Clinical Trials of Texas

ABSTRACTThe management of diabetic foot ulcers in patients with peripheral artery disease remains challenging. Human placenta‐derived cells (PDA‐002), a mesenchymal stromal cell‐like population obtained from full‐term placental tissue, possess angiogenic and tissue regenerative properties. Participants were stratified based on peripheral artery disease status. A total of 159 individuals were randomly assigned to receive intramuscular PDA‐002 at one of three doses (3 × 106, 10 × 106 and 30 × 106 cells) or a placebo. This Phase 2 multi‐center, randomised, double‐blind, placebo‐controlled trial evaluated adults with chronic diabetic foot ulcers with and without peripheral artery disease. The primary efficacy endpoint was the proportion of participants achieving complete wound closure of the index ulcer within 3 months, with sustained closure maintained for an additional 4 weeks. PDA‐002 was well‐tolerated, with no treatment‐related serious adverse events. Intramuscular PDA‐002 treatment achieved the highest efficacy at the 3 × 106 cell dose within the peripheral artery disease subgroup (38.5% vs. 22.6% for placebo), meeting a stringent 4‐week durability endpoint that surpassed the U.S. Food and Drug Administration's recommended 2‐week sustainability criterion. PDA‐002 shows promise as a breakthrough treatment for diabetic foot ulcers and peripheral artery disease, demonstrating efficacy with two intramuscular doses and no re‐treatment.Trial Registration:ClinicalTrials.gov identifier: NCT # 02264288

Abstract Background: Treatment (Tx) with fianlimab (anti-LAG-3) + cemiplimab (anti-PD-1) resulted in a 57% ORR by BICR in pts with adv Mel, with an acceptable risk-benefit profile. Here, we present an efficacy analysis by BICR in subgroups of pts with adv Mel (neoadjuvant/adjuvant pretreated [NAP], elevated LDH, BRAF status, adrenal insufficiency [AI], and ctDNA status). Methods: Three independent expansion cohorts of pts who were anti-PD-(L)1 Tx-naïve for adv Mel (NCT03005782) received fianlimab 1600 mg + cemiplimab 350 mg IV every 3 weeks (wks) for ≤24 months (mos). Results: Overall, 98 pts were enrolled (median age: 68 years). At the data cutoff (Oct 31, 2023), median follow-up was 23 mos, and median Tx duration was 36 wks. Grade ≥3 TEAEs occurred in 47% of pts, serious TEAEs in 39%, and immune-mediated AEs in 39%. Of the 76 pts (78%) who discontinued Tx, 17 discontinuations (22%) were due to TEAEs. Overall BICR-assessed median PFS (mPFS), median OS (mOS), CR rate, and ORR were 24 mos (95% CI 12-NE), NR (95% CI 42-NE), 25%, and 57% (95% CI 47-67), respectively. Estimated survival probability was 83% at 12 mos and 71% at 24 mos. A total of 31% and 4% of pts completed 1 and 2 years of Tx, respectively. In NAP pts who had received anti-PD-(L)1 Tx (n=13), the mPFS, CR rate, and ORR were NR (95% CI 1-NE), 31%, and 46% (95% CI 19-75), respectively. There were no differences in mOS in NAP pts (NR [95% CI 26-NE]) versus NAP-naïve pts (NR [95% CI 31-NE]). In NAP and NAP-naïve pts, mPFS was NR (95% CI 3-NE) and 24 mos (95% CI 12-NE), respectively. In pts with LDH > ULN (n=31), the mPFS, mOS, CR rate, and ORR were 14 mos (95% CI 4-NE), 42 mos (95% CI 23-NE), 13%, and 55% (95% CI 36-73), respectively. In pts with BRAF mutation (n=48), the mPFS, mOS, CR rate, and ORR were NR (95% CI 39-69), NR (95% CI NE-NE), 31%, and 54% (95% CI 46-70), respectively. In pts with any-grade drug-related AI (n=12), the mPFS, mOS, CR rate, and ORR were NR (95% CI 8-NE), NR (95% CI 21-NE), 58%, and 92% (95% CI 62-100), respectively. The mPFS was NR in pts with PD-L1 expression <1% (95% CI 4-NE) and ≥1% (95% CI 24-NE), and in pts with LAG-3 expression <1% (95% CI 1-NE) and ≥1% (95% CI 19-NE). The mOS was NR in pts with PD-L1 expression <1% (95% CI 23-NE) and ≥1% (95% CI NE-NE), and in pts with LAG-3 expression <1% (95% CI 12-NE) and ≥1% (95% CI NE-NE). The ORR was 50% and 71% in pts with PD-L1 expression <1% and ≥1%, and 50% and 61% in pts with LAG-3 expression <1% and ≥1%, respectively. By Day 1 of Cycle 4, ctDNA was cleared in 15/31 pts. The mOS and mPFS for pts with uncleared ctDNA was 20.8 mos and 2.6 mos, respectively. The mOS and mPFS were NR in pts who were ctDNA-negative at Wk 9. Conclusions: With longer follow-up, fianlimab + cemiplimab continued to demonstrate high clinical activity and a generally acceptable safety profile in subgroups of pts with adv Mel. AI was reported in 12% of pts receiving the Tx; efficacy rates were higher in pts who experienced AI than in the overall study population. Citation Format: Meredith McKean, Amy M. Weise, Kyriakos P. Papadopoulos, John Crown, Sajeve S. Thomas, Janice Mehnert, John M. Kaczmar, Kevin B. Kim, Nehal J. Lakhani, Melinda L. Yushak, Jayakumar Mani, Fang Fang, Shuquan Chen, Jingxiao Chen, Laura Brennan, JuAn Wang, Israel Lowy, Mark Salvati, Matthew G. Fury, Karl D. Lewis, Omid Hamid. Fianlimab + cemiplimab in patients (pts) with advanced (adv) melanoma (Mel): Subgroup analyses by blinded independent central review (BICR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB366.

