Incidence Of Dose-limiting Toxicities Research Articles

Vascular adhesion protein-1 blockade in primary sclerosing cholangitis: Open-label, multicenter, single-arm, phase II trial.

Primary sclerosing cholangitis is a progressive inflammatory liver disease characterized by biliary and liver fibrosis. Vascular adhesion protein-1 (VAP-1) is important in the inflammatory process driving liver fibrosis. We evaluated the safety and efficacy of VAP-1 blockade with a monoclonal antibody (timolumab, BTT1023) in patients with primary sclerosing cholangitis. BUTEO was a prospective, single-arm, open-label, multicenter, phase II trial, conducted in 6 centers in the United Kingdom. Patients with primary sclerosing cholangitis aged 18-75 years had an alkaline phosphatase value of >1.5 times the upper limit of normal. The dose-confirmatory stage aimed to confirm the safety of timolumab through the incidence of dose-limiting toxicity and sufficient trough levels of circulating antibody to block VAP-1 function. The primary outcome of the dose-expansion portion of the trial was patient's response to timolumab at day 99, as measured by a reduction in serum alkaline phosphatase by 25% or more from baseline to day 99. Twenty-three patients were recruited: 7 into the initial dose-confirmatory stage and a further 16 into an expansion stage. Timolumab (8mg/kg) was confirmed to be safe for the duration of administration with sufficient circulating levels. Only 2 of the 18 evaluable patients (11.1%) achieved a reduction in alkaline phosphatase levels of 25% or more, and both the proportion of circulating inflammatory cell populations and biomarkers of fibrosis remained unchanged from baseline. The BUTEO trial confirmed 8mg/kg timolumab had no short-term safety signals and resulted in sufficient circulating levels of VAP-1 blocking timolumab. However, the trial was stopped after an interim assessment due to a lack of efficacy as determined by no significant change in serum liver tests.

Abstract CT087: A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC)

Abstract Background: Progression to metastatic castration-resistant prostate cancer (mCRPC) occurs in most patients treated with androgen receptor signaling inhibitors (ARSi) for advanced disease. Preclinical studies demonstrate that AR and PI3K - AKT - mTOR (PAM) pathways interact through reciprocal negative feedback, whereby inhibition of one pathway activates the other. Thus, combining a PAM inhibitor with an ARSi may deliver improved anti-cancer activity in patients with mCRPC. A Phase 2 trial in 129 patients with mCRPC who progressed on abiraterone demonstrated improved median radiographic progression-free survival (rPFS) when samotolisib, a dual PI3K-mTOR inhibitor, was added to enzalutamide. These results form the basis for this clinical trial of gedatolisib, a potent PAM inhibitor, in combination with darolutamide in men with mCRPC who have previously progressed on ARSi (NCT06190899). Methods: This open-label, multicenter, Phase 1/2 study will evaluate the safety and efficacy of gedatolisib in combination with darolutamide in men with mCRPC who have progressed on ARSi. In Phase 1, 36 patients will be randomized to one of two dose arms to evaluate dose limiting toxicities (DLTs) and determine the recommended Phase 2 dose (RP2D). Gedatolisib will be administered once weekly for 3-weeks-on/1-week-off: Arm 1 - 120 mg and Arm 2 - 180 mg, with darolutamide 600 mg orally administered twice daily. Arm 2 may be dose de-escalated depending on the number of DLTs observed. In Phase 2, 12 additional patients will be enrolled at the RP2D (n= 30). Key inclusion criteria include adult males (≥ 18 years) with mCRPC who have progressed on or after treatment with one next-generation ARSi. Key exclusion criteria include males with adenocarcinoma with a small cell component and with ≥10% neuroendocrine type cells; prior treatment with PI3K, AKT, or mTOR inhibitor; prior chemotherapy or radiopharmaceutical therapy for mCRPC; uncontrolled type 1/2 diabetes; or active brain or leptomeningeal metastases. Primary endpoints for Phase 1 are safety and tolerability (incidence of DLTs, adverse events, and determination of maximum tolerated dose) determination of the recommended Phase 2 dose (RP2D), PK, and Bayesian Optimal Interval utility score. Primary endpoints for Phase 2 are rPFS rate at 6 months based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with modifications as specified in Prostate Cancer Working Group 3 criteria. Secondary endpoints include rPFS rates at 9 and 12 months, overall rPFS, prostate-specific antigen response of ≥50% decrease from baseline at 4, 8, 12, and 16 weeks, overall response rate, duration of response, clinical benefit rate, overall survival rate at 18 and 24 months, and safety. The trial is currently open for enrollment. Citation Format: Adam Sharp, Alice Bernard-Tessier, Delphine Borchiellini, Johann de Bono, Karim Fizazi, Gwenaelle Gravis, David Lorente, Hakim Mahammedi, Begona Mellado, David Olmos, Simon Pacey, Jose Piulats, Sara P. Ramirez, Igor Gorbatchevsky, Elisabeth Heath. A phase 1/2, open-label, randomized, dose-finding and dose expansion study of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT087.

