti-tumor activity when compared to tucatinib in BM model. ZN-1041 could synergize with capecitabine and trastuzumab to demonstrate significantly improved intracranial efficacy in BM models, while maintaining good tolerability. In total, 21 HER2+ mBC pts were enrolled to complete phase 1a and 1b. No dose-limiting toxicities or treatment-related SAE were observed across all dose levels. PK exposure was increased with dose escalation and Kpuu,CSF of ZN-1041 was 4.9. In ZN-1041 monotherapy, the overall ORR and iORR were 50% in TKI naïve, unequivocal HER2+ pts. The longest treatment duration was 15 months. As of data cutoff (Dec 02, 2022), totally 35 TKI naïve, HER2+ BCBM pts with median 2L treatments were enrolled for phase 1c and all pts were well tolerated to date. Adverse reactions of grade 3 or higher (≥5%) were hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), ALT increased (5.7%), AST increased (5.7%), GGT increased (5.7%) and WBC decreased (5.7%). Among 19 BCBM pts with at least twice tumor assessment, the overall ORR was 78.9% (95% CI: 54.4–93.9) and iORR was 73.7% (95% CI: 48.8–90.9), DCR was 100%. In addition, 6 pts completed first tumor assessment and 5 achieved PR and 1 had SD per RECISIT 1.1. Conclusions: Encouraging efficacy and tolerability was observed for ZN-1041 monotherapy or combined with capecitabine and trastuzumab in TKI naïve, HER2+ BCBM patients. A Phase 2 pivotal trial for HER2+ BCBM with ZN-1041, capecitabine and trastuzumab combination therapy is planned. Clinical trial information: NCT04487236 .

Longitudinal mutational analysis of TP53 in plasma circulating tumor DNA (ctDNA) in patients (pts) with solid tumors in a phase I study of BI 907828, an MDM2–p53 antagonist.

3036 Background: Inactivation of p53 can occur due to TP53 mutations or downregulation of wild-type p53 by its primary negative regulator, MDM2. Targeting the MDM2–p53 interaction may therefore restore p53 function. BI 907828, a highly potent MDM2–p53 antagonist, is being evaluated in a phase Ia/b study in pts with advanced solid tumors (NCT03449381). During dose escalation (phase Ia), BI 907828 demonstrated a manageable safety profile and early signs of efficacy. Here we present data from a longitudinal mutational analysis of TP53 using ctDNA. The objective of the analysis was to identify if mutations in TP53 can be associated with possible acquired resistance to BI 907828. Methods: Collection of blood samples for ctDNA analyses was optional and sampled longitudinally from pts at baseline and every cycle until end of treatment (EoT). ctDNA was purified from plasma and analyzed using tumor-specific next generation sequencing (NGS; custom-made 8-gene panel using KAPA HyperCap technology, including TP53) to identify tumor-derived somatic mutations that may be relevant to understanding resistance mechanisms to BI 907828. The limit of detection was determined to be 0.5% mutant allele frequency; common polymorphisms were filtered out. Results: Plasma samples for ctDNA analysis were available from 44/54 (81%) pts enrolled to phase Ia. Baseline plasma samples from 26/54 (48%) pts and EoT samples from 41/54 (76%) pts were analyzed. Mutations were found in 6/26 (23%) samples at baseline. In 2 pt samples, mutations were found in both tumor and ctDNA, but concordant results were limited to 1 pt. At EoT, no (0) mutations were found in 16/41 (39%) samples, 1 mutation in 11/41 (27%), 2 mutations in 6/41 (15%), 3 mutations in 2/41 (5%) and 4 mutations in 6/41 (15%). No sample had more than 4 mutations. The most frequent mutation at EoT (in 9/41 [22%] samples) was R175H, a known p53 loss of function (LOF) mutation, followed by R248Q/W LOF (in 6/41 [15%) samples). Mutations in non- TP53 genes were detectable independent of TP53 mutation status, suggesting ctDNA was present in all samples. No clear association of induction of mutations could be identified for any BI 907828 dose or dosing schedule, treatment duration, or tumor type. 9/20 (45%) pts with no detectable mutations at baseline maintained wild-type TP53 status at EoT. Signs of efficacy were observed in pts with acquired TP53 LOF mutations, suggesting that these mutations have no effect on efficacy. Analysis of TP53 mutational status at EoT in conjunction with correlative clinical efficacy will be presented. Conclusions: This mutation analysis represents one of the most comprehensive assessments of longitudinal ctDNA by NGS for TP53 from a clinical trial of an MDM2–p53 antagonist. Preliminary data suggest that BI 907828 does not systematically lead to broad acquisition of resistance by inducing alterations in TP53. Clinical trial information: NCT03449381 .

