Incidence Of Dose-limiting Toxicities Research Articles

Axicabtagene Ciloleucel in Combination with the 4-1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11.

Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy. In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose, 2 × 106 cells/kg) plus utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics. No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10. Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

A phase 2 randomized study of magrolimab combination therapy in adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC): ELEVATE-TNBC.

TPS1130 Background: Improving outcomes in patients (pts) with TNBC remains a high unmet need. Immune checkpoint inhibitors (ICIs) + chemotherapy (chemo) is approved for newly diagnosed pts with PD-L1+ tumors. Further, single-agent sacituzumab govitecan (SG), a Trop-2–directed antibody-drug conjugate, is approved for pts with mTNBC who received ≥2 prior systemic therapies (≥1 for metastatic disease). However, more options are needed for pts with PD-L1–negative mTNBC and for those with disease progression on chemo ± ICI. Magrolimab is a monoclonal antibody that blocks CD47, a “don’t eat me” signal often overexpressed on TNBC cells. Magrolimab blockade of CD47 induces macrophage-mediated phagocytosis of tumor cells and has shown preclinical activity and promising clinical efficacy in hematologic malignancies. Certain chemos, including taxanes, enhance prophagocytic signals on tumor cells, which may lead to synergistic antitumor activity with magrolimab. This study is evaluating the safety, tolerability, and efficacy of magrolimab + nab-paclitaxel/paclitaxel or + SG in mTNBC. Methods: This open-label study has 2 cohorts (C) with safety run-in and phase (ph) 2 portions. Eligible pts are ≥18 y with measurable disease per RECIST 1.1. C1 pts have PD-L1–negative untreated mTNBC. C2 pts have mTNBC and received 1 prior line of therapy in the advanced setting, a taxane in the neoadjuvant/adjuvant or metastatic setting, and, if PD-L1+, an ICI. Exclusion criteria include active central nervous system disease, RBC transfusion dependence, and prior treatment with CD47/SIRPα-targeting agents. C1 assesses nab-paclitaxel/paclitaxel + magrolimab (safety run-in) or ± magrolimab (ph 2; randomized 1:1). C2 assesses magrolimab + SG (safety run-in and ph 2). In C1 safety run-in, magrolimab is given intravenously (IV) as a 1-mg/kg priming dose on day (D) 1 of cycle 1 to mitigate on-target anemia, followed by 30 mg/kg (cycle 1: D8, 15, 22; cycle 2: D1, 8, 15, 22; cycle 3+: D1, 15) (28-d cycles). In C2 safety run-in, pts receive a 1-mg/kg priming dose on D1, followed by 30 mg/kg (cycle 1: D8, 15; cycle 2: D1, 8, 15) and 60 mg/kg (cycle 3+: D1) (21-d cycles). The recommended ph 2 dose (RP2D) is determined in the safety run-in, with de-escalation if prespecified dose-limiting toxicity (DLT) criteria are met. Once RP2D is determined, the ph 2 cohorts will follow their respective dose schedules. Nab-paclitaxel/paclitaxel and SG are given IV per standard of care. The primary endpoints are incidence of DLTs, adverse events, and abnormal lab results by CTCAE v5.0 (safety run-in); progression-free survival by RECIST 1.1 (ph 2 C1); and confirmed objective response rate by RECIST 1.1 (C2; pooled safety run-in and ph 2). Planned enrollment is ≈144 pts. Clinical trial information: NCT04958785 .

Safety and efficacy of CRISPR-based non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells in patients with relapsed or refractory Non-Hodgkin's lymphoma: a first-in-human phase I study.

Thus far, all approved chimeric antigen receptor (CAR)-T products are manufactured using modified viruses, which increases the risk of tumorigenesis, costs and production time. We aimed to evaluate the safety and efficacy of a kind of virus-free CAR-T cells (PD1-19bbz), in which an anti-CD19 CAR sequence is specifically integrated at the PD1 locus using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9, in adults with relapsed/refractory (r/r) B cell non-Hodgkin's lymphoma (B-NHL). This single-arm phase I dose-escalation clinical trial evaluated PD1-19bbz in adult patients with r/r B-NHL from May 3rd 2020 to August 10th 2021. The patients were recruited and treated at the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Patients underwent leukapheresis and lymphodepleting chemotherapy before PD1-19bbz infusion. After the dose-escalation phase including three cohorts: 2×106/kg, 4×106/kg, 6×106/kg with three patients at each dose level, the optimal biological dose was determined to be 2×106/kg, which was then applied to an extended cohort of nine patients. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the response and survival. This trial was registered at www.clinicaltrials.gov as #NCT04213469. Twenty-one patients received PD1-19bbz infusion. Among all treated patients, 19 (90%) patients were diagnosed with stage III or IV disease. Meanwhile, 19 (90%) were stratified as intermediate risk or worse. Of note, four participants had >50% programmed death ligand-1 (PD-L1) expression in pre-treatment tumour sample, including two with extremely high levels (∼80%). There was no DLT identified. Fourteen patients had low-grade (1-2) cytokine release syndrome and two patients received tocilizumab. Four patients experienced immune effector cell-associated neurotoxicity syndrome of grade 1-2. The most common adverse events were hematologic toxicities, including anaemia (n=6), lymphocyte count decreased (n=19), neutrophil count decreased (n=17), white blood cell count decreased (n=10), and platelet count decreased (n=2). All patients had objective response and 18 patients reached complete response. At a median follow-up of 19.2 months, nine patients remained in remission, and the estimated median progression-free survival duration was 19.5 months (95% confidence interval: 9.9-infinity), with the median overall survival not reached. In this first-in-human study of non-viral specifically integrated CAR-T products, PD1-19bbz exhibited promising efficacy with a manageable toxicity profile. A phase I/II trial of PD1-19bbz in a larger patient cohort is underway. National Key R&D Program of China, National Natural Science Foundation of China, Key Project of Science and Technology Department of Zhejiang Province, Shanghai Zhangjiang National Independent Innovation Demonstration Area, Key Projects of Special Development Funds.