Abstract LB236: Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses

Abstract Background: The undeniable success of CD19 CAR-T cell therapy in managing relapsed or refractory (r/r) B-cell hematological malignancies, such as diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL), underscores its significance. Despite the favorable complete remission (CR) rates of around 50% for r/r DLBCL and up to 90% for r/r B-ALL, a notable challenge persists as more than half of patients experiencing CR after CD19 CAR-T cells treatment encounter relapse within a year, attributed to inadequate CAR-T persistence in both indications. Urgent attention is required to devise innovative strategies to overcome these challenges. Recently, we developed metabolically armed CD19 CAR-T cells expressing IL-10 can enhance OXPHOS metabolism, proliferation, and persistence of CAR-T cells in vivo. Significantly, these IL-10-expressing CAR-T cells trigger stem-like memory responses in various lymphoid organs, leading to robust tumor eradication and durable protection. Motivated by these promising findings, an open-label, single arm, investigator-initiated trial (IIT, ClinicalTrials.gov identifier: NCT05715606, NCT05747157) was conducted to assess the safety and efficacy of newly developed metabolically armed IL-10-expressing CD19 CAR-T (product name: Meta10-19 infusion) for treating patients with r/r DLBCL or r/r B-ALL. Method: From Feb 2023 to Dec 2023, this IIT clinical trial evaluated Meta10-19 infusion in adult patients with r/r DLBCL or r/r B-ALL. The patients were recruited and treated at the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China. Patients in 3 dose cohorts (2.0 × 104, 5.0 × 104, or 1.0 × 105 CAR-T cells/kg, corresponding to 1%, 2.5%, or 5% doses of commercialized CAR-T infusion) underwent lymphodepleting chemotherapy with cyclophosphamide and fludarabine before Meta10-19 infusion. The primary endpoint was the incidence of dose-limiting toxicities. The secondary endpoint was the response and survival. Results: The treatment with Meta10-19 infusion has successfully induced CR in all 12 cases of r/r DLBCL (n=6) or r/r B-ALL (n=6), as evaluated by PET-CT scan, NMR spectroscopy or minimal residual disease assessment of bone marrow. No server cytokine storm syndrome or neurotoxicity was observed. All treated patients achieved CR at 3 months post treatment, with the first patient maintaining continuous remission up to 9 months until now. Notably, these metabolically armed CD19 CAR-T cells demonstrated efficacy even for patients with bulky mass (≥7.5 cm) of DLBCL at extremely low infusion dose (1~5% doses of commercialized CAR-T). Conclusion: Preliminary findings suggest that Meta10-19 infusion exhibits promising breakthrough efficacy and safety profile, and active enrollment is ongoing to validate the initial results. Citation Format: Yugang Guo, Qianwen Xu, Lei Xue, Erling Chen, Chonglin Liu, Min Gao, Youjia Li, Jingjing Ren, Jinping Li, Li Tang, Xingbing Wang. Metabolically armed CD19 CAR-T cells for safe and effective treatment of relapsed or refractory CD19+ B cell hematological malignancies at extremely low doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB236.

KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.

Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100mg orally twice-daily, pembrolizumab 200mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination. Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%. The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC. ClinicalTrials.gov , NCT02862457.

FRONTiER: A feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E)—Primary safety and short-term efficacy results for cohort E.

