Dose Escalation Cohorts Research Articles

Abstract CT157: Phase 1 trial of MEK1 inhibitor E6201 plus dabrafenib in patients (pts) with BRAF V600-mutated metastatic melanoma (MM) with central nervous system (CNS) metastases (mets)

Abstract Background: The prognosis of patients with MM with CNS mets is poor. E6201 is an intravenous (IV) MEK inhibitor with activity against BRAF V600-mutated MM cell lines, including MAPK resistance alteration. A previous phase I trial demonstrated activity of E6201 in BRAF V600E mutated MM with a Maximal Tolerated Dose of 320mg/m2 given IV once a week x 3 weeks q 28 days. 2/23 (8.7%) of patients had a PR, 8/23 (34.8%) had SD. Two patients with MM and brain mets achieved near-CR which led to preclinical studies that demonstrated E6201 is unaffected by P-gp and BCRP transport and achieved higher brain to blood concentration (266%).In this trial, patients with BRAF mutation + MM with brain mets, single agent E6201 given at 320mg/m2 twice weekly x 3 weeks q 28 days was determined to be safe. One patient had CNS SD and a PR in lung mets, and a second patient achieved CNS stable disease and CR in a leg melanotic lesion. The drug was well-tolerated with one reversible AE thrombocytopenia (Gr 2). The final review showed intracranial response of SD in 2/4 (50%) patients and systemic SD in 3/4 (75%) patients. Methods: We are currently accruing to the dose escalation cohort of E6201 with dabrafenib 150 mg twice daily orally (n=up to 22 evaluable patients). E6201 is administered IV at 320mg/m2 twice weekly for 3 weeks every 28 days. Patients must have stage IV melanoma with BRAF mutation with at least one active lesion in the brain. Prior local therapy is allowed if done at least 3 weeks prior to cycle 1. Participants must be on a stable dose of steroids for at least 7 days and have an ECOG <!–=2. The study allows one prior BRAF/MEK inhibitor therapy. The primary objectives are to determine the MTD of E6201 when combined with dabrafenib and the response rate of brain mets. The secondary objectives include duration of response, extracranial response, progression free survival, overall survival, and impact of BRAF mutation subtype and safety of the combination. Clinicaltrials.gov: NCT05388877

181 Initial Experience With Sonodynamic Therapy Using Low-Intensity Focused Ultrasound and ALA for Pediatric Patients With Diffuse Intrinsic Pontine Glioma

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain tumor with poor prognosis. Aminolevulinic acid (ALA) sonodynamic therapy (SDT) is a non-invasive strategy where tissues sensitized with ALA are exposed to MR-guided focused ultrasound (MRgFUS). Preclinical studies have demonstrated significant slowing in growth of gliomas and increased survival in animal models. METHODS: A Phase1/2 study (NCT05123534, clinicaltrials.gov) in patients with newly diagnosed DIPG is ongoing. MRIs at 24hrs and 1- and 3-months post procedure are obtained to evaluate safety and efficacy. A total of 18-45 patients will be enrolled in 9 different dose-escalation cohorts. The three patients from the first cohort are described below. RESULTS: Three patients with DIPGs were treated with 5 mg/kg of ALA and 200 J of MRgFUS in the first cohort. They were aged 5-7 years and 2 were females. They had received radiotherapy 8-10 weeks prior and interval imaging showed no disease progression. The first patient received two treatments with one half of the pons treated during each visit. The other two received one treatment targeting the entire pons. They all tolerated the procedure well. One of the patients noted a transient worsening of his diplopia after the treatment. No significant edema or hemorrhage were noted on postoperative scans obtained within 24 hrs of treatment. MRIs obtained 1- and 3-months after treatment have shown significant decrease in tumor burden in 2 of the patients. CONCLUSIONS: The first-in-human experience with a new therapeutic modality for DIPG patients demonstrates safety and efficacy. Future procedures will involve ascending drug and MRgFUS energy dose combinations. The use of focused ultrasound signals an innovative approach for challenging to treat pediatric brain tumors.

Joint modeling of tumor dynamics and progression-free survival in advanced breast cancer: Leveraging data from amcenestrant early phase I-II trials.

A joint modeling framework was developed using data from 75 patients of early amcenestrant phase I-II AMEERA-1-2 dose escalation and expansion cohorts. A semi-mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure-driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of treatment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of amcenestrant. This joint modeling framework integrated complex RECISTv1.1 criteria information, linked TS metrics to progression-free survival (PFS), and was externally evaluated using the randomized phase II trial AMEERA-3. We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I-II data. This provides a good modeling and simulation tool to inform early development decisions.