Towards Response ADAptive Radiotherapy for organ preservation for intermediate-risk rectal cancer (preRADAR): protocol of a phase I dose-escalation trial

IntroductionOrgan preservation is associated with superior functional outcome and quality of life (QoL) compared with total mesorectal excision (TME) for rectal cancer. Only 10% of patients are eligible for organ...

Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials.

3149 Background: In recent years, the landscape of clinical trial development has evolved to include immunotherapy and targeted therapies, which have different lengths of administration and toxicity profiles compared to standard chemotherapy. As treatments have evolved, the classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new strategies for design of trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We aimed to describe the overall incidence of dose-limiting toxicities (DLTs) during and after cycle 1, the frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 DLTs on conclusions drawn from oncology phase I clinical trials. Methods: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. Only trials that included more than one cycle of therapy were included. Data elements captured included: year of publication, study design, trial sponsor type, intervention type, number of anti-cancer therapies involved, primary diagnosis, incidence and type of cycle 1 DLT, incidence of dose modification in cycle 1, incidence and type of post-cycle 1 DLTs, incidence of dose modification in post-cycle 1, presence of a recommended phase 2 dose (RP2D) and impact of subsequent cycle toxicity on RP2D. Results: From 2000 to 2020, we identified 489 full-text articles reporting on therapeutic phase I clinical trials. Of these, 421 (86%) reported data regarding cycle 1 DLTs and 170 (35%) reported cycle 1 dose modifications. The overall median cycle 1 DLT rate was 8.89%. Only 47 (9.6%) publications reported whether or not there were post-cycle 1 DLTs and only 92 (19%) reported whether or not there were dose modifications beyond cycle 1. The overall median post-cycle 1 DLT rate among trials that reported post-cycle 1 data was 14.8%. A RP2D was reported in 76% (371 of 489) trials. Among these 371 studies, 89% did not report whether post-cycle 1 toxicities impacted the RP2D. Independent predictors of reporting toxicity data beyond cycle 1 included year of publication, investigational agent type, novelty, disease type, trial size, and sponsor. Conclusions: Reporting of subsequent cycle DLTs and dose modification is uncommon in oncology phase I clinical trial publications. As newer oncology treatments trend towards longer duration of treatment, there will be an increased need to understand toxicities occurring post-cycle 1. Guidelines for reporting of phase I clinical trials should expand to include toxicity data beyond the first cycle.

ARC-20: A phase 1 dose-escalation and dose-expansion study to investigate the safety, tolerability, and pharmacology of HIF-2α inhibitor AB521 monotherapy in patients with clear cell renal cell carcinoma and other solid tumors.

TPS4602 Background: Renal cell carcinoma (RCC) is one of the 10 most common neoplasms in the United States. Patients with clear cell RCC (ccRCC) commonly have inactivation of the von Hippel-Lindau tumor suppressor protein, resulting in accumulation of hypoxia-inducible factor alpha (HIFα) subunits (especially HIF-2α) and leading to tumor growth. AB521, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. Single doses of AB521 (3 mg, 10 mg, 30 mg, and 100 mg) and multiple ascending doses of AB521 (15 mg, 30 mg, and 50 mg) have been previously studied in healthy volunteers. ARC-20 is a first-in-patient study to investigate the safety, tolerability, and pharmacology of AB521 monotherapy in patients with solid tumors and evaluate the clinical activity of AB521 in previously treated patients with ccRCC. Methods: ARC-20 (NCT05536141) is a phase 1, multicenter, open-label study. Eligible patients are adults with solid tumors with ≥1 measurable lesion(s) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group performance status of 0 or 1. ARC-20 has 2 stages, dose escalation and dose expansion. The dose escalation stage uses a standard 3+3 design and includes patients with pathologically confirmed solid tumors and no other available treatment options. Patients will be sequentially assigned to 1 of 4 cohorts evaluating doses of AB521 ranging from 20 to 200 mg/day. Intermediate dose cohorts may be evaluated based on emergent safety or pharmacologic data. The dose expansion stage will evaluate approximately 30 patients with histologically confirmed ccRCC who have received previous treatment for metastasis with an anti-programmed cell death protein 1 (anti-PD-1) therapy and a vascular endothelial growth factor (VEGF)-targeting tyrosine kinase inhibitor (TKI). Patients previously treated with a HIF-2α-targeting therapy are not eligible for dose expansion. Results from the dose-escalation stage will inform the dose and schedule used during dose expansion. Primary endpoints are the incidence of dose-limiting toxicity and adverse events. Secondary endpoints include objective response rate, AB521 plasma concentration, and AB521 pharmacokinetics. Exploratory endpoints include changes in expression of erythropoietin and other HIF-2α driven biomarkers in blood and tumor tissues, along with progression-free survival for ccRCC patients during dose expansion. Clinical trial information: NCT05536141 .

A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors.

The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors. T-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST). Fifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to <12 years old (melanoma, n = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response. T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed. ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.