326 Background: The standard neoadjuvant treatment in Japan for resectable locally advanced esophageal squamous cell carcinoma (ESCC) is DTX + CDDP + 5-FU (DCF). In addition, immune checkpoint inhibitors (ICIs) have shown a survival benefit for ESCC and are promising as neoadjuvant treatment for several cancers. We previously reported that neoadjuvant CDDP + 5-FU + nivolumab (Nivo) or DCF + Nivo therapy was tolerable and showed promising efficacy for ESCC. However, the efficacy of neoadjuvant treatment and safety of subsequent surgery remain unclear for 5-FU + l-LV + L-OHP + DTX (FLOT), the global standard of care for perioperative esophagogastric adenocarcinoma, plus ICI for ESCC. Methods: JCOG1804E (FRONTiER) is a multi-cohort phase I study designed to evaluate the safety and efficacy of Nivo combined with neoadjuvant chemotherapy in ESCC. The eligibility criteria were histologically proven ESCC staged as cT1N1-3M0 or cT2-3N0-3M0 (8th UICC TNM classification), age 20-75 years, performance status (PS) ≤1, and no prior cancer therapy. The primary endpoint was the incidence of dose-limiting toxicity (DLT) from the initial dose to postoperative day 30. The secondary endpoints included adverse events during the perioperative period and at 30 days and the objective response rate, R0 resection rate, histopathological complete response rate, and completion rate of the protocol treatment including planned chemotherapy as below followed by R0 resection. Among five study cohorts, patients in cohort E were planned to receive four courses of FLOT+Nivo–5-FU (2600 mg/m2), l-LV (200 mg/m2), L-OHP (85 mg/m2), DTX (50 mg/m2), and Nivo (240 mg)–on day 1 every 2 weeks. Results: Of the 12 patients enrolled in cohort E (median age [range]: 64.5 [53-71] years, PS 0/1: 12/0, clinical stage I/II/III/IVA: 4/5/3/0), 4 developed DLT (grade 3 mucositis, erythema multiforme, and pneumonitis, n=1 each; grade 5 pneumonitis, n=1), which was within the prespecified range of safety (n ≤ 4). Other grades≥3 adverse events were neutropenia (n=7), leukopenia (n=6), fever, fatigue, febrile neutropenia, rash, elevated amylase, elevated hepatic enzyme, hypotension, and thrombocytopenia (n=1 each) during FLOT + Nivo, and anastomotic leakage (n=1) during the postoperative period. One patient discontinued FLOT + Nivo due to DLT of erythema multiforme, eleven patients (91.7%) completed the protocol treatment and R0 resection rate achieved 91.7% (11/12). In cohort E, the objective response rate in patients with measurable lesion was 0% (0/4). However, 5 patients (41.7%) achieved a pathological complete response, and 6 (50.0%) achieved a pathological complete response in primary tumors among 12 patients. Conclusions: Neoadjuvant FLOT + Nivo followed by surgery for locally advanced ESCC was tolerated and showed promising efficacy. Clinical trial information: NCT03914443 .

Abstract B160: A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors

Abstract Introduction: CDK4/6 mediate cell cycle progression and are important for cancer initiation, growth, and survival. CDK4/6 inhibitors are approved for patients with advanced HR+/HER2– breast cancer but are ineffective against primary or metastatic brain tumors. PRT3645 is an investigational, highly selective, and potent CDK4/6 inhibitor, designed to achieve high tissue and brain penetration. This phase 1 dose-escalation study (NCT05538572) aims to evaluate safety, preliminary efficacy, and pharmacokinetic/pharmacodynamic profile of PRT3645. Methods: Patient eligibility criteria include: age ≥18 years; Eastern Cooperative Oncology Group/Karnofsky performance status ≤1/≥80; adequate organ function; histologically confirmed advanced, recurrent, or metastatic solid tumor malignancy: breast cancer (HR+/HER2– or HR+/HER2+), glioblastoma (isocitrate dehydrogenase [IDH] wild type), CDKN2A/B homozygous deleted IDH–mutant astrocytoma, non-small cell lung cancer (KRAS mutant), or select solid tumors with CDK pathway alterations; and progression on, ineligibility for, or refusal of standard therapy. Patients with treated and untreated brain metastases (lesion <1.5 cm) could enroll if they had no neurological symptoms and did not require immediate local treatment. PRT3645 was taken orally once daily for 28 days (1 cycle) with dose escalation employing a Bayesian optimal interval design to evaluate the safety, tolerability, incidence of dose-limiting toxicities, and pharmacokinetic/pharmacodynamic profile. Results: At data cutoff (May 18, 2023), 8 patients received 20 and 40 mg once daily (first 2 dose levels of dose escalation). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. Median age was 62 (range, 53-76) years; 50% of patients were male; in these early dose cohorts 75% of patients discontinued therapy (all due to progressive disease; median duration of therapy: 8 [range, 4-16] weeks); 5 patients had glioblastoma, 2 had breast cancer, and 1 had sarcoma. All-cause, any-grade adverse events (AEs) reported in ≥1 patients were anemia and dizziness. One grade 1 AE (fatigue) was considered related to PRT3645. No patients had grade ≥3 AEs, serious AEs, diarrhea, QTcF prolongation, or hepatotoxicity. No patients had dose reductions, interruptions, withdrawals, or deaths due to AEs. Between pre-dose and 2 weeks post first dose, a reduction in phosphorylated Rb (>70% in 3/4 patients) and Ki67 (>60% in 2/4 patients) expression was seen at 40 mg; both markers showed a correlation between histochemical score and drug exposure. Conclusions: Treatment with the next-generation CDK4/6 inhibitor PRT3645 was associated with a substantial decrease in phosphorylated Rb and Ki67 expression, indicating a high level of target engagement at a low dose. PRT3645 exhibited tolerable dose escalation in the initial 2 cohorts of patients with no significant gastrointestinal or hematologic events reported to date, leveraging its enhanced selectivity profile. Dose escalation is ongoing. Citation Format: Amita Patnaik, Mohamad A. Salkeni, Manish R. Patel, Atrayee Basu-Mallick, Dale Shepard, Christine Lihou, William Sun, Jennifer Xavier, Sri Sahasranaman, Neelesh Sharma, Erika Hamilton. A phase 1 open-label, dose-escalation study of central nervous system–penetrant cyclin-dependent kinase (CDK)4/6 inhibitor PRT3645 in patients with select advanced or metastatic solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B160.