Abstract 3641: Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors

Abstract Background: NGM707 is a dual antagonist antibody that binds a shared epitope of the immune inhibitory receptors ILT2 (LILRB1) and ILT4 (LILRB2). In preclinical studies, NGM707 reprogrammed suppressive myeloid cells via blockade of ILT2/ILT4 and enhanced NK and CD8+ T cell activity via blockade of ILT2; furthermore, NGM707 and pembrolizumab acted additively in vitro to enhance CD4+ T cell activation in mixed lymphocyte reactions. NGM707-IO-101 (NCT04913337) is a first-in-human Phase 1/2 clinical trial of NGM707 monotherapy and combination with pembrolizumab. Here we report pharmacodynamic and predictive biomarker data from NGM707-IO-101 monotherapy and combination dose escalation cohorts. Methods: Eligible patients with advanced or metastatic solid tumors were enrolled into escalating dose cohorts from 6 to 1800 mg NGM707, alone or in combination with 200 mg pembrolizumab, administered Q3W iv. Biomarker assessments of tumors comprised RNA-sequencing and immunohistochemistry (including ILT2, ILT4, CD163) of archival/baseline (N= 41 IHC, 47 RNA) and paired on-treatment tumor biopsies (N=13 IHC, 21 RNA). Peripheral blood biomarker samples were collected on days 1, 4, 8, and 15 of cycle 1 and prior to dosing at each subsequent cycle. Blood biomarker assessments included circulating cytokines/chemokines, PBMC RNA-sequencing, and flow cytometry immunophenotyping. Baseline biomarkers were associated with anti-tumor activity per RECIST v1.1. Results: Pre-treatment biopsies from patients with disease control (DC) showed higher expression of genes in the 18-gene tumor inflammation signature (TIS) than patients with progressive disease (PD). A composite gene signature incorporating gene sets related to TIS, NK cell activity, and tumor cell proliferation had a statistically stronger association with DC than TIS genes alone. Baseline ILT2/ILT4 target expression (≥1% of tumor area) was observed in 31 (75.6%) patients, with similar levels observed in patients with DC and PD. Pharmacodynamic changes were observed in tumor samples following treatment, including increased expression of gene signatures that reflect myeloid cell activation and a proinflammatory tumor microenvironment. Decreased protein expression of the immunosuppressive myeloid marker CD163 was observed following treatment in both blood and tumor for a subset of patients. Proinflammatory chemokines including CXCL9 increased in serum following treatment. Conclusion: Baseline gene expression signatures have shown an encouraging association with clinical benefit from NGM707 and merit further investigation as promising predictive biomarkers. Protein and gene expression changes reflecting the expected modes of action of NGM707 and pembrolizumab were observed in both peripheral blood and tumor biopsies following treatment. Citation Format: Lisa K. Blum, Hung-I H. Chen, Anushka De Costa, Anjushree Iyer, Geoffrey W. Stone, Nicole D. Galicia, Jerry Chan, Brenda Dampier, Katherine Wu, Ursula Jeffry, Kefei Zhou, Joanne Sloan-Lancaster, Dhiraj Abhayankar, Vladimir Hanes, Hsiao D. Lieu, Daniel D. Kaplan, Julie M. Roda. Pharmacodynamic and predictive biomarker results from the phase I dose escalation study of NGM707, an ILT2/ILT4 dual antagonist antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3641.

Abstract 6221: First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin

Abstract Background: Suboptimal delivery of anti-cancer agents to cancer tissue compromises the effectiveness of therapeutics. PS101 consists of microclusters of perfluorobutane microbubbles and perfluoromethylcyclopentane (PFMCP) microdroplets. Acoustic cluster therapy (ACT) consists of PS101 administered intravenously and insonated over a tumour with diagnostic ultrasound (2 MHz or above), which fuses the components of PS101 to form larger ACT bubbles that are temporarily trapped in capillaries, followed by low frequency (0.5 MHz) insonation, which induces oscillation of the ACT bubbles, stretching capillaries. Given concurrently with chemotherapy, this enhances delivery of chemotherapy to target tissues. Methods: We describe a first-in-human phase1 study to evaluate the safety and tolerability, pharmacokinetics, and preliminary anti-cancer activity of ACT treatment and the chemotherapy regimens FOLFOX or FOLFIRI in patients with liver metastases of colorectal origin (NCT04021277). The dose escalation cohorts evaluated safety of 20 µL/kg and 40 µL/kg dose levels of PS101 combined with chemotherapy. The primary assessment of anti-tumor activity consisted of within-patient comparison of radiographic responses between ACT-treated lesions (insonated) and control lesions (non-insonated). Results: We had previously treated mice bearing SW620 xenografts treated with a control arm of Irinotecan at 60 mg/kg IP or Irinotecan plus PS101 at 2ml/kg and insonation in the experimental arm and showed a difference in survival in the experimental arm 34 days Vs 54 days p <0.01 (1). In the first in human clinical trial 8 patients were enrolled into the dose escalation part of the study, of which 2 subjects were not evaluable for dose escalation decision. There were no CTCAE grade 3, or above AEs or SAEs related to PS101 or the ultrasound. 4/8 patients discontinued treatment due to AEs - all related to chemotherapy. Median plasma concentration of PFMPC 5 minutes after the injection was 117 ng/ml (n=3, range 82 to 158) in the 20 µl/kg cohort and 233 ng/ml (n=4, range 217 to 275) in the 40 µl/kg cohort. 5 out of 6 patients had greater shrinkage of the insonated lesion compared with control lesions. The median percentage difference in maximum diameter of lesions between baseline and week 8 assessments, for insonated and non-insonated lesions, was -16% (range 25 to -42) and -3% (range 12 to -19), respectively. The dose expansion part of the study is ongoing, randomizing patients receiving FOLFIRI chemotherapy up to 10 patients each between 20 µl/kg and 40 µl/kg dose levels. Conclusions: Following preclinical activity in xenograft models, the ongoing first in human study of ACT in patients with colorectal cancer has shown clinical translation of differential activity in insonated metastasis. Reference: Reference: 1.Bush N et al Front Pharmacol 2019, 10:1299 Citation Format: Udai Banerji, Wing Yau, Mark T. O'Leary, Nigel Bush, Sumita Gurung, Amir Snapir, Jeff C. Bamber, Nina Tunariu. First-in-human study of acoustic cluster therapy consisting of PS101 combined with chemotherapy and insonation in patients with liver metastases of colorectal cancer origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6221.

Entinostat, nivolumab and ipilimumab for women with advanced HER2-negative breast cancer: a phase Ib trial.

We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.

Phase I Study of GS-3583, an FMS-like Tyrosine Kinase 3 Agonist Fc Fusion Protein, in Patients with Advanced Solid Tumors.