A Phase I Study of CD19‐targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory Diffuse Large B‐cell Lymphoma

Background: The redundancy of CD28 and CD3 signaling in a CAR design incorporating all 3 immunoreceptor tyrosine-based activation motifs (ITAMs) might negatively affect T cell differentiation and promote exhaustion. Therefore, we created a novel CD19 CAR construct with calibrated CAR signaling potential by mutating 2 of the 3 ITAMs, termed 1XX. In mouse models, 19-28z1XX CAR successfully induced tumor eradication at low CAR T cell doses with improved survival compared to conventional 19-28z CAR and with enhanced persistence of functional CAR T cells. We report on adult pts with DLBCL treated with 19(T2)28z-1XX CAR T cells (NCT04464200). Methods: This is a single center, phase I, dose-escalation and expansion trial of 19(T2)28z1XX CAR T cells in adult pts with R/R DLBCL. Pts received lymphodepleting chemotherapy followed by escalating doses of CAR T cells: 25–200 × 106. The primary objective was to evaluate safety and tolerability and determine the recommended phase 2 dose. Secondary objectives include overall response rate and duration of response. Results: Sixteen pts were treated on the dose escalation phase of the study. Median age was 62 (range, 50–80), and median number of prior treatments was 2 (range, 1–5). 4, 6, 3 and 3 pts were treated at DL1, DL2, DL3 and DL4 CAR T cells, respectively. 15 pts (94%) experienced cytokine release syndrome (CRS): grade 1 (n = 9), grade 2 (n = 6). No pts experienced ≥ grade 3 CRS. Two pts (13%) experienced neurotoxicity (NTX): 1 pt with grade 1 and 1 pt with grade 3. NTX was transient and reversible in both cases.Ten of 16 pts (63%) achieved a complete response (CR) and 2 pts (13%) achieved a partial response (PR), with overall response rate (ORR) of 75%. One pt who achieved initial PR spontaneously converted to CR without further treatment after month 6, resulting in best CR rate of 69%. Responses were seen across all dose levels. With a median follow-up of 155 days (range, 33–667), no pt in CR has experienced relapse including 7 pts with >6 months of follow-up (Figure 1). Peak CAR T cell expansion occurred at a median of 14 days after CAR T cell infusion (range, 7–83.3 days). CAR T cell detection beyond 350 days has been noted. DL 1 (25 × 10e6 cells) was chosen as the recommended dose for the expansion phase. Updated responses in the dose escalation cohort and the full expansion cohort, as well as PK data, will be presented. Conclusions: Treatment with 19(T2)28z1XX CAR T cells was safe. No severe CRS was observed and only 1 pt experienced transient grade 3 NTX. The overall CR rate was 69% and durable with no relapse observed with a median follow-up of 155 days. CRs were observed at DL1, which was chosen for the expansion phase. These findings corroborate our preclinical data and suggest that the 1XX signaling domain may lead to enhanced efficacy of CD19 CAR and allow infusion of a lower T cell dose with favorable toxicity profile. Keyword: Cellular therapies Conflicts of interests pertinent to the abstract. M. L. Palomba Consultant or advisory role: Synthekine, Cellectar, Kite, Bristol Meyer Squibb I. Riviere Consultant or advisory role: Fate Therapeutics, Akron Biotechnology Stock ownership: Mnemo Therapeutics, J. Li Employment or leadership position: Takeda L. Sellner Employment or leadership position: Takeda M. Sadelain Consultant or advisory role: Atara Research funding: Takeda, Mnemo Therapeutics S. Chen Employment or leadership position: Takeda Y. Zhao Employment or leadership position: Takeda J. H. Park Consultant or advisory role: Novartis, Kite, Kura, Astra-Zeneca, Servier, Curocell, Intella, Autolus, Allogene, Affymmune, Amgen Research funding: Genentech