Phase 1b Trial of Irak 1/4 Inhibition for Low-Risk Myelodysplastic Syndrome Refractory/Resistant to Prior Therapies: A Trial in Progress

Background and Significance: Chronic stimulation of both the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to promote a proinflammatory environment in the bone marrow that causes persistent cytopenia in patients with low-risk myelodysplastic syndrome (LR-MDS). The serine/threonine kinases IRAK1 and IRAK4 are critical for the signaling downstream of IL-1R and most TLRs that promotes production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis, leading to bone marrow inflammation and cell death. Therefore, inhibition of IRAK1/4 is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow, allowing for restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases that inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 study in healthy volunteers (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the phase 1 trial results supported the further study of R289. An open-label phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently recruiting patients. Study Design and Methods: The R289 phase 1b study (NCT05308264) is an open label, single arm, multi-center study, which includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of low-risk MDS (International Prognostic Scoring System-R ≤3.5) and ≤5% bone marrow myeloblasts. Patients must be relapsed or refractory/resistant or intolerant to prior MDS therapies. Exclusion criteria include prior MDS treatment(s) within 4 weeks of study treatment, clinically significant anemia (from iron deficiency, hemolysis, or GI bleeding), and chronic myelomonocytic leukemia. Dose Escalation Phase: A 3+3 dose escalation design will be used to determine the maximum tolerated dose (MTD). An initial R289 dose of 250 mg qd, will be given orally, with or without food, progressing to 500 mg qd with dose limiting toxicity (DLT) assessed at both doses. The DLT evaluation period will be 28 days. After completion, patients not experiencing DLTs may remain at their respective dose levels as long as they demonstrate continued clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled, with R289 administered to all patients at a dose not exceeding the MTD determined in the dose escalation phase. The primary endpoint of the study is safety and tolerability of R289, assessed by incidence of AEs, discontinuation/interruption of R289 due to AEs, and incidence of DLTs. Secondary endpoints include preliminary efficacy, assessed by red blood cell transfusion independence by Week 24 (% achieving ≥50% reduction in transfusions), and pharmacokinetics of R289. Change from baseline in plasma biomarkers, including C-reactive protein and TNFα, and bone marrow biomarkers will be assessed. Statistical analyses will be primarily descriptive. Tabulations will be produced for disposition, demographics, disease characteristics, safety, pharmacokinetics, pharmacodynamics, and clinical activity. For analyses of clinical activity, such as proportion of patients with RBC transfusion independence, complete responder rate, overall response rate, and proportion of subjects with hematologic improvements, the summary will be produced separately for the dose escalation phase and dose expansion phase. For the dose escalation phase, data will be summarized by dose level and overall. The trial is currently recruiting at 9 US sites. The study has enrolled 7 patients in the dose escalation phase.