Investigating the Effects of Brain Cholesterol Metabolism Using CYP46A1 Gene Therapy in Subjects with Huntington’s Disease (P1-11.016)

<h3>Objective:</h3> To report the clinical trial study design evaluating the safety, tolerability, and preliminary efficacy of investigational gene therapy rAAVrh10.CYP46A1wt (AB-1001) in subjects with Huntington’s disease (HD). <h3>Background:</h3> HD is a progressive, genetic neurodegenerative disorder linked to cholesterol dysregulation and subsequent protein aggregation in the brain. A neuron-specific enzyme, cholesterol-24-hydroxylase (CYP46A1), assists in regulating brain cholesterol synthesis and metabolism, and is deficient in subjects with HD. CYP46A1 restoration in striatal neurons using the adeno-associated virus (AAV) therapy AB-1001 led to reduced mutant Huntingtin protein aggregation and improved pathology hallmarks in two mouse models. <h3>Design/Methods:</h3> This first in-human, Phase 1/2, open-label, dose-finding study will consist of one-time intracerebral bilateral injections of AB-1001, an investigational AAV gene therapy comprising an AAVrh10 vector carrying gene encoded CYP46A1, within the striatum. To be eligible for enrollment, subjects will be 18–65 years old, possess a CAG expansion in the huntingtin gene ≥40, have early manifest HD, and have striatal MRI volumes per hemisphere compatible with local delivery of study drug. The trial will include screening (8 weeks), treatment and initial follow-up (52 weeks), and long-term follow-up (4 years). The treatment phase includes dose-finding (Cohort 1: n=3–6, single dose of 4.0E8 vg/μL; Cohort 2: n=3–6, single dose of 1.1E9 vg/μL) and dose-expansion (n=6, nonsequential dosing with selected dose). The primary endpoint will be the incidence of dose-limiting toxicities, treatment-emergent adverse events, and serious adverse events. Secondary endpoints include change from baseline to week 52 in MRI-assessed measures of HD-impacted brain regions, composite Unified Huntington’s Disease Rating Scale (cUHDRS), and MRS metabolic profile. Other endpoints include additional HD biomarkers and quality-of-life measures. <h3>Results:</h3> N/A <h3>Conclusions:</h3> Preclinical results show the potential for CYP46A1 gene therapy with AB-1001 to demonstrate therapeutic benefits in subjects with HD and rationalize progression to the first in-human Phase I/II clinical trial. <b>Disclosure:</b> Dr. Schultz has received personal compensation for serving as an employee of AskBio. The institution of Dr. Durr has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. The institution of Dr. Durr has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology Genetics. The institution of Dr. Durr has received research support from NIH. The institution of Dr. Durr has received research support from BIOGEN. The institution of Dr. Durr has received research support from MINORYX. The institution of Dr. Durr has received research support from TRIPLETS THERAPEUTICS. The institution of Dr. Durr has received research support from Servier. The institution of Dr. Durr has received research support from ANR. The institution of Dr. Durr has received research support from PTC. Prof. Karachi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston scientific / Medtronic / Neurotrials. Dr. O’Callaghan has received personal compensation for serving as an employee of Asklepios Biopharmaceuticals. Dr. O’Callaghan has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Asklepios Biopharmaceuticals. Dr. O’Callaghan has stock in Asklepios Biopharmaceuticals. Dr. O’Callaghan has received intellectual property interests from a discovery or technology relating to health care. Dr. ALVES has nothing to disclose. Dr. Lamontagne has received personal compensation for serving as an employee of Asklepios Biopharmaceutical Inc. Mrs. HURMIC has nothing to disclose. Dr. Cartier has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for askbio. Dr. Cartier has stock in brainvectis.

Abstract CT129: Trial in progress: ATHENA-1 - a phase 1, open-label, first-in-human study to assess safety and tolerability of REGN5837 in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas

Abstract Background: Many patients with relapsed/refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL) are unable to tolerate, access, or benefit from intensive chemo-therapeutic approaches or cellular therapies and will invariably relapse; therefore, novel approaches are urgently required. Odronextamab (REGN1979) is a hinge-stabilized, human CD20 × CD3 IgG4-based bispecific antibody that elicits T-cell-mediated cytotoxicity of malignant B cells. In a Phase 1 study, odronextamab monotherapy showed a manageable safety profile with encouraging preliminary activity in heavily pre-treated patients with R/R B-NHL (Bannerji R, et al. Lancet Haematol. 2022;9(5):e327-39). REGN5837 is a hinge-stabilized, human CD28 × CD22 IgG4-based bispecific antibody that provides a co-stimulatory signal (signal 2). When combined with odronextamab (signal 1), REGN5837 improved anti-tumor efficacy and survival in in vivo diffuse large B-cell lymphoma tumor models via enhanced T-cell expansion. We hypothesize that combining REGN5837 with odronextamab may deepen and extend anti-tumor activity in patients with aggressive lymphoma. Methods: ATHENA-1 (NCT05685173) is a Phase 1, open-label, first-in-human study of REGN5837 in combination with odronextamab in patients with R/R aggressive B-NHL. During induction, odronextamab and REGN5837 will be administered weekly over 21-day cycles. To mitigate potential CRS events, odronextamab will be introduced with step-up dosing as a monotherapy, followed by introduction of REGN5837 on C2 D15 with step-up dosing. Maintenance will consist of 28-day cycles (odronextamab and REGN5837 administration on D1, 15). Patients who achieve a sustained complete response (≥9 months) will have study drug(s) administration changed to once every 4 weeks. Patients must be aged ≥18 years, have Eastern Cooperative Oncology Group performance status ≤1, with adequate organ function, and have CD20+ aggressive B-NHL that progressed after ≥2 lines of systemic therapy containing at least an anti-CD20 antibody and an alkylating agent, with or without prior chimeric antigen receptor T-cell therapy. Exclusion criteria include prior allogeneic stem cell transplant, organ transplant, or CD20xCD3 bispecific antibodies, or mantle cell lymphoma or central nervous system lymphoma. Primary endpoints are incidence of dose-limiting toxicities and the incidence and severity of treatment-emergent adverse events. Secondary endpoints include pharmacokinetics of odronextamab and REGN5837, anti-drug antibody incidence, objective response rate, complete response rate, duration of response, progression-free survival, and overall survival. Enrolment is planned to open in early 2023. Citation Format: John Baird, Pim G. Mutsaers, Jeremy S. Abramson, Manjusha Namuduri, Jingjin Li, Nickolas A. Sophos, Min Zhu, Jurriaan Brouwer-Visser, Hesham Mohamed, Aafia Chaudhry, Andrew J. Davies. Trial in progress: ATHENA-1 - a phase 1, open-label, first-in-human study to assess safety and tolerability of REGN5837 in combination with odronextamab in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT129.