GS-3583, an FMS-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein, expanded conventional dendritic cells (cDC) in the periphery of healthy volunteers, suggesting potential for GS-3583 to increase cDCs in the tumor microenvironment and promote T cell-mediated antitumor activity in cancer patients. This phase Ib open-label study assessed GS-3583 in adults with advanced solid tumors. Multiple escalating doses of GS-3583 (standard 3+3 design) were administered intravenously on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle for up to 52 weeks. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 at each dose level. Thirteen participants enrolled in four dose-escalation cohorts, after which the study was terminated following safety review. Median (range) age was 71 (44-79), and 7 (54%) participants were male. There were no DLTs. Seven participants had grade ≥3 AEs; 2 participants had grade 5 AEs, including a second primary malignancy (acute myeloid leukemia) considered treatment-related. Dose-dependent increase in GS-3583 serum exposure was observed in the dose range of 2-20 mg with GS-3583 accumulation at higher dose levels. Expansions of cDCs occurred at all four doses with a dose-dependent trend in the durability of the cDC expansion. GS-3583 was relatively well tolerated and induced dose-dependent expansion of cDCs in the periphery of patients with advanced solid tumors. However, development of a second primary malignancy provides a cautionary tale for the FLT3 agonist mechanism. See related commentary by Raeder and Drazer, p. 2857.

Evaluation of the tolerability and safety of [225Ac]Ac-PSMA-I&T in patients with metastatic prostate cancer: a phase I dose escalation study

BackgroundLife expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10–20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [177Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [225Ac]Ac-PSMA (225Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of 225Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered.MethodsThe 225Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with 225Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first 225Ac-PSMA-I&T administration.DiscussionThis trial will assess the safety and tolerability of 225Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial.Trial registrationClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.

Results of a phase 1b/2 study of ADG126 (a masked anti-CTLA-4 SAFEbody) in combo with pembrolizumab (Pembro) in patients (Pts) with metastatic microsatellite-stable (MSS) colorectal cancer (CRC).

127 Background: ADG126 is a fully human anti-CTLA-4 IgG1 SAFEbody that has a cleavable masking peptide that blocks the antigen binding site. ADG126 is preferentially activated in the tumor microenvironment to afford prolonged on-tumor drug exposure and limited off-tumor toxicity. Activated ADG126 binds to a unique CTLA-4 epitope to prime T cells via partial ligand blockade and deplete immunosuppressive Tregs through strong antibody-dependent cellular cytotoxicity (ADCC)/phagocytosis (ADPC). Preclinical studies showed that ADG126/Pembro combination effectively increases Teff/Treg ratio. In Phase 1b/2 studies, ADG126 demonstrated a favorable safety profile and clinical efficacy as monotherapy and in combination with anti-PD-1 therapy. Here we present results of the entire dose escalation and ongoing dose expansion cohorts including a cohort of patients with MSS CRC free of liver metastasis (NCT05405595). Methods: This is a Phase 1b/2, open-label, multicenter dose escalation and expansion study of ADG126/Pembro. Pts received ADG126 [6 or 10 mg/kg (mpk), Q3W or Q6W, IV] plus Pembro (200 mg, Q3W, IV). Primary endpoints are safety and tolerability. Secondary endpoints are PK, ADA, ORR, DCR, DOR and PFS per RECIST 1.1. Results: As of Aug 29, 2023, a total of 47 Pts have been treated in dose escalation (N=11) and expansion cohorts (N=36). The median age is 60.5 yrs (26-78); 31.9% Pts had at least 3 prior therapies, 12.8% Pts received prior IO therapies. A majority of Pts (74.5%) have what are considered immunologically “cold” tumors. ADG126 was dosed at 6 mpk Q6W (1 Pt) and Q3W (5 Pts), 10 mpk Q6W (17 Pts) and Q3W (24 Pts), and Pembro was dosed at 200 mg Q3W. No DLT or Grade 4/5 TRAE was observed at any dose level. TRAEs more than 10% are pruritis (N=9, 19.1%) and diarrhea (N=5, 10.6%). Grade 3 TRAEs were observed in 5 subjects: 1 G3 diarrhea (6 mpk, 16.7%), 1 G3 adrenal insufficiency (10 mpk Q6W, 5.9%), 1 each G3 pancreatitis, blurred vision and lipase increase (10 mpk Q3W, 12.5%); all TRAEs occurred after repeat dosing. For the MSS CRC expansion cohort, 7 SDs at ADG126 10 mpk Q6W dose level (N=11) were observed, and 2 PRs (including 1 initial PR) and 4 SDs at 10 mpk Q3W (N=13) were observed. Conclusions: ADG126/Pembro combination is well-tolerated up to the maximally administered dose of 10 mpk Q3W, with limited G3 TRAEs comparable to Pembro monotherapy. The 10 mpk ADG126 Q3W repeat dosing regimen maintains a favorable safety profile and demonstrates anti-tumor activity. The MSS CRC cohort of 10 mpk ADG126 Q3W surpassed the threshold set for part 1 of the Simon’s 2-stage design, and the second stage of the cohort is now enrolling. In conclusion, ADG126/Pembro has a significantly improved therapeutic index over the same class agents in combination with anti-PD-1 therapy, and encouraging early outcomes in patients of MSS CRC without liver metastasis. Clinical trial information: NCT05405595 .

Phase 1 trial of navitoclax and sorafenib in patients with refractory solid tumors with a hepatocellular carcinoma expansion cohort.

