phase-I Study Research Articles

Phase I study of BMS-986299, an NLRP3 agonist, as monotherapy and in combination with nivolumab and ipilimumab in patients with advanced solid tumors

PurposeBMS-986299 is a first-in-class, NOD-, LRR-, and pyrin-domain containing-3 (NLRP3) inflammasome agonist enhancing adaptive immune and T-cell memory responses.Materials and methodsThis was a phase-I (NCT03444753) study that assessed the safety...

Implementation and evaluation of Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) for the treatment of patients with malignant pleural effusion: study protocol for the Danish phase-I PITAC-OPC5 study.

Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) is a minimally invasive cancer-directed therapy for patients with malignant pleural effusion (MPE) and/or pleural metastasis (PLM). PITAC is based on Pressurized IntraPeritoneal Aerosol Chemotherapy, which has proven to be safe and feasible. Since 2012, 47 PITACs have been published, and prospective data on feasibility, safety and potential local response are lacking. The prospective, controlled, phase-I study is designed to treat MPE with PITAC. There are no data to support the estimated number of patients needed, but previous experience estimates the non-access rate to 20 %. Twenty eligible patients with MPE will receive two or more PITACs at four-week intervals. During video-assisted thoracoscopy, MPE and/or pleural lavage fluid is evacuated, and the extent of visible PLM is assessed. Pleural biopsies are collected, if possible, for histological response as per Thoracic Regression Grading Score (TRGS). Patients are screened for treatment-related intra- and postoperative complications. The primary outcome is the number of patients with Clavien-Dindo≥3b or Common Terminology Criteria for Adverse Events≥4 within 30days. Secondary objectives include PLM-score, TRGS and cytology, length of hospitalization, personnel safety, quality of life, and change in MPE volume. PITAC is expected to be safe and feasible for patients and personnel, and achieve positive results in the reduction of MPE volume. The results may significantly impact the next clinical, technical, and scientific steps in the implementation of PITAC. Given the suboptimal treatment options for MPE and the seemingly promising results of PITAC, we find the implementation of PITAC ethically reasonable and sound.

Phase I Study of Fianlimab, a Human Lymphocyte Activation Gene-3 (LAG-3) Monoclonal Antibody, in Combination With Cemiplimab in Advanced Melanoma.

Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma. Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria. ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded. The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.

Safety, Tolerability, and Pharmacokinetics of Nebulized GB05-Human IFNα1b Inhalation Solution: A Randomized, Placebo-Controlled, Dose-Escalation PhaseI Study in Healthy Chinese Adult Volunteers.

Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection, especially in children and older people. However, no effective treatment is currently available. TypeI interferons (IFNs) are a group of cytokines that help regulate the activity of the immune system. GB05, human IFNα1b inhalation solution, was developed under US Food and Drug Administration (FDA) standard guidelines to combat RSV infection. This randomized, double-blind, placebo-controlled, dose-escalation phaseI trial evaluated the safety, tolerability, and pharmacokinetics of nebulized GB05. A total of 35 eligible healthy Chinese adult volunteers were enrolled in this study. In the single ascending dose (SAD) study, volunteers were randomized into 0.2, 0.6, 1.2, and 1.8million IU of GB05 or placebo. In the multiple ascending dose (MAD) study, volunteers received 1.2 or 1.8million IU of GB05 or placebo for four consecutive days. Safety, tolerability, immunogenicity, and plasma pharmacokinetics were assessed for all groups. All adverse events were mild or moderate and resolved spontaneously. The most common adverse event was decreased white blood cell count (8.6% in SAD and 10% in MAD). No serious adverse events, deaths, or adverse events that reached the termination criteria occurred during the study. In SAD, the maximum concentration and area under the curve increased across the dose range of 1.2-1.8million IU in a non-linear relationship. The maximum plasma concentration after GB05 nebulization (1.06IU/ml in the 1.8million IU group) reflected a low concentration in the blood, suggesting a better lung uptake of GB05 and reduced incidence or risks of adverse events. In MAD, a steady state was reached after continuous administrations of twice daily for 3days. Overall, nebulized GB05 exhibited satisfactory safety, tolerability, and favorable pharmacokinetic (PK) profiles in healthy adult volunteers, supporting further clinical investigation in patients infected with respiratory syncytial virus. ClinicalTrials.gov Identifier NCT06277167.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

Exploratory prospective, randomized phaseII study of neoadjuvant transcatheter arterial chemoembolization plus surgery versus surgery alone for large hepatocellular carcinoma (CSGO-HBP-005): Clinical Study Group of Osaka University, Hepato-Biliary-Pancreatic Group.