A phase I/II study of carfilzomib, iberdomide (CC-220), and dexamethasone (KID) in patients with newly diagnosed transplant-eligible multiple myeloma.

e20043 Background: Iberdomide is a next generation cereblon-E3 ligase modulating agent (CELMoD) that has increased antitumor activity relative to earlier thalidomide analogs (IMiDs). This is due to direct effects on tumor cells and increased immune surveillance. Herein, we report the dose escalation, safety and efficacy data from this ongoing study of carfilzomib (CFZ), iberdomide, and dexamethasone (DEX) (KID) in patients with newly diagnosed transplant-eligible multiple myeloma (MM). Methods: This is a phase I/II, multicenter study of KID in patients with newly diagnosed transplant-eligible MM. Patients were enrolled in a standard 3+3 design to determine the maximum tolerated dose (MTD) of iberdomide (starting dose 1 mg; D1-21) in combination with CFZ (IV; 20 mg/m2 on C1D1; 56 mg/m2 C1D8, D15; 56 mg/m2 C2-4, D1, 8, 15) and DEX (D1, 8, 15) in 28-day cycles. Enrollment is ongoing with a 3 level dose escalation phase (max dose of iberdomide 1.6 mg) followed by a planned dose expansion phase. The phase I primary objective is to determine the safety of KID. The phase II primary objective is to evaluate the rate of complete remission (CR) + stringent CR (sCR) for patients receiving 2-4 cycles of KID followed by ASCT and 6 cycles of iberdomide consolidation. Results: At data cutoff (Feb 6, 2023), there were 8 patients who had signed consent for the trial, of whom 1 is actively receiving treatment, 5 are in follow up, and 2 were screen failures. Of the 6 patients on trial, the median age was 61 years (range 46-74), 33% male, 67% white, and 17% with ISS stage II MM. Two patients had high-risk cytogenetics, including one patient with t(14;16) and one patient with 1q21 duplication and TP53 mutation. Three patients enrolled at the starting dose level of iberdomide 1 mg orally on D1-21. Grade 1-2 TEAEs occurred in all 3 patients, and one patient experienced a grade 3 TEAE (neutropenia). Three patients were enrolled at the next dose level of iberdomide 1.3 mg orally on D1-21. Grade 1-2 TEAEs occurred in 2 patients (rash and pruritus), but no grade ≥3 TEAEs occurred in any of these 3 patients. To date, no patients have experienced a DLT and the MTD has not been reached. The median number of cycles of KID was 3 (range 3-4) for the 5 patients who completed treatment. Four patients proceeded to ASCT and 2 patients are pending evaluation. The median amount of stem cells mobilized was 9.42 x 106 cells/kg (range 6.7-11.45). Response data at 3 months post-ASCT is available for 1 patient, who is in CR + sCR and MRD-negative. Conclusions: Induction therapy with KID appears safe with the only grade 3 TEAE reported being neutropenia. In patients who completed treatment, induction cycles with KID did not interfere with stem cell mobilization. Correlative and additional clinical data are being collected and will be presented. Clinical trial information: NCT05199311 .

A phase Ia trial to evaluate the safety and efficacy of HB0030, an anti-TIGIT antibody, in patients with advanced solid tumors: Preliminary results.