507 Background: Navitoclax (ABT-263) is an oral Bcl-2 homology-3 mimetic that binds with high affinity to pro-survival Bcl-2 proteins, resulting in apoptosis. Sorafenib, an oral multi kinase inhibitor inhibits tumor angiogenesis and also promotes apoptosis. The efficacy of either agent alone is limited; however, preclinical studies demonstrate synergy with the combination of navitoclax and sorafenib. Methods: In this phase 1 pharmacokinetic and pharmacodynamic study (NCT01364051), we evaluated the combination of navitoclax and sorafenib in a dose escalation cohort of patients with refractory solid tumors, with an expansion cohort in hepatocellular carcinoma (HCC). The study agents were provided by the Cancer Therapy Evaluation Program at National Cancer Institute under CRADA. Navitoclax and sorafenib were administered continuously on days 1 through 21 of 21-day cycles. The maximum tolerated dose (MTD) was determined using the continual reassessment method. Results: Ten patients were enrolled in the dose escalation cohort and 15 patients with HCC were enrolled in the expansion cohort. Two dose levels were tested, dose level 1 (navitoclax 150 mg daily plus sorafenib 400 mg twice daily) and dose level 2 (navitoclax 200 mg daily plus sorafenib 400 mg twice daily). At dose level 1, one dose limiting toxicity (DLT) [grade 3 aspartate aminotransferase elevation] was observed among 6 patients treated at this dose level. In a cohort of 3 patients treated at dose level 2, two DLTs were observed (grade 3 hypertension, and grade 3 rash), hence dose level 1 was identified as the MTD. Among all patients, the most common grade 3 toxicity was thrombocytopenia (5 patients, 20%): there were no grade 4 or 5 toxicities (Table). Patients received a median of 2 cycles (range 1-36 cycles) and all patients were off study treatment at data cut off. Six patients in the expansion cohort had stable disease, 5 had progressive disease and 4 with unavailable data. There were no partial or complete responses. Drug-drug interaction between navitoclax and sorafenib was not observed. The combination of navitoclax and sorafenib did not increase induction of apoptosis compared with navitoclax alone. Conclusions: Navitoclax plus sorafenib resulted in manageable, but not ideal toxicities for continuous oral administration which precluded dose escalation. The lack of clinical benefit in the HCC expansion cohort does not support further development of this combination for the treatment of advanced HCC. Clinical trial information: NCT01364051 . [Table: see text]

Phase 1/2 evaluation of revumenib in patients with advanced colorectal cancer and other solid tumors.

TPS227 Background: Aberrant transcription in cancer can be reversed by targeting critical epigenetic regulators. For example, in acute leukemias driven by increased HOX gene expression, inhibition of the menin-KMT2A interaction by revumenib induced remission in patients with heavily pretreated disease (Issa et al 2023). In solid tumors promoted by the aberrant activation of the Wnt/β-catenin pathway, in vitro data and in vivo studies have shown that small molecule inhibition of the menin-KMT2A interaction restricts growth, with potential therapeutic benefit in colorectal cancer (CRC), castration-resistant prostate cancer, estrogen receptor–positive breast cancer, gastrointestinal stromal tumors, and Ewing sarcoma. To test the therapeutic strategy of inhibiting the menin-KMT2A interaction in solid tumor malignancies, this study (NCT05731947) will evaluate revumenib in patients with CRC and other solid tumors. Revumenib is an oral, potent, selective inhibitor of the menin-KMT2A interaction. Methods: This phase 1/2 study is evaluating revumenib in adults aged ≥18 years with locally recurrent or metastatic CRC who have failed ≥1 prior line of therapy and in patients with other solid tumors who have failed available standard therapies. Inclusion criteria include diagnosis of microsatellite stable/proficient mismatch repair CRC or other solid tumors. Patients with CRC must be unable to receive or have disease that progressed on oxaliplatin, irinotecan, and bevacizumab; if left-sided RAS wild-type CRC, the patient must have received anti–epidermal growth factor receptor therapy. The primary phase 1 objectives are to determine the safety, tolerability, maximum tolerated dose, and recommended phase 2 dose of revumenib in patients with CRC and other solid tumors and to assess its antitumor effects. The phase 2 primary objective is to assess the antitumor effects of revumenib by blinded radiographic review. Phase 1 consists of all-comers’ dose escalation (phase 1a), and signal-seeking expansion in CRC (phase 1b). Using a rolling 6 design, the revumenib starting dose will be 163 mg 3 times daily in 28-day cycles. Up to 6 patients will be enrolled in a dose cohort. Dose escalation cohorts may be expanded and used for signal seeking in non-CRC tumor types. Phase 1b in CRC will begin when a potential phase 2 dose has been identified. The disease control rate at 6 cycles and overall response rate will be used to assess antitumor activity and will determine initiation of phase 2. In phase 2, patients with advanced CRC will be randomized 2:1 to revumenib or investigator's choice of 1 of 2 standard-of-care therapies. Patients will be followed for progression-free survival, with response assessments evaluated locally and confirmed by blinded radiographic review. As of September 5, 2023, 13 patients were enrolled in phase 1a of this study. Clinical trial information: NCT05731947 .

Pharmacokinetics, safety, and efficacy of an alternative dosing regimen of sasanlimab in participants with advanced NSCLC and other malignancies.

Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction. To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens. An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies. conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W). Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: C trough and AUC. A total of 155 participants (phase Ib, n = 34; phase II, n = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUCtau was 231.2 (90% CI, 190.1-281.2) and C trough was 111.5 (90% CI, 86.3-144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2-42.9)) and 12/80 (15.0% (95% CI, 8.0-24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively. Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUCtau and C trough metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration. NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT).

Safety of intranasal insulin administration in patients undergoing cardiovascular surgery: An open-label, nonrandomized, dose-escalation study

ObjectiveThis study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. MethodsThis open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. ResultsIn total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. ConclusionsThe administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.

Abstract B047: Phase I trial of αvβ3 integrin cytotoxin ProAgio in patients with previously treated advanced pancreatic cancer and other solid tumor malignancies