Neoadjuvant transcatheter arterial chemoembolization (TACE) for large tumors is controversial, especially in the minimally invasive surgery era. The aim of this study was to compare features between groups treated with neoadjuvant TACE followed by surgery (TACE+surgery) or upfront surgery for hepatocellular carcinoma >5cm. In this exploratory, multicenter, randomized phaseI study, the primary measure was 2-year disease-free survival (DFS). Secondary measures were resection rate, necrosis rate by TACE, 2-year overall survival, and site of recurrence. A total of 30 patients were randomly allocated to each arm. The two arms did not differ in patient characteristics. The median time to surgery from randomization was 48days for TACE+surgery and 29 for surgery only (p<0.001). Postoperative morbidities did not differ between arms. The 2-year DFS, overall survival, and resection rates were 56.7%, 80.0%, and 93.3%, respectively, in the TACE+surgery arm, and 56.1%, 89.9%, and 90.0% in the upfront surgery arm. Minimally invasive surgery was carried out in 35.7% in the TACE+surgery arm and in 29.6% in the upfront surgery arm. The median necrosis rate by TACE was 90.0%. In resected specimens, invasion to the hepatic vein was less with TACE+surgery (3.6% vs. 22.2%, p=0.0380). In cases of 100% necrosis with TACE, 2-year DFS was 100%. Site of recurrence did not differ between groups. Neoadjuvant TACE did not improve 2-year DFS, and neoadjuvant TACE allowed delay of surgical treatment without increased morbidity and cancer progress. UMIN: 000005241.

A First-in-Human Randomized Study to Assess the Safety, Tolerability, Pharmacokinetics, and Neutralization Profile of Two Investigational Long-Acting Anti-SARS-CoV-2 Monoclonal Antibodies.

COVID-19 remains a significant risk for the immunocompromised given their lower responsiveness to vaccination or infection. Therefore, passive immunity through long-acting monoclonal antibodies (mAbs) offers a needed approach for pre-exposure prophylaxis (PrEP). Our study evaluated safety, anti-SARS-CoV-2 neutralizing activity, nasal penetration, and pharmacokinetics (PK) of two half-life-extended investigational mAbs, AER001 and AER002, providing the first demonstration of upper airway penetration of mAbs with the LS-modification. This randomized, double-blind, placebo-controlled phaseI study enrolled healthy adults (n = 80) who received two long-acting COVID mAbs (AER001 and AER002), AER002 alone, or placebo. The dose ranged from 100mg (mg) to 1200mg per mAb component. The primary objective was to describe the safety and tolerability following intravenous (IV) administration. Secondary objectives were to describe PK, anti-drug antibodies (ADA), neutralization activity levels, and safety evaluation through 6months of follow-up. The majority (97.6%) of the reported adverse events (AE) post administration were of grade1 severity. There were no serious adverse events (SAE) or ADAs. AER001 and AER002 successfully achieved an extended half-life of 105days and 97.5days, respectively. Participants receiving AER001 and AER002 (300mg each) or AER002 (300mg) alone showed 15- and 26-fold higher neutralization levels against D614G and omicron BA.1 than the placebo group24h post-administration. Single 300 or 1200mg IV dose of AER001 and AER002 resulted in nasal mucosa transudation of approximately 2.5% and 2.7%, respectively. AER001 and AER002 showed an acceptable safety profile and extended half-life. High serum neutralization activity was observed against D614G and Omicron BA.1 compared to the placebo group. These data support that LS-modified mAbs can achieve durability, safety, potency, and upper airway tissue penetration and will guide the development of the next generation of mAbs for COVID-19 prevention and treatment. EudraCT Number 2022-001709-35 (COV-2022-001).