e14673 Background: HB0030 is an IgG1 type humanized monoclonalanti-TIGIT antibody. Its heavy chain Fc fragment is wild-type that preserves function for inducting CDC and ADCC effects. Nonclinical data showed that HB0030 has a good affinity for TIGIT and anti-tumor activity. Methods: This is an ongoing single-center, open-label, dose escalation Phase Ia study to mainly evaluate HB0030 safety, antitumor activity and immunogenicity in patients (pts) with advanced solid tumor. HB0030 is administered by IV infusion every 21 days. An accelerated titration method combined the standard 3+3 design was utilized for dose escalation, which of contained 8 dose groups (0.1, 0.3, 1.0, 3.0, 10, 20, 30, 40mg/kg). The tumor assessment evaluated by investigator according to RECIST v1.1. Results: As of Jan 9, 2023, 20 pts (4Male/16Female) with advanced malignant solid tumor have been enrolled and dosed at 0.1mg/kg (n = 1), 0.3mg/kg (n = 3), 1mg/kg (n = 3), 3mg/kg (n = 4), 10mg/kg (n = 3) and 20mg/kg (n = 6). The median age was 56.9 years. All pts had stage IV disease and failed from the anti-tumor standard therapy with a median of 3 lines. The main tumor types included lung(n = 6), breast(n = 3), colorectal(n = 3) and cervical (n = 2) cancer. Total 16 pts have completed at least once tumor assessment. The ORR and DCR were 6.3% (1/16) and 62.5% (10/16), respectively. The best response was a PR with 47% tumor regression pt who was diagnosed non-small cell lung cancer (NSCLC) accompanied with TP53 gene mutation. The pt relapsed with multiple metastasis after radical operation and adjuvant chemotherapy, and failed to systemic chemotherapy combined targeting anti-vascular therapy. He achieved PR with 3 cycles of 20mg/kg HB0030 treatment, and PR status continued at present. A NSCLC pt maintained 24 weeks SD after 3mg/kg HB0030 administration. The most common treatment related adverse events (TRAEs) were lymphopenia (9/20, 45%) and shortened activated partial thromboplastin time (APTT) (6/20,30%). Grade 3 TRAEs occurred in 15% of pts (3/20) which included thrombocytopenia, anemia, syncope and hypertension. There were no Grade 4-5 AEs, serious adverse events (SAEs), dose-limiting toxicity (DLT) and death. The anti-drug antibodies (ADAs) were detected in 2 pts in 20 mg/kg dose group, and not caused by HB0030 therapy because it had existed in baseline. Conclusions: HB0030 showed very well safety in the stage of dose escalation from 0.1 to 20 mg/kg, and potential promising anti-tumor activity above 3mg/kg dose in advanced solid tumors pts, especially in NSCLC. Currently, 30mg/kg and 40mg/kg dose escalation are ongoing. Clinical trial information: NCT05706207 .

Mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose expansion results.

3027 Background: Mirzotamab clezutoclax (ABBV-155; Mirzo-C) is a first-in-class antibody-drug conjugate with three components: an anti–B7-H3 monoclonal antibody, a solubilizing linker, and a BCL-XL inhibitor payload. By specific targeting of BCL-XL, synergy with other anticancer agents was observed in preclinical models. When combined with a taxane, clinical antitumor activity was reported in relapsed and/or refractory (R/R) solid tumors during the dose escalation phase of an ongoing Phase 1, open-label study (NCT03595059). Methods: In the dose expansion phase of the Phase 1 study, patients were treated as follows: (i) R/R small cell lung cancer (SCLC) with Mirzo-C monotherapy, (ii) non-small cell lung cancer (NSCLC) with Mirzo-C + docetaxel, and (iii) hormone positive, Her2 negative, post–CDK4/6 inhibitor breast cancer (BrCa) with Mirzo-C + paclitaxel. Mirzo-C was administered at the recommended Phase 2 dose determined at dose escalation. Primary objectives were safety and overall response rate (ORR). Results: As of November 18, 2022, 78 patients were enrolled (SCLC n=14; NSCLC n=36; BrCa n=28). The median (range) follow-up was 2.0 (0.6–9.1) months for the SCLC cohort, 4.9 (0.6–8.5) for NSCLC, and 10.4 (0.8–13.3) for BrCa. The median number of prior lines of systemic therapy was 2 in the SCLC cohort, 2 in NSCLC, and 6 in BrCa. Prior taxane therapy was received by 7% of patients in the SCLC cohort, 36% in NSCLC, and 64% in BrCa. The most common adverse events (AEs) in SCLC were fatigue, increased aspartate aminotransferase, diarrhea, and headache (21%, n=3 for each AE); fatigue was the most common AE in NSCLC (58%, n=21; Grade 3/4: 3%, n=1) and in BrCa (61%, n=17). Thrombocytopenia, a result of the systemic effects of BCL-XL inhibitors, was not observed in the Mirzo-C monotherapy cohort. Neutropenia/decreased neutrophil count was not observed in the SCLC monotherapy cohort but was common with BrCa paclitaxel combo (64%, n=18; Grade 3/4: 29%, n=8) and NSCLC docetaxel combo (53%, n=19; Grade 3/4: 44%, n=16); 5 patients in the NSCLC cohort (14%) and 1 in BrCa (4%) had febrile neutropenia. Confirmed ORR was 0% in the SCLC cohort, 11% in NSCLC, and 18% in BrCa. Conclusions: Mirzo-C demonstrated a tolerable safety profile as monotherapy and with taxanes. No thrombocytopenia or neutropenia was observed with monotherapy. No single-agent activity of Mirzo-C was observed in SCLC. Combination treatments were active with high best overall response (BOR) and disease control rates in heavily pretreated NSCLC and BrCa patients, where Grade 3/4 neutropenia was observed. It is unknown if Mirzo-C exacerbated the neutropenia risk associated with taxanes. Clinical trial information: NCT03595059 . [Table: see text]