Abstract Background: ProAgio is a pegylated peptide drug that targets and kills cells that express integrin αvβ3 including cancer associated fibroblasts (CAFs) and endothelial cells within the tumor microenvironment. ProAgio utilizes a novel binding site to directly trigger apoptosis of target cells in pre-clinical models. Here we describe the interim results of a first-in-human phase 1 trial of ProAgio in patients with advanced solid malignancies, including pancreatic cancer. Methods: The trial is enrolling adults with previously treated and histologically confirmed advanced solid malignancy for which no curative therapy exists. The dose escalation cohort uses a modified 3+3 design to determine the recommended phase 2 dose (RP2D) of ProAgio. This will be followed by a dose expansion cohort which will enroll only participants with non-neuroendocrine advanced pancreatic cancer. The primary objective of the trial is to determine the RP2D of ProAgio. Secondary objectives assess the safety (CTCAE v. 4.03), pharmacokinetics and objective response rate (ORR) of Proagio. Ascending doses of ProAgio were administered as an intravenous infusion every 1-2 weeks depending on dose level. Response is determined by serial imaging (CT or MRI) and tumor marker assessment (CA 19-9 or appropriate tumor-specific marker). Exploratory objectives include assessing biologic effect of ProAgio on pre- and on-therapy tumor biopsy specimens (apoptosis of tumor cells, integrin αvβ3 expression, CAF population, tumor vasculature and architecture), as well as identifying putative surrogate circulating biomarkers (circulating αvβ3 expressing cells among others). Results: Sixteen participants (14 with pancreatic adenocarcinoma and 2 with other gastrointestinal malignancies) have been treated on the dose escalation as of June 30, 2023. Preliminary pharmacokinetic measurements demonstrate a plasma half-life of 17.35 hours, distribution volume of 17.62 L, and clearance of 0.522 L/hr. ProAgio has been exceptionally well tolerated with only transient grade 1 or 2 treatment-related adverse events observed in most participants. Two participants had grade 2 infusion related reaction but were able to continue treatment with increased dose of diphenhydramine pre-medication. A serious adverse event of grade 3 hyperglycemia was observed in 1 participant with insulin-dependent diabetes within 24 hours of ProAgio infusion. No other treatment-associated hyperglycemia has been observed. Two participants with pancreatic cancer receiving weekly dosing of ProAgio had stable disease for &amp;gt;4 months and interval stabilization in CA 19-9 tumor marker. Conclusions: ProAgio is safe and well-tolerated. Upon completion of the dose escalation, a dose expansion phase of 15 participants treated at the RP2D will begin enrolling. NCT05085548 Citation Format: Nebojsa Skorupan, Cody J. Peer, Eve Koehler, Seth Steinberg, Jane B Trepel, William D Figg, Zhi-Ren Liu, Christine Alewine. Phase I trial of αvβ3 integrin cytotoxin ProAgio in patients with previously treated advanced pancreatic cancer and other solid tumor malignancies [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 B047.

Abstract B048: NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302)

Abstract Background: Fluoropyrimidines, such as 5-FU, exert anti-cancer activity via fluorodeoxyuridine-monophosphate (FUDR-MP). NUC-3373, a phosphoramidate transformation of FUDR-MP, generates high intracellular levels of FUDR-MP; avoiding toxic metabolite generation; and improving pharmacokinetics to enable more convenient administration. NuTide:302 is a three-part study investigating NUC-3373 in combination with chemotherapy agents used for the treatment of metatstaic CRC (mCRC). Part 1 established the safety of NUC-3373 in combination with leucovorin (LV) . Part 2 investigated NUC-3373 + LV in dose-escalation cohorts with either irinotecan (NUFIRI) or oxaliplatin (NUFOX) and determined the MTDs. Parts 1 and 2 established that LV had no effect on the safety or PK profile of NUC-3373 and the addition of oxaliplatin and irinotecan was well-tolerated. Here we present data from Part 3 (ongoing) which investigates NUFIRI and NUFOX in combination with bevacizumab (NUFIRI-bev; NUFOX-bev). Methods: Patients (pts) who had received 1 prior fluropyrimindine-containing therapy for mCRC were treated with either NUFIRI-bev (1,500 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 180 mg/m2 irinotecan (Q2W); 5 mg/kg bevacizumab (Q2W)) or NUFOX-bev (1,875 mg/m2 NUC-3373 (Q1W); 400 mg/m2 LV (Q1W); 85 mg/m2 oxaliplatin (Q2W); 5 mg/kg bevacizumab (Q2W)). Results: At the time of data cut-off, 14 pts had been treated (NUFIRI-bev n=8; NUFOX-bev n=6); median age 60 (range: 37-81), 36% female, 38% ECOG 0 and 36% with liver metastases. In the NUFIRI-bev arm, there were no Grade 3 TRAEs. Seven pts (88%) achieved prolonged SD (median= 5.5 mo; range= 3.7-7.4) and 5 pts are ongoing. In the NUFOX-bev arm, Grade 3 TRAEs (occurring in 2 pts) were pancreatitis, ALT increased and hypokalaemia. Four pts (67%) achieved prolonged SD (median= 5 mo; range= 3-6.5) and 5 pts are ongoing. Updated safety and efficacy data will be presented. Conclusions:This study demonstrated safety and anti-tumour activity of NUFIRI-bev and NUFOX-bev in previously treated mCRC patients . A randomised Phase 2 study is currently investigating the safety and efficacy of NUFIRI-bev vs FOLRIFI-bev in 171 second-line pts with CRC (NuTide:323). Clinical trial information: NCT03428958 Citation Format: Khurum Khan, Uma Mukherjee, Benjamin L Schlechter, Kristen K Ciombor, Aglaia Skolariki, Andrew L Coveler, Janet S Graham, Mary Linton Peters, Stacey A Cohen, Niharika Mettu, Hélène Marijon, David Cosgrove, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Sarah P Blagden, Aimery de Gramont, Jordan Berlin, T.R. Jeffry Evans. NUC-3373 in combination with irinotecan (NUFIRI) or oxaliplatin (NUFOX) and bevacizumab for second-line treatment of patients with advanced colorectal cancer (NuTide:302) [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 B048.