Development and validation of a chiral UPLC-MS/MS method for quantifying S-Oxiracetam and R-Oxiracetam in human plasma, urine and feces: Application to a phase-I clinical pharmacokinetic study

A chiral UPLC-MS/MS method was developed and validated to determine oxiracetam enantiomers in human plasma, urine, and feces. The R-Oxiracetam and S-Oxiracetam were quantified using a CHIRALPAK ®AD3 column at 25 ℃, and the resolution was greater than 3.2. The S-Oxiracetam is the eutomer that isresponsible for the treatment of various brain damage. Isocratic elution was conducted at a flow rate of 0.9 mL/min for 6 min using the mixture of methanol and acetonitrile (methanol:acetonitrile, 15:85) containing 0.3‰ formic acid. The methods showed linearity at the range of 0.5–100 µg/mL for each oxiracetam enantiomer. A comprehensive validation process was carried out, covering aspects including linearity, selectivity, carryover, accuracy, precision, interferences, matrix effect, recovery, dilution integrity and stability in matrix and solution. The validated methods were successfully applied to quantifying R-Oxiracetam and S-Oxiracetam in human plasma, urine, and feces of 12 healthy subjects treated with either a single dose of 2 g S-Oxiracetam injection or 4 g Oxiracetam injection in a phase-I clinical trial. There was no significant difference for plasma pharmacokinetic parameters of S-Oxiracetam between the two regimens (P＞0.05). The S-Oxiracetam and Oxiracetam were primarily eliminated through urine in their original form, with cumulative excretion rates of 92.16% and 85.92%, respectively, within 24 h after administration. Enantiomers interconversion was not observed in the plasma, urine, or feces. The results of this study suggest that replacing 4 g Oxiracetam injection with 2 g S-Oxiracetam injection could offer clinical benefits by lowering the dosage and mitigating potential risks, based on the pharmacokinetic characteristics.

PhaseI study of a novel therapeutic vaccine as perioperative treatment for patients with surgically resectable hepatocellular carcinoma: The YCP02 trial.

Developing effective adjuvant therapies is essential for improving the surgical outcomes in patients with hepatocellular carcinoma (HCC). Immunotherapy against HCC has become a promising strategy; however, only approximately 30% of all HCC patients respond to immunotherapy. Previously, we generated the novel therapeutic vaccine comprising multi-human leukocyte antigen-binding heat shock protein70/glypican-3 peptides with a novel adjuvant combination of hLAG-3Ig and poly-ICLC. We also confirmed the safety of this vaccination therapy, as well as its capacity for the effective induction of immune responses in a previous clinical trial. In this phaseI study, we administered this vaccine intradermally six times before surgery, and 10 times after surgery to patients with untreated, surgically resectable HCC (stage II to IVa). The primary end-points of this study were the safety and feasibility of this treatment. We also analyzed the resected tumor specimens pathologically using hematoxylin-eosin staining and immunohistochemistry for heat shock protein70, glypican3, CD8 and programmed death-1. A total of 20 human leukocyte antigen-matched patients received this vaccination therapy with an acceptable side-effect profile. All patients underwent planned surgery without vaccination-related delay. Immunohistochemical analyses revealed that potent infiltration of CD8+ Tcells into tumors with target antigen expression was observed in 12 of 20 (60%) patients. This novel therapeutic vaccine was safe as perioperative immunotherapy for patients with HCC, and has the potential to strongly induce CD8+ Tcells infiltration into tumors.

Nonparametric Control Charts for Monitoring Serial Dependence based on Ordinal Patterns

We consider the problem of monitoring for the existence of serial dependence in real-valued and continuously distributed processes. These can exist when a process goes out-of-control. Besides, as many control charts are designed under the assumption of independent and identically distributed observations, the validity of this assumption needs to be checked. In the literature, the majority of studies handled this problem by using a specific case of autoregressive moving-average time series models. Also a moving-window approach is often considered, which leads to the drawback that at least a window length of observations need to be collected before an out-of-control situation can be detected. Here, we use ordinal patterns and propose charts that are fully nonparametric and distribution-free, have a unique chart design, and can be used almost instantaneously at the start of process monitoring. The proposed control charts do not require any model fitting, thus, eliminating the problems associated with estimation errors, but might be used as part of a Phase-I study. Through a comprehensive performance comparison study under various out-of-control scenarios, the effectiveness of the charts in uncovering serial dependence is shown and recommendations for selection are given. Implementations of the proposed charts are illustrated by using batch yield data from a chemical process.