Phase 1 study of oral selective estrogen receptor degrader (SERD) amcenestrant (SAR439859), in Japanese women with ER-positive and HER2-negative advanced breast cancer (AMEERA-2)

BackgroundThis AMEERA-2 study evaluated the pharmacokinetics, efficacy, and safety of the oral selective estrogen receptor degrader amcenestrant as a monotherapy with dose escalation in Japanese postmenopausal women with advanced estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer.MethodsIn this open-label, nonrandomized, phase I study, patients received amcenestrant 400 mg once daily (QD) (n = 7) and 300 mg twice daily (BID) (n = 3). The incidence of dose-limiting toxicities (DLT), recommended dose, maximum tolerated dose (MTD), pharmacokinetics, efficacy, and safety were assessed.ResultsNo DLTs were observed and MTD was not reached in the 400 mg QD group. One DLT (grade 3 maculopapular rash) was reported in a patient treated with 300 mg BID. After repeated oral administration of either dosing regimen, steady state reached before day 8, without accumulation. Four out of 5 response-evaluable patients from 400 mg QD group achieved clinical benefit and showed tumor shrinkage. No clinical benefit was reported in the 300 mg BID group. Overall, most patients (8/10) experienced a treatment-related adverse event (TRAE), with skin and subcutaneous tissue disorders most commonly reported (4/10 patients). No ≥ grade 3 TRAE in 400 mg QD group and 1 grade 3 TRAE in 300 mg BID group were reported.ConclusionsAmcenestrant 400 mg QD has a favorable safety profile and has been selected as the recommended Phase II dose for monotherapy for evaluating the safety and efficacy of amcenestrant in a larger, global, randomized clinical trial of patients with metastatic breast cancer.Trial registrationClinical trial registration NCT03816839.

Abstract P4-01-07: FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study

Abstract Background: FS-1502 is a HER2-targeting antibody drug-conjugate with a cleavable β-glucuronide linker and an antimitotic agent (monomethyl auristatin F) which showed promising antitumor activity in preclinical studies. We are evaluating the safety and tolerability of FS-1502 in patients with HER2-expressing advanced solid tumors (NCT03944499). Methods: Patients with HER2-expresssing advanced solid tumors who had failed prior standard of care therapies were enrolled in a single-arm, open-label, dose-escalation phase Ia study in China. FS-1502 was given IV once in 21-day or 28-day cycles. The primary endpoint was incidence of dose-limiting toxicity (DLT). Adverse events (AEs), objective response rate (ORR) and duration of response (DoR) were also assessed. Data cutoff was December 30, 2021. Results: A total of 67 patients, 64 with breast cancer and 3 with other solid tumors, with median 3 prior therapies (range 1-10), were enrolled in 5 sites and treated with FS-1502 at doses of 0.1-3.5 mg/kg. Two DLTs, as defined by the protocol, were observed, with one G2 decrease in creatinine clearance at 3.0 mg/kg and one G3 thrombocytopenia with hemorrhage at 3.5 mg/kg. No Grade 4/5 events were observed. Grade 3 TRAEs were observed in 24 (35.8%) patients with the most common AEs of hypokalemia (14.9%) and decreased platelet count (9.0%). ORRs were observed at doses at or above 1.0 mg/kg with an ORR of 66.7% (4/6) at the recommended phase 2 dose (RP2D) of 2.3 mg/kg. Median duration of response (DoR) across all dose levels was 9.2 months (95%CI 5.6-NR). ORR for HER2-low patients was 42.9% (3/7). Plasma concentration and exposure (AUC) based on total ADC and total antibody increased dose proportionally at ≥1.0 mg/kg, with a T1/2 of 2.4-4.9 days. The incidence and magnitude of immunogenicity were low. While no MTD was determined, the 2.3mg/kg dose once in a 21-day cycle was selected as the RP2D based on safety, antitumor activity and PK data. Conclusions: FS-1502 was well-tolerated and demonstrated encouraging antitumor activity in both HER2-high and -low patients. Phase Ib and phase II clinical trials with FS-1502 are currently ongoing in various solid tumor indications including breast, gastric, and colorectal cancer. Citation Format: Qiao Li, Xian Wang, Ying Cheng, Yunjiang Liu, Jianhua Chang, Zhuo Wang, Chunjiao Wu, Mingxia Wang, Ai-Min Hui, Zhuli Wu, Yongli Jin, Xin Huang, Liping Zhong, Lei Diao, Han Zhao, Binghe Xu. FS-1502, an anti-HER2 ADC, in Patients with HER2-Expressing Advanced Solid Tumors: A Phase 1a Dose-Escalation Study [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-07.

Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.

TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein &lt;2+ or ≥2+ but 24-h urine protein:creatinine ratio &lt;2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .

A phase 1, open-label trial to evaluate feasibility and safety of intramural injection of belzupacap sarotalocan (AU-011) in non-muscle–invasive bladder cancer (NMIBC).