Abstract A050: A Phase 1 dose escalation study of TACH101, a first-in-class KDM4 inhibitor for advanced solid tumors

Abstract The KDM4 family of histone demethylases (KDM4A, B, C, D) have been identified as key oncogenic drivers in various cancers. KDM4 proteins control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histones H3K9 and H3K36 and have been shown to play an important role in epigenetic dysregulation during tumorigenesis. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform is not effective. TACH101 is a novel, first-in-class small molecule KDM4 inhibitor that targets isoforms A-D. In vitro and in vivo studies have shown potent anti-proliferative activity and strong tumor growth inhibition across multiple xenograft models. Preclinical studies demonstrated favorable pharmacokinetics (PK) and safety profiles. Initial clinical development of TACH101 will target advanced or metastatic solid tumors. TACH101-CS-0001 is an open-label, single-arm, phase 1 dose escalation study evaluating the safety and tolerability of orally administered TACH101 in subjects with solid tumors. Patients receive TACH101 in a single-dose lead-in period followed by repeated dosing on a weekly schedule. Using a Bayesian optimal interval (BOIN) design, the trial will evaluate up to 8 dose levels following a 3-days on/4-days off dosing schedule. Escalation across 2 dose cohorts (5 and 10mg) has been completed and enrollment into cohort 3 (25 mg) has begun. The planned enrollment is up to 33 patients including dose escalation and dose expansion (highest safe dose level) cohorts. Inclusion criteria include advanced or metastatic solid tumor that has progressed or was non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists. Patients must have disease that is measurable according to RECIST (v1.1) and an ECOG performance status score of 0 to 1. Exclusion criteria include severe hematologic, hepatic, or renal insufficiency. Primary endpoints will assess safety and tolerability to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints will evaluate PK and preliminary anti-tumor activity as assessed by objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). Exploratory endpoints include evaluation of circulating tumor DNA (ctDNA)-based genetic markers as well as molecular characterization of optional tissue biopsies. This trial will be the first to evaluate the full potential of KDM4 inhibition in solid tumors with the novel epigenetic-targeting drug candidate TACH101 in subjects with advanced or metastatic cancers. (NCT05076552). Citation Format: Apostolia Tsimberidou, Andrae L Vandross, David Sommerhalder, Charmaine Joseph, Chandtip Chandhasin, Frank Perabo, Michael F Clarke. A Phase 1 dose escalation study of TACH101, a first-in-class KDM4 inhibitor for advanced 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 A050.

Abstract PR018: IMA203 TCR-T targeting PRAME demonstrates potent anti-tumor activity in patients with different types of metastatic solid tumors

Abstract T cell receptor (TCR)-based adoptive cell therapy represents an innovative and promising treatment for pts with solid cancers who continue to have a high unmet medical need. This ongoing trial (NCT03686124) evaluates IMA203, an autologous TCR-engineered T cell therapy (TCR-T) utilizing a novel, pairing-enhanced TCR with high affinity and specificity against an HLA-A*02:01-presented peptide derived from PRAME. PRAME is a multi-cancer target with a prevalence of 80-100% in cut. and uveal melanoma, sarcoma subtypes, uterine and ovarian cancer; it has a high prevalence in many other solid cancer types, such as lung, triple-negative breast and head and neck cancer, among others. Eligible pts have recurrent and/or refractory solid cancer, are ≥18 y, ECOG PS of 0-1 and have exhausted all available SOC treatments. PRAME expression is assessed by RT-qPCR analysis of archived or fresh tumor tissue. After lymphodepletion with Cy/Flu (500 mg/m2 and 30 mg/m2 IV x 4d), IMA203 is infused followed by low-dose IL-2 (1 mil IU SC daily x 5d, then twice daily x 5d). Herein, we present preliminary results from 38 pts treated across the phase 1a dose escalation (N=27) and phase 1b dose expansion cohort A at the provisional RP2D (N=11) (data cut-off April 04, 2023). Pts were heavily pre-treated with a median of 4 prior systemic therapies. At baseline, tumor burden was 113 mm (median sum of diameters of target lesions) and LDH &amp;gt;ULN in 63% of pts. Pts in phase 1a (dose level, DL, 1-4) received a median of 0.41x109, pts in phase 1b (DL4/5) a median of 3.94x109 IMA203 T cells. TEAEs were manageable with most common events being expected cytopenias (100%), CRS (92% G1-2, 3% G3) and ICANS (13% G1-2). 61% (11/18) of pts in phase 1a and phase 1b treated at DL4/5 above 1x109 IMA203 T cells showed an initial objective response according to RECIST1.1 at week 6 post infusion. 11 pts in phase 1b were infused with IMA203 T cells manufactured with an improved process leading to significantly increased TCR-T levels and persistence. In these pts IMA203 achieved an initial objective response rate (ORR) of 64% (7/11) at week 6 and a confirmed ORR of 67% (6/9) at month 3. Objective responses were observed across multiple tumor types, including PD1-refractory cut. melanoma, uveal melanoma, platinum-resistant ovarian cancer, synovial sarcoma and head and neck cancer. 5 of 7 responders in phase 1b had an ongoing response at 9 (N=2), 6 (N=1), 3 (N=1), and 1.5 months (N=1) post infusion. At a mFU of 8.5 months, mDOR was not reached (min 1.3+, max 8.8+ months). IMA203 T cells were detectable in all evaluable post treatment tumor tissues and degree of infiltration was associated with objective responses. Objective responses were observed at low, medium and high PRAME expression levels. In summary, IMA203 showed a manageable tolerability profile and, to our knowledge, is the first TCR-T product candidate achieving a high rate of objective responses independent of tumor type, thus providing a potential innovative treatment option for many solid cancer pts with PRAME-positive tumors. Citation Format: Martin Wermke, Winfried Alsdorf, Dejka Araujo, Manik Chatterjee, Norbert Hilf, Tobias A.W. Holderried, Amir A. Jazaeri, Mamta Kalra, Andrea Mayer-Mokler, Regina Mendrzyk, Ali Mohamed, Sapna P. Patel, Ran Reshef, Arun Satelli, Harpreet Singh, Apostolia-Maria Tsimberidou, Steffen Walter, Toni Weinschenk, Cedrik M. Britten, Jason Luke. IMA203 TCR-T targeting PRAME demonstrates potent anti-tumor activity in patients with different types of 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 PR018.