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

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

Contact-Active Layer-by-Layer Grafted TPU/PDMS Blends as an Antiencrustation and Antibacterial Platform for Next-Generation Urological Biomaterials: Validation in Artificial and Human Urine.

Urinary tract infections and urinary encrustation impede the long-term clinical performance of urological implants and medical devices. Together, biofilm formation and encrustation constitute serious complications, driving the development of next-generation urological biomaterials. The currently available bioengineered solutions have limited success during long-term usage in the urinary environment. In addressing this unmet clinical challenge, contact-active, antiencrustation surface grafting were conceived onto a dynamically cross-linked polydimethylsiloxane (PDMS) modified thermoplastic polyurethane (TPU) blend using the layer-by-layer (LbL) assembly route. To the best of the authors' knowledge, the present study is the first to investigate the LbL grafting in developing an antiencrustation platform. These multilayered assemblies strategically employed covalent cross-linking and electrostatic interaction-assisted progressive depositions of branched polyethyleneimine and poly(2-ethyl-2-oxazoline). While polyethyleneimine conferred the contact-killing bactericidal activity, the much-coveted antiencrustation properties were rendered by incorporating a partially hydrolyzed derivative of poly(2-ethyl-2-oxazoline). The performance of the resultant surface-modified TPU/PDMS blends was benchmarked against the conventional urological alloplasts, in a customized lab-scale bioreactor-based dynamic encrustation study and in human urine. After 6 weeks of exposure to an artificial urine medium, simulating urease-positive bacterial infection, the surface-modified blends exhibited a remarkable ability to suppress Ca and Mg encrustation. In addition, these blends also displayed superior grafting stability and antibacterial efficacy against common uropathogens. As high as 4-fold log reduction in the planktonic growth of Gram-negative P. mirabilis and Gram-positive MRSA was recorded with the LbL platform vis-à-vis medical-grade TPU. In conjunction, the in vitro cellular assessment with human keratinocytes (HaCaT) and human embryonic kidney cells (HEK) established the uncompromised cytocompatibility of the multilayered grafted blends. Finally, the physiologically relevant functionality of the LbL grafting has been validated using clinical samples of human urine collected from 129 patients with a broad spectrum of disease conditions. The phase-I pre-clinical study, entailing 6 week-long incubation in human urine, demonstrated significantly improved encrustation resistance of the blends. The collective findings of the present work clearly establish the success of LbL strategies in the development of stable, multifunctional new-generation urological biomaterials.

Abstract P020: Schlafen 11 (SLFN11) as a predictive biomarker of the response to TAS1553, a novel small molecule ribonucleotide reductase subunit interaction inhibitor