TPS596 Background: A high unmet medical need exists for new therapies in NMIBC to reduce common risks of recurrence, progression and, ultimately, cystectomy. Belzupacap sarotalocan, a novel investigational virus-like drug conjugate (VDC), has a dual mechanism of action designed to provide 1) selective binding to malignant cells, causing acute necrosis upon light activation, and 2) long-term anti-tumor immunity as demonstrated in pre-clinical models. This Phase 1 trial is designed to evaluate the feasibility and safety of intramural injection with or without intratumoral injection of belzupacap sarotalocan for treatment of NMIBC. The hypothesis is that after near infrared light activation, targeted distribution of belzupacap sarotalocan at high concentrations at the tumor base could necrose the tumor where it is most likely to be invasive. In turn, the tumor targeted pro-immunogenic cell death could potentially lead to an anti-tumor immune response preventing the risk for recurrence, progression and metastasis. Methods: This is an actively enrolling “window of opportunity” trial (NCT05483868) in low, medium or high risk NMIBC subjects scheduled to undergo TURBT or cystectomy per standard of care. A pre-treatment biopsy will be performed in up to 23 adult subjects enrolled in 4 cohorts, who will be given belzupacap sarotalocan +/- laser as shown in the table. The primary endpoint is incidence and severity of treatment-related adverse events, serious adverse events regardless of attribution, and incidence of dose-limiting toxicities. Each cohort will have a safety review for the injection procedure and laser (as needed), after 3 subjects have been treated and followed for 28 days. Secondary endpoints are based on histopathology and include assessment of local biodistribution of belzupacap sarotalocan measured via immunohistochemical staining, tumor necrosis, and evidence of an immune response via comparison of pre-treatment biopsy to TURBT/cystectomy samples after treatment. Statistical analysis plan includes descriptive statistics for the above endpoints. Clinical trial information: NCT05483868 . [Table: see text]

A phase Ia/Ib, open-label, dose escalation study of the TRAILR2 agonist BI 905711 in combination with chemotherapy (CT) in patients (pts) with advanced GI cancers.

TPS820 Background: Activation of the tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAILR2) induces apoptosis via the extrinsic pathway. Targeting TRAILR2 presents an attractive therapeutic strategy, but some early TRAILR2 agonists showed low efficacy or severe hepatotoxicity. BI 905711 (TRAILR2 agonist) is a novel, liver-sparing, tetravalent bispecific antibody that cross-links TRAILR2 with the membrane protein cadherin 17 (CDH17; highly expressed in GI cancers), inducing CDH17-dependent TRAILR2 oligomerization. CDH17 is not expressed in normal hepatocytes, thus increasing BI 905711 selectivity to GI cancer cells while sparing hepatocytes. Preclinical models and studies in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) showed BI 905711 activity ± CT, and synergy with standard of card CT irinotecan, respectively. Methods: This Phase Ia/Ib, open-label, multicenter study (NCT05087992) aims to determine the maximum tolerated dose (MTD), recommended dose for expansion (RDE), pharmacokinetics (PK), and efficacy of BI 905711 with CT (FOLFIRI; irinotecan, leucovorin, and fluorouracil) ± bevacizumab (BEV) in pts with advanced GI cancers. Up to 100 pts with histologically/cytologically confirmed, advanced, unresectable, or metastatic GI cancers will be enrolled. In Phase Ia, ~20 pts with CRC will receive BI 905711 intravenously every two weeks at escalating doses (starting dose 0.6 mg/kg) on Day 3 of 14-day cycles, + FOLFIRI and BEV (5 mg/kg intravenous infusion for 30 minutes) on Day 1. A Bayesian logistic regression model with overdose control based on dose-limiting toxicities (DLTs) during the MTD evaluation period (first 2 cycles) will guide BI 905711 dose escalation. BI 905711 will be administered until disease progression, unacceptable toxicity, or other reasons requiring treatment discontinuation. In Phase Ib, pts with CRC or PDAC will be enrolled to one of two dose expansion cohorts. In the CRC cohort, pts with prior progression on oxaliplatin-based therapy will be randomized 2:1 to receive FOLFIRI and BEV ± BI 905711. In the PDAC cohort, pts with CDH17+ PDAC with prior progression on gemcitabine-based first-line therapy will receive FOLFIRI + BI 905711. Both cohorts will receive BI 905711 at the RDE defined in Phase Ia. A safety run-in period will confirm the Phase Ia RDE result before enrolling pts to the PDAC cohort. Primary endpoints: MTD based on incidence of DLTs (Phase Ia) and confirmed objective response (OR; RECIST 1.1; Phase Ib). Secondary endpoints include PK assessments (Phase Ia), progression-free survival, tumor shrinkage, duration of OR, and disease control (Phase Ib). Further endpoints include immunogenic response assessment and pharmacodynamic biomarker modulation. As of September 2022, eight pts have been enrolled; one additional pt is in screening. The study is ongoing. Clinical trial information: NCT05087992 .

Trials in progress: A phase 1, open-label, pharmacokinetic, safety and tolerability study of PF-07265807 (selective TAM kinase inhibitor) alone or with sasanlimab in patients with advanced or metastatic solid tumors.