Abstract LB_C02: A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels

Abstract Background: Cancer cachexia is a complex metabolic syndrome characterized by involuntary weight loss, muscle wasting and weakness leading to resistance to therapy and high mortality. Elevated levels of circulating GDF-15, an inflammatory cytokine involved in stress response and body weight regulation, are common in cancer pts with cachexia. Furthermore, GDF-15 expression increases in proportion to disease severity, and preclinical models have shown that elevated levels of circulating GDF-15 elicit cachexia. AV-380 is an antibody that binds with high affinity to GDF-15 resulting in its elimination from circulation. It has been shown to reverse weight loss and increase recovery of muscle in animal cancer models and was well tolerated without serious AEs in a phase 1 study in healthy subjects. The current study is designed to determine if adding AV-380 to standard-of-care (SoC) chemotherapy will confer additional clinically meaningful benefits in metastatic cancer pts with cachexia. Methods: This is an open-label, dose escalation, multicenter phase 1b study to assess the safety, PK, and PD of AV-380. Eligible pts must be ≥18 years of age, have confirmed metastatic colorectal or pancreatic cancer, actively receiving 1st-line SoC chemotherapy (&amp;gt;2 cycles of FOLFOX/FOLFOXIRI±bevacizumab for colorectal, FOLFOX/FOLFIRINOX for pancreatic), have cachexia defined by Fearon criteria (weight loss &amp;gt;5% over past 6 months w/o simple starvation, or BMI &amp;lt;20 kg/m2 or sarcopenia plus any degree of weight loss &amp;gt;2%), life expectancy ≥3 months, GDF-15 &amp;gt;1200 pg/mL, and ECOG PS 0/1. Those with brain metastases (unless treated and stable for ≥2 weeks prior to study treatment), significant cardiovascular disease, corrected QT interval &amp;gt;460 ms, uncontrolled pleural or pericardial effusion, parenteral nutrition, or non-cancer related cachexia are excluded. Primary endpoints are AE characterization, serum PK parameters, and serum levels of GDF-15; secondary endpoints include assessments of weight/BMI, cachexia measures, and anti-AV-380 antibodies; and exploratory endpoints include best objective response and biomarkers. Five escalating dose cohorts of AV-380 are planned (50, 100, 200, 400, 800 mg IV) with 4-6 pts in each and following a standard 3+3 design. Dose de-escalation will be performed if the lowest dose cohort is successful. The study is structured into 28-day courses with Course 1 being the single-dose phase of AV-380 and Course 2 starting the multiple-dose phase where AV-380 is administered every 14 days. Pts will remain enrolled until they start 2nd-line systemic anticancer therapy, have unacceptable toxicity related to AV-380, complete 4 courses of AV-380, withdraw consent, or sponsor terminates study. Statistical analyses will be done by cohort and summarized descriptively. Clinicaltrials.gov: NCT05865535 Encore abstract. Originially accepted at the annual Cancer Cachexia Society meeting, 28-30 September 2023, Edinburgh Scotland. Citation Format: Arvind Chaudhry, RIchard Zuniga, J. Eva Selfridge, Bruno Bastos, Vipin Lohiya, Martin Birkhofer. A phase 1b dose escalation study of AV-380 in combination with standard of care chemotherapy in metastatic cancer patients (pts) with cachexia and elevated GDF-15 levels [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 LB_C02.

A Phase I/II Trial of the FLT3 Kinase Inhibitor XY0206 in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Abstract Background: The FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients, which are associated with worse survival and higher relapse risk. XY0206 is a novel oral FLT3 inhibitor with preclinical activity against FLT3 internal tandem duplication mutations (FLT3-ITD). The Phase Ⅰ/Ⅱ clinical trail with XY0206 (NCT04471064) is currently underway to explore the initial efficacy, safety and pharmacokinetic (PK) of XY0206 in patients with relapsed/refractory AML (R/R AML). Methods: This open-label, multicenter, dose-escalation and dose-expansion Phase Ⅰ/Ⅱ trail enrolled subjects from August 2020 to September 2022 who were aged ≥18 years with R/R AML. Six dose-escalation or dose-expansion cohorts (12.5, 25, 37.5, 50, 62.5 mg per day, or 25 mg twice a day) were set up to explore the safety/tolerability and antileukemic activity of XY0206, and to determine the maximal tolerated dose (MTD) of XY0206. Safety and tolerability were assessed by monitoring dose-limiting toxicities (DLT), treament-emergent adverse events (TEAE) and adverse drug reaction (ADR). Cohort expansion was based on safety and antileukemic activity. Results: As of December 14, 2022, a total of 61 subjects were enrolled (37 with FLT3 mutation-positive). Demographics and baseline characteristics of patients are presented in Table 1. MTD of XY0206 was established as 50 mg when two of the three patients enrolled in the 62.5 mg dose-escalation cohort could not tolerate continuous medication. The 37.5 mg, 50 mg and 25 mg BID dose cohorts were further expanded. Antileukemic activity was assessed in the Full Analysis Set (FAS, n=61), with overall response rate (ORR) was 34.4% (n=21/61), composite complete remission (CRc) was 32.8% (n=20/61), complete remission (CR) was 6.6% (n=4/61) and CR with partial hematologic recovery (CRh) was 9.8% ( n=6/61 ). Among the patients with FLT3 mutation-positive (FLT3 mut+, n= 37), ORR was 48.6%(n=18/37), CRc was 45.9% ( n=17/37), CR was 2.7% (n=1/37) and CRh was 16.2% (n=6/37). Among the patients with FLT3-ITD mutation (n=30), ORR was 56.7% (n=17/30), CRc was 53.3% (n=16/30), CR was 3.3% (n=1/30) and CRh was 20%( n=6/30). The 37.5 mg dose cohort as the target dose was further expanded to include FLT3 mut+ patients only. CRc in FLT3 mut+ patients ( n= 19 ) and FLT3-ITD mutation patients (n=16) was 57.9% (n=11/19) and 68.8% (n=11/16 ), CR was 5.3% (n=1/19) and 6.3% (n=1/16), CRh was 26.3% (n=5/19 ) and 31.3% (n=5/16), respectively. In terms of safety, the overall incidence and severity of TEAE/ADR in 61 subjects did not correlate with dose significantly. The most common grade 3 and above adverse events (≥ 50% ) were leukopenia (65.6% ), thromobocytopenia (63.9%), neutropenia (62.3%), animia (52.5%) and hypokalemia (50.8%). The fatal adverse event was disease progression, which was mostly related to AML. Conclusion: XY0206 is a novel FLT3 inhibitor that showed a good safety profile, a potent anti-leukemic activity and improved efficacy in patients with FLT3 mut+ R/R AML.