Homozygosity for the PNPLA3 risk allele is linked to liver fat accumulation. In phase 1 trials, JNJ-75220795, a hepatocyte-targeted GalNAc-conjugated PNPLA3 siRNA, reduced liver fat in PNPLA3 I148M homozygous patients with metabolic dysfunction–associated fatty liver disease.

To evaluate the equivalence of immunogenicity, safety and efficacy of Gan & Lee (GL) Glargine (Basalin®; Gan & Lee Pharmaceutical) with that of the reference product (Lantus®) in adult participants with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label, equivalence trial conducted across 57 sites. In total, 567 participants with type 2 diabetes mellitus were randomized in a 1:1 ratio to undergo treatment with either GL Glargine or Lantus® for 26 weeks. The primary endpoint was the proportion of participants in each treatment arm who manifested treatment-induced anti-insulin antibodies (AIA). Secondary endpoints included efficacy and safety metrics, changes in glycated haemoglobin levels, and a comparative assessment of adverse events. Results were analysed using an equivalence test comparing the limits of the 90% confidence interval (CI) for treatment-induced AIA development to the prespecified margins. The percentages of participants positive for treatment-induced glycated haemoglobin by week 26 were similar between the GL Glargine (19.2%) and Lantus® (21.3%) treatment groups, with a treatment difference of -2.1 percentage points and a 90% CI (-7.6%, 3.5%) (predefined similarity margins: -10.7%, 10.7%). The difference in glycated haemoglobin was -0.08% (90% CI, -0.23, 0.06). The overall percentage of participants with any treatment-emergent adverse events was similar between the GL Glargine (80.1%) and Lantus® (81.6%) treatment groups. GL Glargine was similar to Lantus® in terms of immunogenicity, efficacy,and safety, based on the current study.

Abstract Background: Acute myeloid leukemia (AML) with NUP98 fusions is associated with poor prognosis in adults and especially children. Pediatric AML is a rare and heterogeneous disease characterized by a high prevalence of gene fusions as driver mutations, including the NUP98-KDM5A fusion found in a particular subgroup of patients with complex karyotypes. To better understand this subtype of AML, we established and characterized a XPDX model designated ST1653 representing NUP98-KDM5A-driven disease from a previously treated AML patient. We performed DNA and RNA-based sequencing of the model. Further we evaluated in vivo sensitivity towards cytarabine and inhibitors targeting the JAK and CDK6 pathways, which have been shown to be important in NUP98-KDM5A-driven AML. Methods: ST1653 was established from a bone marrow aspirate collected from a 63-year-old Caucasian male who had AML recurrence following high dose cytarabine. The sample was injected subcutaneously into a triple-deficient mouse and the P0 model passaged after seventy days into CB-17 SCID and athymic nude mice and further developed until stable. WES and RNAseq were then performed. For in vivo studies, ST1653 was evaluated against cytarabine and the JAK inhibitors ruxolitinib, baricitinib and tofacitinib and the CDK4/6 inhibitors palbociclib, abemaciclib and ribociclib. Endpoints in all studies included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Results: Growth of the ST1653 AML XPDX model was similar in CB-17 SCID or athymic nude mice with a median time to endpoint of forty-five days, although the take rate in the SCID strain was superior. Sequencing identified the presence of the NUP98-KDM5A fusion and chimeric protein expression was confirmed. In vivo, ST1653 was insensitive to cytarabine and the JAK inhibitors but demonstrated limited sensitivity to CDK4/6i treatment. Conclusion: We have established and characterized a XPDX model of NUP98-KDM5A-driven AML including sequencing and in vivo evaluation. This model is an important tool for developing novel therapies to this high-risk leukemia subtype. Citation Format: Armando Diaz III, Alyssa Simonson, Johnnie Flores, Joseph Holahan, Kyriakos P Papadopoulos, Jim Lund, Drew Rasco, Amita Patnaik, Michael J Wick. Establishment and characterization of an NUP98-KDM5A-driven AML XPDX model [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 C099.