Abstract Background: Ribonucleotide reductase (RNR) plays a crucial role in dNTP biosynthesis, which is required for DNA synthesis and repair, and is thought to be an attractive cancer therapeutic target. However, the precise significance of RNR inhibition remains to be elucidated, since reported RNR inhibitors exhibit limited pharmacological potency and off-target effects. We have developed a highly potent and novel small molecule RNR inhibitor, TAS1553, and reported that TAS1553 disrupted the protein-protein interaction between RNR subunits and exhibited the broad antiproliferative activity against human cancer cells in both in vitro and in vivo via oral administration. Phase-I study is currently ongoing and the identification of a predictive biomarker is essential to maximize clinical benefit of TAS1553. Here, we report a predictive biomarker of the response to TAS1553, and a clinical development strategy with the biomarker use. Material and methods: TAS1553 was synthesized at Taiho Pharmaceutical Co., Ltd. DNA replication stress, apoptosis, caspase activity and cellular growth inhibition induced by TAS1553 were assessed by western blotting, immunofluorescence staining, Caspase-Glo 3/7 assay and CellTiter-Glo® 2.0 assay, respectively. Cells were transfected with 2 nM siRNAs against SLFN11 (siSLFN11) and used for caspase-3/7 activation assay and cell proliferation assay. Results: TAS1553 induced intracellular pChk1, pRPA2 and γH2AX, followed by cleavage of PARP and caspase-3, suggesting that TAS1553 causes massive DNA replication stress. Then, we explored factors, involved in DNA replication stress, to predict response to TAS1553. Cytotoxicity profiling revealed broad antiproliferative activity of TAS1553 against both human hematological and solid cancer cell lines in a dose-​dependent manner (GI50 = 228-4150 nmol/L), and global gene expression profiling revealed that cells with high SLFN11 mRNA expression showed a higher sensitivity to TAS1553. TAS1553 exerted growth inhibitory activity without any cell killing effect against cells with low SLFN11 expression even at a concentration of 10 μmol/L, but cell killing activity against cells with high SLFN11 expression. Depletion of SLFN11 by siSLFN11 treatment in A673 cells which have high SLFN11 expression suppressed cytotoxic effect but not the growth inhibitory effect of TAS1553. Furthermore, we observed suppression of caspase-3/7 activation induced by TAS1553 in A673 cells transfected with siSLFN11. SLFN11 appeared to sensitize cancer cells to TAS1553 via promoting apoptosis. Conclusions: TAS1553, a novel orally available RNR inhibitor, showed potent antitumor activity in preclinical models of both hematological and solid tumors. Thus, TAS1553 could be a promising therapeutic agent for cancer, and SLFN11 could be a predictive biomarker in order to maximize clinical response to TAS1553. Citation Format: Hiroto Fukushima, Hiroyuki Ueno, Takuya Hoshino, Wakako Yano, Hiraku Itadani, Miki Terasaka, Sayaka Tsukioka, Takamasa Suzuki, Shoki Hara, Yoshio Ogino, Khoon Tee Chong, Tatsuya Suzuki, Yoshihiro Otsu, Satoshi Ito, Nozomu Tanaka, Seiji Miyahara. Schlafen 11 (SLFN11) as a predictive biomarker of the response to TAS1553, a novel small molecule ribonucleotide reductase subunit interaction inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P020.

Logistic regression analysis of two-phase studies using generalized method of moments.

Two-phase designs can reduce the cost of epidemiological studies by limiting the ascertainment of expensive covariates or/and exposures to an efficiently selected subset (phase-II) of a larger (phase-I) study. Efficient analysis of the resulting data set combining disparate information from phase-I and phase-II, however, can be complex. Most of the existing methods, including semiparametric maximum-likelihood estimator, require the information in phase-I to be summarized into a fixed number of strata. In this paper, we describe a novel method for the analysis of two-phase studies where information from phase-I is summarized by parameters associated with a reduced logistic regression model of the disease outcome on available covariates. We then setup estimating equations for parameters associated with the desired extended logistic regression model, based on information on the reduced model parameters from phase-I and complete data available at phase-II after accounting for nonrandom sampling design. We use generalized method of moments to solve overly identified estimating equations and develop the resulting asymptotic theory for the proposed estimator. Simulation studies show that the use of reduced parametric models, as opposed to summarizing data into strata, can lead to more efficient utilization of phase-I data. An application of the proposed method is illustrated using the data from the U.S. National Wilms TumorStudy.

Outcome of Donor-Derived Tumor Associated Antigen-Specific T Cell Therapy in Patients with High-Risk or Relapsed Acute Leukemia Post Allogeneic BMT