Safety, Pharmacodynamic, and Anti-Tumor Activity of SL-172154 As Monotherapy and in Combination with Azacitidine (AZA) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) and Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Patients (pts)

Background: CD47 blocking antibodies and SIRPα-Fc fusion proteins have demonstrated activity in combination with azacitidine (AZA) in previously untreated (UnTx) HR-MDS and AML pts. SL-172154 (SIRPα-Fc-CD40L), a hexameric, bi-functional fusion protein consisting of SIRPα domains linked to CD40L domains through an inert Fc linker demonstrated improved anti-tumor activity in comparison to naked CD47 blocking antibodies in pre-clinical studies [de Silva et al. Cancer Immunol Res 2020]. SL-172154, as a CD47 inhibitor, requires combination with AZA to enhance pro-phagocytic signals on leukemic stem cells/blasts thereby potentiating macrophage phagocytosis in AML/HR-MDS. Here we report the results from the Phase 1 Dose Escalation. cohorts for SL-172154 monotherapy [SL-mono] and for SL-172154 + AZA combination [SL-AZA] in pts with HR-MDS or AML. Methods: The objectives of the dose escalation cohorts include evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic effects and efficacy per IWG 2006 for MDS and ELN 2017 for AML. SL-172154 was administered IV weekly of a 28-day cycle as monotherapy or with AZA 75 mg/m 2 for 7 days per cycle. mTPI-2 was used for dose escalation with a DLT threshold of 20%. Pts ≥ 18 years old with R/R HR-MDS or R/R AML were eligible for dose escalation cohorts. In addition, UnTx pts with TP53 mutant (TP53m)-MDS were eligible for SL-AZA cohorts. Results: As of May 25, 2023, 37 pts were enrolled (19 in SL-mono; 18 in SL-AZA cohorts): 14 women; median age 70 years [range 44-81]. 27 pts had R/R AML (16 de novo; 11 secondary), 5 had R/R MDS, and 5 were UnTx TP53m-MDS. 23 (85%) of 27 R/R AML pts had adverse genetic abnormalities per 2017 ELN classification, including 9 (33%) with TP53m or del 17. The median number of prior lines of AML therapy was 2 [range 1-4]; 25 (93%) had received venetoclax (VEN) and 23 (85%) had received a hypomethylating agent (HMA). All 5 pts with R/R MDS had previously received HMA and 2 pts were previously treated with VEN. SL-172154 was dose escalated as monotherapy or with AZA as shown in Table 1. Infusion-related reactions (IRRs) were the most common SL-172154-related treatment-emergent AEs (TEAEs) reported in 13 (68%) and 8 (44%) pts in SL-mono and SL-AZA cohorts, respectively. IRRs (51 events) were Grade (G) 1 or 2 except for 3 G3 events (1 each at 6 mg/kg SL-mono and SL-AZA; 1 at 3 mg/kg SL-mono). Other SL-172154-related TEAEs observed in ≥ 3 pts were AST increased (4; 21%), ALT increased (3; 16%) and nausea (3; 17%) in SL-mono cohorts, and nausea (3; 17%) in SL-AZA cohorts. All events of AST/ALT increased were transient. Only one DLT (G3 IRR in the 6 mg/kg SL-AZA cohort) was reported, which required a dose reduction to 3 mg/kg. As of July 10, 2023, in SL-mono cohorts, 1 pt with R/R AML post 7+3, FLAG and VEN/AZA achieved Morphologic Leukemia-Free State (blast reduction from 19% to &amp;lt;5%) after 1 cycle of 6 mg/kg SL-172154 and proceeded to allogeneic hematopoietic cell transplant (allo-HCT) after cycle 2. In 12 evaluable pts with R/R AML receiving SL-AZA, although no objective responses (OR) were observed, relative reduction in bone marrow (BM) blasts from baseline was reported in 2/5 pts at 1 mg SL-AZA (-50%, -75%) and 5/7 pts at 3 mg SL-AZA (ranging from -35% to -90%). One pt underwent an allo-HCT. In 4 evaluable pts with UnTx TP53m-MDS, the ORs were 1 complete remission (CR), 1 marrow CR, and 2 stable disease. 2 of them proceeded to allo-HCT. SL-172154 induced elevations in serum IL-12p40, IP-10, IL-8, IL-10, MIP3α and MCP1: greater response at 3 mg/kg compared to 1 mg/kg while similar between 3 and 6 mg/kg. In the BM, SL-172154 induced a dose-dependent increase in phagocytic cells (CD11b, HLA-DR, CD16, CD36 and CD64) within mature myeloid immune cell compartments (CD45highCD34-). Reduction in leukemic blasts (CD45lowCD34+) was associated with an increase in mature myeloid and phagocytic cell phenotypes (3 mg/kg SL-AZA &amp;gt; 1 mg/kg SL-AZA). Conclusions: SL-172154 was well tolerated up to 3 mg/kg as monotherapy and in combination with AZA. Preliminary efficacy signals were detected in UnTx TP53m-MDS and R/R AML. A response to SL-172154 monotherapy, dose-dependent increases in serum cytokines and accumulation of mature myeloid cells in BM suggest a potential role for CD40 stimulation. Based on the safety, preliminary efficacy and pharmacodynamic activity, 3 mg/kg SL-172154+ AZA is being evaluated in treatment naïve pts with TP53m AML and HR-MDS.