TPS270 Background: Inhibition of Mer Proto-oncogene tyrosine kinase (MERTK) and AXL may lower the threshold for immune activation thereby promoting anti-tumor activity. PF-07265807 (ARRY-067) is a selective small-molecule inhibitor of the tumor-associated macrophage kinases MERTK and AXL. In preclinical models, PF-07265807 plus anti-programmed cell death protein 1 (anti-PD-1) antibodies show antitumor activity that results in long-term cures and resistance to tumor re-challenge. Sasanlimab is a monoclonal antibody to PD-1 administered subcutaneously (300 mg every 4 wk or equivalent); it has an acceptable safety profile and is being tested in a Phase 3 trial in non-muscle invasive bladder cancer. This first-in-human study will evaluate safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of PF-07265807 alone and with sasanlimab in patients (pts) with selected advanced or metastatic solid tumors. Study design of PF-07265807 monotherapy dose escalation (Part 1) was presented at ASCO 2021 (TPS2671). Here, we describe dose escalation (Part 2) and dose expansion (Part 4) cohorts for the doublet combination of PF-07265807 + sasanlimab. Methods: This is a Phase 1, open-label, multi-center study (NCT04458259) of PF-07265807. Adult pts with selected advanced or metastatic solid tumors who are intolerant or resistant to standard therapy will enroll into doublet therapy dose escalation (Part 2). Pts who are anti-PD-1/PD-L1 treatment naïve with intermediate tumor mutational burden (defined as ≥6 and &lt; 16 microsatellite stable) colorectal cancer (CRC) or PD-L1+ (defined as combined positive score ≥1) gastric cancer will enroll into doublet therapy dose expansion cohorts (Part 4). Other key eligibility criteria: measurable or non-measurable disease by RECIST 1.1; ECOG PS 0–2; adequate bone marrow, renal and liver function; and resolved acute effects of any prior therapy. Each cycle will be 21 days. Treatment will continue until disease progression or unacceptable toxicity, whichever occurs first. The doublet maximum tolerated dose (MTD) will be guided by a Bayesian analysis of dose limiting toxicity (DLT) data for doublet therapy (Part 2). The recommended phase 2 dose (RP2D) will then be determined via holistic data review with/without the MTD identification. Primary endpoints in Part 2 include the incidence of DLTs, adverse events and laboratory abnormalities. After doublet MTD/RP2D is identified in Part 2, the preliminary anti-tumor activity of PF-07265807 + sasanlimab will be explored in Part 4. Primary endpoints in Part 4 include objective response and complete response rates; secondary endpoints include disease control rate and response duration, adverse events and laboratory abnormalities. The study began in Q4 2020 and is recruiting pts. Clinical trial information: NCT04458259 .

Phase 1 Study of the Selective c-MET Inhibitor, HS-10241, in Patients With Advanced Solid Tumors

Introductionc-MET is an important therapeutic target for various cancers; however, the People’s Republic of China currently retails only one specific c-MET inhibitor. Our preclinical study has revealed the high selectivity of HS-10241 to suppress c-MET. This phase 1 study aims to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of the selective c-MET inhibitor (HS-10241) in patients with advanced solid tumors. MethodsPatients with locally advanced or metastatic solid tumors orally received a single or multiple dose of HS-10241 once daily or twice daily for 21 consecutive days, which included the following six regimens: 100 mg once daily, 200 mg once daily, 400 mg once daily, 600 mg once daily, 200 mg twice daily, and 300 mg twice daily. The treatment continued until disease progression, unacceptable toxicity, or treatment termination. The primary end point was the incidence of dose-limiting toxicity and maximal tolerated dose (MTD). Secondary end points included safety, tolerability, pharmacokinetics, and pharmacodynamics. ResultsA total of 27 patients with advanced NSCLC received HS-10241, and dose-limiting toxicity was observed in three patients after 600 mg once-daily HS-10241 treatment. For once-daily dosing, MTD was 400 mg, and for twice-daily dosing, the maximal safe escalated dose was 300 mg, and MTD was not reached. Nausea (48.1%, 13 of 27), fatigue (37.0%, 10 of 27), and anemia (33.3%, 9 of 27) are the three most frequent treatment-emergent adverse events. At 400 mg once daily, Css,max was 5076 ng/mL and steady state area under the curve was 39,998 h × ng/mL. Patients (n = 5) with positive MET (MET exon 14-skipping, MET amplified, and MET immunohistochemistry 3+) had confirmed partial responses (n = 1) or stable disease (n = 3), with a disease control rate of 80.0%. ConclusionsThe selective c-MET inhibitor HS-10241 was well tolerated and had clinical activity in advanced NSCLC, especially in patients with positive MET. Furthermore, this study expounds on the therapeutic potential of HS-10241 in patients with cancer.

Siremadlin Monotherapy and in Combination with Donor Lymphocyte Infusion for Patients with Acute Myeloid Leukemia Post Allogeneic Stem Cell Transplantation Who Are in Complete Remission but at High Risk for Relapse