Phase I Study of FT538 + Daratumumab for Treatment of r/r AML

Introduction: Relapsed and refractory (r/r) acute myeloid leukemia (AML) remains an unmet need with immune-therapy based treatments such as hematopoietic stem cell transplantation (HSCT) providing the longest relapse-free survival (RFS). Natural Killer (NK cells) have been shown to effect lysis of AML cells, both in vitro and in vivo across multiple platforms. In particular, “adaptive” NK cells induced in vivo in HSCT recipients after CMV reactivation have been shown to confer an RFS advantage. These cells are characterized phenotypically by the expression of NKG2C, CD57, KIR and downregulation of CD38. CD38 is an ectoenzyme broadly expressed on hematopoietic cells, including approximately 60% of AML. It catalyzes the conversion of nicotinamide-adenine dinucleotide (NAD+) and nicotinamide-adenine dinucleotide phosphate (NADP+) to cyclic adenosine diphosphate (cADP) ribosyl. CD38 knock-out NK cells have increased persistence by having enhanced metabolic fitness and resistance to oxidative stress via a reduction of reactive oxygen species. FT538 is an iPSC-derived NK cell product with a non-cleavable CD16 receptor to augment antibody-dependent cytotoxicity (ADCC), IL-15/IL-15R fusion to increase activation and persistence, and CD38 knockout to enhance its metabolic fitness and avoid fratricide when combined with CD38 monoclonal antibodies. Daratumumab (Dara) is a monoclonal antibody targeting CD38 on the surface of AML cells as well as activated lymphocytes. We hypothesized that the addition of Dara to fludarabine and cyclophosphamide would enhance lymphodepletion and augment ADCC for CD38+ AML leading to better response rates when combined with FT538. Methods: This (NCT04714372) is a phase I, dose-escalation study, utilizing FT538 in combination with fludarabine, cyclophosphamide, and Dara for the treatment of r/r AML. A study schema is presented in Figure 1A. Patients received 5 weekly doses of Dara starting day -12, 2 doses of fludarabine and cyclophosphamide at day -4, and 3 weekly doses of FT538. They were followed for DLT for 28 days after FT538 infusion. Patients with r/r AML after 2 or more lines of therapy and good organ function were enrolled. The primary objective was the safety of this combination, and the endpoints were the incidence of dose-limiting toxicities (DLTs) and incidence of adverse events. Secondary endpoint was the efficacy and predictors of efficacy. Patients evaluable for safety are those who received at least one dose of FT538. Patients evaluable for efficacy are those who completed all doses. Fast-track enrollment was utilized where one patient per dosing level (DL) was enrolled as long as no DLTs were seen with cohort expansion in the event of DLTs or related severe adverse events. Results: Six patients were enrolled on 4 DLs with increasing dose of FT538 from 1x10 8 - 1.5x10 9 cells. Median age was 70 years. Median number of prior lines is 3.5 (3-4). All patients were refractory to most recent therapy. One patient was enrolled on each DL1, DL2, and DL3. Three enrolled on DL4 with 1 completing therapy. Five patients are evaluable for safety and 4 for efficacy. There were no DLTs and we were able to enroll one patient per cohort. Eighty percent (4/5) experienced febrile neutropenia and infections. One patient with a prior biliary stent had choledocholithiasis requiring a complicated intervention. No prolonged cytopenias attributable to FT538 were seen. One patient experienced a G1 CRS lasting 1 day. There were no neurotoxicity events. One patient on DL2 achieved stable disease and one patient on DL4 achieved a CR for an ORR of 50% (2/4). Both went on to receive HSCT and continue to be alive and well without disease with a median follow up of 5 months. This is summarized in Figure 1.B. Macrochimerism (donor cells) was detected for up to 8 days post-infusion. Macrochimerism did not correlate with response but did show that Ki67 expression was present on donor cells suggesting proliferation. Conclusions: FT538 in combination with daratumumab has been tolerated in a highly pre-treated cohort of patients with expected toxicities and a signal of efficacy.

Long Term Follow-up Results of Brl-201 Phase I Study, a Crispr-Based Non-Viral PD-1 Locus Specific Integrated Anti-CD19 CAR-T Cells in Treating Relapsed or Refractory Non-Hodgkin's Lymphoma