A first-in-human trial of intravesical enfortumab vedotin (EV), an antibody-drug conjugate (ADC), in patients with non-muscle invasive bladder cancer (NMIBC): Interim results of a phase 1 study (EV-104).

4596 Background: A majority of patients (pts) with bladder cancer present with non-muscle invasive disease; for pts with high-risk tumors, standard of care (SOC) is resection of tumor followed by intravesical Bacillus Calmette-Guerin (BCG). Once pts experience recurrence and develop BCG-unresponsive disease, SOC is radical cystectomy (RC), which many pts are unfit for or refuse. EV is an ADC directed to Nectin-4, which is highly expressed in bladder tumors. Intravenous EV has demonstrated survival benefit in pts with previously treated la/mUC. In preclinical models with intravesical administration, EV was well tolerated and showed antitumor activity. Here we present the first clinical data for intravesical administration of EV in pts with NMIBC. Methods: EV-104 (NCT05014139) is an ongoing phase 1, open-label, multicenter, dose-escalation and expansion study of intravesical EV evaluating the safety, tolerability, PK, and antitumor activity of intravesical EV in pts with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) with or without papillary disease who are ineligible for or refuse RC. Dose escalation phase aims to identify the MTD or recommended dose of intravesical EV at the following dose levels: 125mg, 250mg, 500mg, and 750mg. Pts receive intravesical EV weekly for 6 weeks in the induction phase, followed by 9 monthly maintenance doses. Preliminary safety, PK, and efficacy data for 125mg and 250mg doses are presented in this abstract. Results: As of data cutoff (1 Dec 2022), 6 pts received intravesical EV across 2 dose levels: 4 pts at 125mg completed 6 induction cycles and proceeded to maintenance; 2 pts at 250mg had received at least 3 doses of intravesical EV. Of 6 pts across doses, there were no Grade ≥3 TRAEs, treatment-related SAEs, TRAEs leading to dose reduction or discontinuation. 4 of 6 pts (3 at 125mg and 1 at 250mg) experienced ≥1 treatment-related adverse event (TRAE) of Grade 1 or 2. Most common TRAEs were fatigue (3 of 6) and micturition urgency (2 of 6). As of data cutoff, no DLTs were observed for 125mg; the DLT evaluation period for 250mg was not complete. All blood PK analyses (ADC and unconjugated MMAE) for pts at 125mg were undetectable; no PK data was available for 250mg. Of 4 pts receiving 125mg of intravesical EV, 3 achieved CR and continue in response. The fourth pt discontinued tx due to persistent disease but remains on study. Pts at 250mg had not been evaluated for response at data cutoff. Detailed safety and additional efficacy data will be presented. Conclusions: Preliminary data from EV-104 show intravesical EV is well tolerated with no evidence of systemic exposure at 125mg. Preliminary antitumor activity was observed at 125mg with 3 of 4 pts achieving a CR. Dose escalation is ongoing to identify the MTD or recommended dose for dose expansion. Clinical trial information: NCT05014139 .