Background: Relapse post allogeneic stem cell transplantation (SCT) remains the main cause of treatment failure (~40%) for patients (pts) with acute myeloid leukemia (AML). Many pts who ultimately relapse post SCT do so within the first year post transplant, and earlier relapse is associated with poorer survival. Therapeutics that prevent early relapse for these pts are urgently needed. Early cellular or pharmacologic intervention or maintenance strategies that enhance the graft-versus-leukemia (GvL) effect after SCT are of renewed interest as they have the potential to reduce relapse risk post SCT. Siremadlin (HDM201) is a novel investigational MDM2 inhibitor with single-agent, anti-AML activity. MDM2 inhibitors, including siremadlin, possess potent immunomodulatory effects in murine solid tumor and AML models. MDM2 inhibition has been shown to synergize with the allogeneic immune response, increase the vulnerability of AML cells to allogeneic donor T cells, and promote the cytotoxicity and longevity of allogeneic donor T cells in murine models. As such, the post-SCT setting is ideal for investigating the immunomodulatory effects of MDM2 inhibition on enhancing the GvL effect (Ho et al. Blood. 2022). Here we describe the design of a Phase Ib/II, open-label study of siremadlin as monotherapy and in combination with donor lymphocyte infusion (DLI) in pts with AML post SCT who are in complete remission (CR) but at high risk for relapse based on the presence of pre-SCT risk factors (NCT05447663). Study Design: The trial is not yet recruiting but aims to enroll ~38 adult pts with AML who underwent first SCT and are currently between Day 60-120 post SCT. Prior to a patient's SCT, they must have a risk factor that puts them at high risk for relapse, including AML in first CR with adverse risk genetics per 2017 European LeukemiaNet risk stratification, therapy-related AML, or secondary AML; or AML in second or greater CR. The SCT must be from an 8/8 human leukocyte antigen (HLA) matched related or unrelated donor at HLA-A, -B, -C, -DRB1 loci using unmanipulated/T-cell replete bone marrow or peripheral blood stem cells as a stem cell source. Post SCT, pts must have achieved CR or CR with incomplete hematologic recovery (CRi) with no evidence of hematologic relapse. Exclusion criteria include prior exposure to an MDM inhibitor, active graft-vs-host disease (GvHD), past history of grade ≥III acute GvHD (aGvHD) or moderate/severe chronic GvHD (cGVHD), recipient of SCT from a haploidentical family donor or cord blood transplant, and prior systemic AML-directed treatments given at any time after SCT (including DLI). This study contains 2 parts, Part 1 is a dose confirmation of siremadlin monotherapy and will enroll ~12 pts. Siremadlin will be tested at a maximum of 3 dose levels with a starting dose of 30 mg/d on Days 1-5 of a 28-day cycle, dose level +1 at 40 mg/d and dose level -1 at 20 mg/d. The safety and tolerability of these dose levels will be assessed to determine the siremadlin recommended dose (RD) for Part 2. Pts in Part 1 of the study will receive siremadlin monotherapy for the entire duration of the treatment and will not receive DLI. Subsequently, ~26 pts will be enrolled in Part 2 and proceed through a priming phase with siremadlin monotherapy at the RD, followed by a combination phase of siremadlin + DLI, and subsequently a maintenance phase with siremadlin monotherapy (Figure). Primary safety endpoints of the study are incidence of dose-limiting toxicities (DLTs) in Part 1 and time to DLT in Part 2. The primary efficacy endpoint is the proportion of pts in Part 2 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment. Secondary endpoints include number of pts in Part 1 who are alive and maintained CR/CRi without hematologic relapse ≥6 months after the start of study treatment at the RD for Part 2, time to first documented hematologic relapse or death, incidence of relapse at 1 year and 2 years post study treatment, safety, GvHD-free/relapse-free survival, incidence of and time to treatment-emergent grade ≥III aGvHD or moderate/severe cGvHD, and pharmacokinetics. Conclusions: This Phase Ib/II study investigates siremadlin monotherapy and siremadlin in combination with DLI in pts with AML in remission but at high risk of relapse post SCT. The study will evaluate the unique immunomodulatory potential of siremadlin to reduce risk of relapse in this population with high unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Safety and Efficacy of p CAR-19B, a Scfv Humanlized CD19-Directed CAR-T for Patients with Relapsed/Refactory (R/R) CD19+ B-ALL

Introduction: Two murine anti-CD19 scFv based chimeric antigen receptors T cell (CAR-T) products have been approved by FDA for children and adults R/R B-ALL patients, with about 50%-70% complete remission (CR) rates. Humoral and/or cellular immune responses against murine scFv may attenuate the efficacy. To reduce immunogenicity of murine scFv, we developed an optimal humanized anti-CD19 CAR-T product named pCAR-19B, which have a CAR structure including humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Here we report the preliminary safety and efficacy data for the adults R/R B-ALL patients in a phase I clinical trials. Methods: In the phase Istudy (NCT04888442), Eligible patients were histologically confirmed CD19+ B-ALL, KPS＞60, relapsed or refractory to standard therapies. Patients received single-dose of pCAR-19B at dose level 1 (DL1) (0.6×106 CAR/kg), level 2 (DL2) (2×106 CAR/kg) after fludarabine (25-30 mg/m2 × 3 days) and cyclophosphamide (10-20mg/ kg× 3 days) based pre-condition. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Primary endpoint is the incidence of dose-limiting toxicities (DLTs) in the first 28 days. Secondary endpoints are cellular kinetics, overall response rate (CR/CRi), duration of response, and overall survival. Results: As of June 30, 2022, nine patients (3 in DL1, 6 in DL2) were infused with pCAR-19B and all patients have finished at least 6 months follow up visit. Demographics, baseline disease, prior treatment and special concerned adverse events are presented in the table. CAR-T-related adverse events occurred in 9 patients (9/9, 100%), no adverse events leading to patient withdrawal from the study occurred. 8 patients (8/9, 89%) experienced cytokine release syndrome (CRS), including 5 (5/9, 56%) grade 1, 3 (3/9, 33%) grade 2, and no grade 3 or higher CRS occurred. Two patients (2/9, 22%) experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including 1 (1/9, 11%) grade 1, 1 (1/9, 11%) grade 2, and no grade 3 or higher ICANS occurred. No DLTs were reported. 100% (9/9) CR/CRi was achieved in the first month after CAR-T infusion. The relapse-free survival (RFS) is presented in the figure. The median OS and RFS is not reached yet. No anti-CAR antibody was detected in any patients in 1M and 3M after CAR-T infusion. Conclusion: pCAR-19B has demonstrated a good safe profile and 100% CR rate in phase I study for adults R/R CD19+ B-ALL. The muti-center pivotal study is going to recruit patients soon in China. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trial in Progress: A Phase II Window of Opportunity Study of the BCMAxCD3 Bispecific Antibody REGN5458 in Previously Untreated Patients with Symptomatic Multiple Myeloma