BACKGROUND ： CAR-T cell products are manufactured traditionally by using virus, which leads to the potential tumorigenesis risk and makes CAR-T cell therapy expensive and time-consuming. We developed a novel approach to generate non-viral, genome-specific integrated CAR-T cells through CRISPR/Cas9, thereby breaking through both virus usage and random integration simultaneously. Here, we update long term follow up data of trial of non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells (BRL-201) in patients with relapsed/refractory (r/r) Non-Hodgkin's lymphoma (#NCT04213469). Recently, a phase I/II of BRL-201 (#NCT05741359) is ongoing with a large-scale and multi-center design to further evaluate of BRL-201 antitumor activity in lower dose level. METHODS : This phase I investigator initiated trial evaluates BRL-201 in adult patients with r/r B-NHL. Adult patients with r/r B-NHL underwent leukapheresis and a lymphodepletion chemotherapy with cyclophosphamide (500mg/m 2, D -3 to -2) and fludarabine (30mg/m 2, D -4 to -2) before BRL-201 infusion. Dose escalation are based on 3+3 escalation rule, including three cohorts: 2×10 6/kg, 4×10 6/kg, 6×10 6/kg. Besides, 3 subjects received non-standard infusion doses at 0.56~0.8 × 10 6/kg. The primary endpoint was the incidence of dose-limiting toxicities (DLT). The secondary endpoint was the proportion of patients achieving an objective response at 3 months as per investigator's assessment. In the phase I/II sponsor initiated clinical trial, we employed 3+3 rule in the escalation phase. RESULTS: Between May 3, 2020 and August 10, 2021, 25 patients with r/r B-NHL were enrolled and 21 received BRL-201 with a median age of 56 years (34-70) and a median of 4 (1-9) prior lines of therapy. Among all the treated patients, 17 patients (93.8%) were diagnosed with disease stage III or IV, and 13 patients (81.3%) were assessed with high-intermediate to high risk according to IPI or aaIPI score assessment. Two patients had undergone autologous hematopoietic stem cell transplantation (HSCT) and one patient had a history of primary refractory disease. Of 17 patients with pretreatment tumor samples PD-L1 expression detection, 4 (23.5%) had > 50% PD-L1 expression, 13 (76.5%) had ≤50% PD-L1 expression. As of May 17, 2023, the median follow- up of investigaor initiated phase I study was 29.0 months (21.5-36.2 m). All of 21 (100%) patients had an objective response to BRL-201 and 18 (85.7%) patients had a complete response (CR) as best response (Fig. 1). 7 patients achieved and maintained CR at data cut-off date, among these, 3 patients had PD-L1 expression > 50%, 1 patient was negative and 3 unknown. The median duration of response(DOR) for all 21 patients was 18.6 months (95%CI：5.1, NA ) (Fig. 2a). The median progression free survival (PFS) was 20.8 (95%CI：8.2, NA) months (Fig. 2b), while the estimated median overall survival (OS) was not reached, 12-month OS rate was 76.2% (95% CI: 60%, 96.8%) (Fig. 2c). No grade 3-4 CRS and ICANS were observed. 14 patients (66.7%) experienced grade 1-2 cytokine release syndrome (CRS) and only one patient received tocilizumab. 4 patients (19.0%) experienced grade 1-2 immune effector cell-associated neurotoxicity syndrome (ICANS). No new AEs/SAEs were observed during the last follow up. In the ongoing phase I study, 1 patient with DLBCL was treated with BRL-201 and no DLT observed during 28 days after infusion at dose of 2×10 5/kg. CONCLUSIONS : Over a median follow up of 29 months, BRL-201 was demonstrated durable response with a high median PFS of 20.8 months and 12-month OS rate of 76.2%. The median OS was not reached yet for responding patients, and the safety profile was manageable. More data will be collected to prove the value of clinical usage of BRL-201.

An Open-Label, Multicenter, Single-Arm, Phase I Dose Escalation Study of OP-2100, an Orally Bioavailable Prodrug of Decitabine, for Patients with Relapsed or Refractory Higher-Risk Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia

CONCLUSIONS Hypomethylating agents (HMA) are commonly used to treat high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML).Decitabine (DEC), one of the HMAs, is S phase-specifically incorporated into DNA to exert its effect, and sustained plasma concentration may increase its efficacy (Saunthararajah et al. J Clin Invest. 2015). Therefore, we developed OP-2100, an orally bioavailable prodrug of DEC. It showed equal efficacy to conventional HMAs in various blood cancer mouse models and exhibited a favorable safety profile in healthy mice (Watanabe et al. Blood. 2020; Ureshino et al. Mol Cancer Ther. 2021). In addition, it exhibited a sustained-release pharmacokinetic (PK) profile when orally administered to monkeys. In a phase I study, OP-2100 monotherapy showed the expected PK profile on patients with relapsed or refractory higher-risk MDS and CMML, and we reported the preliminary result. We designed a single-arm, multicenter phase I study for Japanese patients with MDS or CMML with intermediate-risk, high-risk, or very high-risk by Revised International Prognostic Scoring System (IPSS-R) and relapsed, refractory, or intolerant to standard therapy. The primary objective was to determine the maximum tolerated dose following the incidence of dose-limiting toxicity (DLT) in the first cycle, whereas the secondary objectives were to evaluate the safety, PK, and efficacy. Treatment-emergent adverse events (TEAEs) and response to therapy were assessed per NCI CTCAE v5.0 and IWG 2018 response criteria, respectively. Oral administration of OP-2100 as a single agent was continued for the patients daily on days 1-5 of each 28-day cycle until meeting discontinuation criteria, including disease progression. The dose level was defined as 30, 50, 80, and 120 mg/day. The initial dose of 50 mg/day was determined based on the highest non-severely toxic dose of OP-2100 in monkeys and the PK of DACOGEN TM in humans. This study was implemented in the 3+3 design according to DLT incidence. The plasma concentration of DEC and OP-2100 was measured on days 1 and 5. Furthermore, the LINE-1 methylation, a common HMA pharmacodynamics marker, was measured. This study is registered in the Japan Registry for Clinical Trials (jRCT2071220035). In total 3 patients with a history of azacitidine treatment for MDS were registered in the 50-mg initial cohort. These patients had been categorized as intermediate to high-risk in the IPSS-R, respectively. Table 1 shows patient characteristics. Out of 3, 2 patients did not experience DLT, while the 3rd one suffered from Grade 4 neutropenia, which was confirmed as DLT. As of April 30, the most common TEAEs were cytopenia of leukopenia, neutropenia, and thrombocytopenia, all of which were Grade 3 or 4. Other adverse events of Grade 3 or 4 include anemia, lymphopenia, COVID-19, and fall. In terms of efficacy, 2 patients had stable disease, while one had progressive, according to the IWG2018 response criteria. However, the 2 patients with stable disease still received administration up to 9 and 5 cycles, respectively (Figure 1). The PK profile of DEC after OP-2100 administration indicated sustained release, with an area under the curve (AUC) similar to that of DACOGEN TM (5-day regimen, 1-h continuous intravenous administration at 20 mg/m 2) and C max approximately 1/5. The LINE-1 methylation exhibited the similar behavior as conventional HMAs. The PK profile of DEC released from the prodrug after 50 mg of OP-2100 oral administration in 3 patients showed a similar AUC to that of the 5-day regimen of DACOGEN TM, and then C max showed a low with sustained plasma concentration. Among the 3 patients, OP-2100 could be administered for at least 5 cycles in 2 patients. To determine maximum tolerated dose, enrollment for this study is ongoing.

Phase I Trial of Systemic Administration of Vesicular Stomatitis Virus Genetically Engineered to Express NIS and Human Interferon, in Patients with Relapsed or Refractory Multiple Myeloma, Lymphomas, or Histiocytic/Dendritic Cell Neoplasms