Abstract Background: Breast cancer (BC) is the most common malignancy in women and metastatic triple negative breast cancer (mTNBC) remains one of the most difficult to treat cancers with few targeted treatment options. RSK is recognized as a critical signaling component in the MAPK/PDK-1 pathways, is an important driver for BC and a signature of poor prognosis. PMD-026 is the first RSK inhibitor to enter clinical trials and is being developed alongside an immunohistochemistry (IHC) companion diagnostic to select patients with increased activated RSK2 in tumor tissue. A Phase 1/1b trial of PMD-026 in patients with metastatic breast cancer (mBC) or metastatic triple negative breast cancer (mTNBC) established safety at a dose of 200 mg Q12h. Efficacy signals in patients with heavily pretreated mBC/mTNBC are explored in this analysis along with evaluation of the effect of food (FE) on systemic exposure to treatment. Methods: PMD-026 was administered to 41 patients as a single agent in this phase 1/1b open-label study, with 30 patients evaluable for efficacy. Exploratory objectives were to identify subgroups of patients who may optimally benefit from PMD-026. Subgroup analysis of patients included 1) comparing BC patients who received ≤5 vs >5 prior therapies; 2) comparing TNBC patients (de novo vs secondary subtypes)1, and 3) comparing patients with low RSK2 H-scores (< 180) vs high (≥180). In addition, PMD 026 PK was evaluated at the 200 mg Q12h dose and a FE sub-study enrolled 12 patients administered a single 200 mg dose. Results: PMD-026 monotherapy was generally well-tolerated in the 41 mBC patients who were enrolled and treated. Kaplan-Meier PFS analysis of 30 evaluable BC patients who were dosed with PMD-026 showed that patients with less prior therapy (≤5) did significantly better (HR, 0.19; 95% CI [0.06–0.52], p=0.0014) than those with > 5 prior therapies. Subgroup analysis of PFS in those with TNBC demonstrated that de novo TNBC (n=17) had longer time on treatment with PMD-026 compared with secondary TNBC (n=9) (HR, 0.31; 95% CI [0.10-0.99], p=0.0476). In those with de novo TNBC with ≤5 prior therapies, a high RSK2 H-score was associated with significantly longer PFS at the RP2D (4.2 vs 1.3 months, HR, 0.17; 95% CI [0.03-0.80], p=0.0254) than patients with a low RSK2 H-score. In patients with CDK4/6 resistant HR+ BC (n=3), PFS was 5.2 (RSK2 high) vs 1.3 months (RSK2 low). Stable disease was observed in 53% (9/17) of patients with de novo TNBC and in 67% (6/9) of de novo TNBC patients with high RSK2. Tumor necrosis or target lesion reduction (< 30%) was observed in 17% of patients (5/30), all of whom had high RSK2 expression. In the FE sub-study, increased interpatient variability in PMD-026 Cmax and Tmax but not AUC, was observed when administered with food, favored dosing in a fasted state, which is consistent with the pH dependent solubility of PMD-026. Notably, all FE patients (12/12) achieved the target concentration of 1µM (IC90 in preclinical studies) within 4 hours when PMD-026 was taken without food. At the RP2D, PMD-026 taken without food showed relatively consistent exposure among patients over 24 hr timeframe. Conclusions: These findings demonstrate that in patients treated with PMD-026 who had received < 5 prior treatment regimens, had de novo TNBC or CDK4/6 refractory HR+ disease and had high RSK2 scores had longer PFS. Overall, PMD-026 is a well-tolerated, orally available RSK2 inhibitor that will be evaluated further for efficacy in TNBC and CDK4/6i refractory HR+ mBC, in a trial that will prospectively enroll patients based on RSK2 activation as defined by the RSK2 IHC H-scores. Clinical trial information: NCT04115306. 1 Patients diagnosed and treated for TNBC from their initial diagnosis (de novo TNBC) vs patients previously treated for hormone receptor positive (HR+) or human epidermal growth factor 2 receptor positive (HER2+) BC, but became HR or HER2 negative (secondary TNBC) Citation Format: Judy S. Wang, Muralidhar Beeram, Pavani Chalasani, Lida Mina, Rebecca A. Shatsky, Sara Hurvitz, Meghna S. Trivedi, Robert Wesolowski, Hyo S. Han, Amita Patnaik, Shakeela Bahadur, My-my Huynh, Aarthi Jayanthan, Gerrit Los, Sandra E. Dunn, Andrew Dorr. High levels of RSK2 in breast cancer patients is associated with longer PFS in patients treated with PMD-026, a first in class RSK inhibitor [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-16.