Background Treatment of multiple myeloma (MM) has advanced significantly in the last 20 years, resulting in improved survival. For patients with newly diagnosed MM (NDMM) who are fit with no comorbidities, currently recommended treatment includes induction with triplets such as bortezomib, lenalidomide, and dexamethasone (VRd), followed by high-dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT), and maintenance therapy using predominantly immunomodulatory agents. Patients who are elderly or ineligible for HDT/ASCT receive multiple drug combination therapies such as VRd or daratumumab with Rd. Despite the availability of these combinations, induction therapy does not induce complete remission with minimal residual disease negativity in all patients, and triplet- or quadruplet-based regimens are expensive and associated with enhanced toxicities including to stem cells. Moreover, MM remains incurable and new therapies with alternative mechanisms may improve or maintain the safety profile while increasing or deepening responses for longer periods. B-cell maturation antigen (BCMA) is a cell surface protein expressed on malignant plasma cells (Lee, et al. Br J Haematol. 2016;176:911-22). Notably, BCMA is detected only at low levels on normal plasma cells, activated B cells, and plasmacytoid dendritic cells, making it an attractive therapeutic target for MM. REGN5458 is a BCMA×CD3 bispecific antibody capable of binding to BCMA on MM cells and CD3 on T cells, inducing T-cell mediated cytotoxicity of MM cells. REGN5458 monotherapy has demonstrated early, deep, and durable responses with a manageable safety and tolerability profile in patients with relapsed/refractory (R/R) MM (NCT03761108; Zonder, et al. EHA 2022. Abstract S189) with a response rate of 75% among patients treated at the 200-800 mg dose levels. Cytokine release syndrome was reported in 38% of patients and was mostly Grade 1, with no Grade ≥3 events. Given the single agent efficacy and tolerability of REGN5458 in heavily pre-treated patients with R/R MM, its use in patients with NDMM (who are thought to potentially have improved T-cell fitness versus R/R patients) is hypothesized to have enhanced therapeutic benefit. Study Design and Methods This open-label, Phase II study aims to assess the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of REGN5458 monotherapy in patients with NDMM who are eligible or ineligible for HDT/ASCT. Transplant-eligible patients will receive REGN5458 induction, HDT/ASCT, followed by REGN5458 consolidation, and standard of care maintenance therapy. Transplant-ineligible patients will receive REGN5458 until disease progression or other discontinuation criteria are met (Figure). The primary objectives during part 1 are to assess safety and tolerability and to determine a recommended regimen for expansion. The objective for dose expansion is to assess preliminary antitumor activity. Secondary objectives are to evaluate the PK properties and immunogenicity of REGN5458 as well as soluble BCMA concentrations in serum at baseline and over time. The primary endpoints for part 1 are: the incidence of dose-limiting toxicities (DLTs) from the first dose of study drug to the end of the DLT observation period; the incidence and severity of treatment-emergent adverse events and adverse events of special interest with REGN5458 through study completion; for expansion: the proportion of patients with a very good partial response or better as determined by the investigator using International Myeloma Working Group response criteria; and the proportion of patients achieving minimal residual disease-negative status (at 10-5). Patients will have a window of opportunity to benefit from treatment; patients who do not meet the specified efficacy thresholds will transition to standard of care therapies. Approximately 92 patients are planned for this study. Eligibility criteria include age ≥18 years; ECOG PS 0-2; histologically or cytologically confirmed symptomatic MM; measurable disease; no prior therapy for MM, except radiation on an emergency/palliative basis or 1 month of single-agent corticosteroid if the patient still has measurable disease; and adequate bone marrow reserves, hepatic, renal, and cardiac function. The study will take place in approximately 20 sites located in North America and Europe. There are no formal hypothesis tests for this study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intravitreal Carboplatin as Salvage Treatment for Progressive Vitreous Disease in Retinoblastoma: A Phase I Clinical Trial

To determine the safety and toxicity profile of intravitreal carboplatin as salvage treatment for retinoblastoma with vitreous disease. Single-institution, interventional prospective clinical trial. Patients with progressive or recurrent vitreous seeds after completion of primary treatment for intraocular retinoblastoma. Eligible eyes received an intravitreal injection of carboplatin every 14 to 21 days with simultaneous focal therapy (laser, thermotherapy, and brachytherapy) provided at the discretion of the ocular oncologist. The evaluation with examination under anesthesia, ultrasound biomicroscopy, and electroretinography (ERG) were performed before each injection to assess for tumor response and drug-related toxicity. A serious adverse event resulted in dose recalculation and ultimately early closure of the study. Regression pattern of vitreous disease and incidence of dose-limiting toxicities. Four patients were enrolled at an initial dose of 0.3 mg. Complete regression of vitreous seeds was noted in all patients after 5, 2, 2, and 1 injections (respectively). Two patients developed recurrent vitreous disease at 3 and 25 months after complete regression and ultimately required enucleation. A serious adverse event occurred in 1 patient who developed acute vision loss with extinguished ERG response 72 hours after the second injection; ultimately, this eye developed a cataract and required enucleation. After temporary suspension and dose modification, 3 patients were enrolled at an injection dose of 3 μg and treated with a total of 5, 2, and 1 injections, respectively. Complete regression of vitreous disease was not achieved in any patient though ERG amplitudes remained stable. After removal from protocol, all 3 patients had a complete response to intravitreal melphalan. Concern for dose escalation and further toxicity in the setting of an effective and safe alternative (melphalan) led to the termination of the study. Intravitreal carboplatin may be effective in treating progressive vitreous seeding at higher doses, but permanent retinal toxicity was observed. Other alternative agents should be considered. Proprietary or commercial disclosure may be found after the references.