Background: Oncolytic virotherapy, an innovative immunomodulatory therapeutic approach, is currently being investigated for its potential in treating relapsed refractory (R/R) hematologic malignancies. This study focuses on the use of an engineered Vesicular Stomatitis Virus called VSV-IFNβ-NIS, a bullet-shaped rhabdovirus which encodes both interferon beta (IFNβ) and sodium iodine symporter (NIS) with particular tumor cell tropism. Viral IFNβ serves as an indicator of viral proliferation and boosts the host's anti-tumor immune response. This is a phase 1 clinical trial with the identifier NCT03017820, wherein patients (pts) with R/R multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) are treated with a single systemic administration of VSV-IFNβ-NIS. Study Design and Methods: Patient Eligibility Criteria: The Mayo Clinic Institutional Review Board approved the protocol. The study includes adult patients with relapsed or refractory multiple myeloma (MM), or T-cell lymphoma (TCL). For MM or plasmacytoma, patients should have <15% plasma cells and a largest diameter of <5 cm. TCL patients should have a mass <5 cm. Study Design: This is a single-center phase 1 trial aiming to determine the maximum tolerated dose of VSV-IFNβ-NIS in patients with R/R MM, and TCL. Secondary objectives included assessing the safety profile and estimating the clinical response rate of VSV-IFNβ-NIS. Correlative objectives involved monitoring viral replication through plasma IFN-β transgene levels and using SPECT/CT imaging with the NIS gene. Viral genomes were measured through quantitative reverse transcription (qRT) polymerase chain reaction (PCR) of VSV RNA, and any virus shedding was examined in body fluids. The tested doses were 5 × 109 TCID50, 1.7 × 1010, 5 × 1010, and 1.7 × 1011 TCID50. The virus was administered via IV infusion over 30 minutes, and patients received 650 mg acetaminophen and 50 mg diphenhydramine hydrochloride before infusion and every 6 hours for 24 hours to manage fever and hypotension. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma and histiocytic neoplasms) to obtain additional data on tolerability and efficacy and biomarkers of response in these histologies. Safety and Response Assessments: All patients undergo toxicity evaluation, and adverse events (AEs) assessment using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria, except for cytokine release syndrome (CRS) grading, which follows the 2014 Lee criteria. Dose escalation and tolerability are based on the standard 3+3 phase 1 trial design. Ruxolitinib is added from days 2-5 or day -1 to day 9 depending on the arm to mitigate IFNβ toxicity. Response assessment followed the International Myeloma Working Group criteria for MM and the Lugano Classification for NHL and histiocytic neoplasms. Pharmacodynamic and Pharmacokinetic Analyses: For viremia and viral shedding assessment, RNA is isolated from whole blood, mouth rinse, buccal swabs, and urine samples. Quantitative RT-PCR determined VSV-nucleocapsid (N) RNA copy number, and virus shedding is assessed through coculturing samples on Vero cells. Anti-VSV antibodies are evaluated using the standard plaque reduction neutralization assay. Plasma cytokine levels are measured with a 30-plex human cytokine kit, and human IFN-β levels is quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Statistical Analysis: Incidence of dose-limiting toxicities and AEs are tabulated by dose level (DL). AEs are summarized by type, maximum grade, and duration across patients in each DL. Spearman rank correlation tests are used evaluated correlations between laboratory-based measures, and Wilcoxon rank sum tests compared continuous measures between response groups. Response rates will be summarized by DL and disease group, with estimated response rates and corresponding 95% binomial confidence intervals calculated.

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

Asciminib (ASC) in Combination with Imatinib (IMA), Nilotinib (NIL), or Dasatinib (DAS) May be a Potential Treatment (Tx) Option in Patients (Pts) with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase or Accelerated Phase (Ph+ CML-CP/AP): Final Results from the Asciminib Phase 1 Study

CTIM-24. REPEATED PERIPHERAL INFUSIONS OF ANTI-EGFRVIII CAR T CELLS IN COMBINATION WITH PEMBROLIZUMAB REMODELS THE TUMOR MICROENVIRONMENT IN DE NOVO GLIOBLASTOMA

Abstract Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n = 7). Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in one patient in the tumor. However, shared TCRs were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CART. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNAseq, and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.

The Double Antibody Drug Conjugate (DAD) phase I trial: sacituzumab govitecan plus enfortumab vedotin for metastatic urothelial carcinoma

The antibody-drug conjugates sacituzumab govitecan (SG) and enfortumab vedotin (EV) are standard monotherapies for metastatic urothelial carcinoma (mUC). Given the different targets and payloads, we evaluated the safety and efficacy of SG+ EV in a phase I trial in mUC (NCT04724018). Patients with mUC and Eastern Cooperative Oncology Group performance status ≤1 who had progressed on platinum and/or immunotherapy were enrolled. SG+ EV were administered on days 1+ 8 of a 21-day cycle until progression or unacceptable toxicity. Primary endpoint was the incidence of dose-limiting toxicities during cycle 1. The number of patients treated at each of four pre-specified dose levels (DLs) and the maximum tolerated doses in combination (MTD) were determined using a Bayesian Optimal Interval design. Objective response, progression-free survival, and overall survival were secondary endpoints. Between May 2021 and April 2023, 24 patients were enrolled; 1 patient never started therapy and was excluded from the analysis. Median age was 70 years (range 41-88 years); 11 patients received ≥3 lines of therapy. Seventy-eight percent (18/23) of patients experienced grade ≥3 adverse event (AE) regardless of attribution at any DL, with one grade 5 AE (pneumonitis possibly related to EV). The recommended phase II doses are SG 8 mg/kg with EV 1.25 mg/kg with granulocyte colony-stimulating factor support; MTDs are SG 10 mg/kg with EV 1.25 mg/kg. The objective response rate was 70% (16/23, 95% confidence interval 47% to 87%) with three complete responses; three patients had progressive disease as best response. With a median follow-up of 14 months, 9/23 patients have ongoing response including 6 responses lasting over 12 months. The combination of SG+ EV was assessed at different DLs and a safe dose for phase II was identified. The combination had encouraging activity in patients with mUC with high response rates, including clinically significant complete responses. Additional study of this combination is warranted.

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 .