Abstract Ras protein plays a critical role in cell growth and proliferation by transmitting signal from cell surface receptor tyrosine kinase to downstream cellular proteins such as RAF and MEK. KRas is one of the most frequently mutated oncogenes, with mutations at residues G12, G13, and Q61, found in lung, colon, pancreatic and other solid malignancies. We have developed an orally bioavailable, covalent inhibitor of KRas G12C, D-1553, with potent in vitro biochemical, cellular activity and in vivo efficacy. Here we report the efficacy of D-1553 in a large panel of patient-derived xenograft (PDX) tumor models with KRas G12C mutation. In the lung cancer PDX models, D-1553 exhibited tumor growth inhibition (TGI) from 43.6% to 124.3%, with 4 out of 8 models showing tumor regression. In the colorectal cancer PDX models, the range of TGI was from 60.9% to 105.7%, with 3 out of 9 models showing regression. Combination treatment of D-1553 with chemotherapy and targeted agents demonstrated enhanced anti-tumor activity resulting in more tumor regression compared to single agent treatment. These observations from PDX models support the combination treatment as a key to increased overall response rate to KRas G12C inhibitor in clinical trial. D-1553 is currently in a Phase 1/2 clinical trial for patients with advanced solid tumors harboring KRas G12C mutation (NCT04585035). Citation Format: Zhe Shi, Jifang Weng, Xiaochong Fan, Qingqing Zhu, Emily Robb, Alyssa Moriarty, Michael Wick, Yueheng Jiang, Ling Zhang, Xing Dai, Yaolin Wang. Potent in vivo anti-tumor activity of D-1553 as a single agent and in combination with targeted therapeutics in a broad spectrum of patient-derived xenograft tumor models with KRas G12C mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1056.

Abstract Background: Hymenoptera stings are one of the common causes of anaphylaxis. The prevalence of systemic allergic reactions seems to be higher in highly exposed populations such as beekeepers and individuals receiving live bee acupuncture (LBA). However, there are a very few of studies on venom allergy in these populations. We performed two observational studies to describe the characteristics and risk factors of venom allergy in beekeepers and the LBA population.Methods: A total of 99 beekeepers and 127 individuals receiving live bee acupuncture were interviewed. Skin prick tests were performed on subjects with suspected bee venom allergy.Results: The prevalence of bee venom allergy was 34.3% among beekeepers and 29.0% in the LBA population. Systemic reactions occurred in 11.3% of the LBA population, and 28.3% of beekeepers. For beekeepers with exposure to 2-4 stings per year and ≥5 stings per year, the risk for developing venom allergy increased to 6.745-fold (95% CI 2.139-21.266) and 42.297-fold (95% CI 7.060-253.399) respectively, compared to the ≤1 sting per year group. Conversely, in the LBA population, compared to frequency ≤2 LBA stings per week, the adjusted OR of venom allergy was 0.281 (95% CI 0.075-1.047) and 0.166 (95% CI 0.045-0.612) for frequency 3-6 LBA stings per week and ≥7 stings per week respectively. The knowledge of adrenaline and venom immunotherapy was limited in both beekeepers and traditional doctors.Conclusion: The frequency of stings with high risk for bee venom allergy was >4/year in beekeepers and <3/week in the LBA population. The education on anaphylaxis management should be strengthened.