Background: Patients with hematologic malignancies relapsing after allogeneic blood or marrow transplantation (BMT) have limited response to conventional salvage therapies with an expected 1-year overall survival (OS) of <20%. Current strategies to treat relapsed hematopoietic cancer after BMT, such as chemotherapy and donor lymphocyte infusions (DLI) to enhance the immunologic graft-versus-leukemia (GVL) effect, have low efficacy and are associated with graft-versus-host disease (GVHD). An alternative strategy to boost the GVL effect is to infuse donor-derived T-cells targeting tumor-associated antigen (TAA) peptides as circulating TAA-specific T-cells are associated with maintenance of remission post-BMT. In this phase-I study, we evaluated the safety and clinical outcomes following administration of a novel T-cell therapeutic targeting three TAAs, WT1, PRAME and survivin in patients with acute leukemia who relapsed or were at high-risk of relapse after allogeneic BMT.Methods: Lymphocytes obtained from the BMT donor were manufactured to target TAAs; WT1, PRAME and survivin, which are over-expressed and immunogenic in most hematologic malignancies. Patients received TAA-T infusions at doses of 0.5-4x10 7/m 2. Patients were evaluated for acute infusion-related toxicity, cytokine release syndrome (CRS), neurotoxicity, GVHD and monitored for clinical response post-infusion. T-cell receptor sequencing was conducted on the TAA-T product and the recipients' peripheral blood prior to and post-infusion to monitor persistence and expansion of the product.Results: Twenty-three BMT recipients with relapsed/refractory (n=11) and/or high-risk (n=12) acute myeloid leukemia (n=20) and acute lymphoblastic leukemia (n=3) were infused post-transplant. No patient developed CRS or neurotoxicity, and only one patient developed grade III GVHD. Of the patients who relapsed post-BMT and received bridging therapy, the majority (n=9/11) achieved complete hematologic remission before receiving TAA-T. Relapsed patients exhibited a 1-year OS of 36% and 1-year leukemia-free survival of 27.3% post-TAA-T (Figure 1A and B). The poorest prognosis patients (relapsed less than 6 months after transplant) exhibited a 1-year OS of 42.8% post-relapse (n=7) (Figure 1C). Median survival was not reached for high-risk patients who received pre-emptive TAA-T post-transplant (n=12) with eight of the nine (88.9%) evaluable patients at 1-year post-infusion remaining alive (Figure 1B). Of those, five (62.5%) were alive and in continued remission at the time of submission. Evaluation of unique T-cell receptor clonotypes (present in the product but not the recipient prior to infusion) demonstrated expansion and persistence in patients up to 1-year post-infusion (Figure 1D).Conclusions: Although as a Phase-I study, concomitant anti-leukemic therapy was allowed, TAA-T cell therapy was shown to be safe and well-tolerated with sustained remissions observed in high-risk and relapsed patients. Moreover, adoptively transferred TAA-T expanded in vivo as detected by T-cell receptor V-beta (TCRVb) sequencing persisted up to at least 1-year post-infusion (Figure 1D). (ClinicalTrials.gov numbers, NCT002203902) [Display omitted] DisclosuresCruz: Mana Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Catamaran Bio: Consultancy, Patents & Royalties, Research Funding. Hanley: Mana Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellevolve: Consultancy; Maxcyte: Membership on an entity's Board of Directors or advisory committees. Bollard: SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cabaletta Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Catamaran Bio: Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ROCHE: Consultancy, Honoraria; Repertoire Immune Medicines: Current equity holder in publicly-traded company; Neximmune: Current equity holder in publicly-traded company; Mana Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Gemtuzumab Ozogamicin Plus Midostaurin in Combination with Standard Intensive Induction Therapy in Newly Diagnosed AML: Results from a Phase-I Study

Gemtuzumab Ozogamicin Plus Midostaurin in Combination with Standard Intensive Induction Therapy in Newly Diagnosed AML: Results from a Phase-I Study

A Phase-Ib/II Clinical Evaluation of Ponatinib in Combination with Azacitidine in FLT3-ITD and CBL-Mutant Acute Myeloid Leukemia (PON-AZA study)

A Phase-Ib/II Clinical Evaluation of Ponatinib in Combination with Azacitidine in FLT3-ITD and CBL-Mutant Acute Myeloid Leukemia (PON-AZA study)

Irreversible Electroporation and Nivolumab Combined with Intratumoral Administration of a Toll-Like Receptor Ligand, as a Means of In Vivo Vaccination for Metastatic Pancreatic Ductal Adenocarcinoma (PANFIRE-III). A Phase-I Study Protocol.

Simple SummaryMetastatic pancreatic ductal adenocarcinoma has a dismal prognosis, and to date no curative treatment options exist. The image guided tumor ablation technique irreversible electroporation (IRE) employs high-voltage electrical pulses through the application of several needle electrodes in and around the tumor in order to induce cell death. IRE ablation of the primary tumor has the ability to reduce pancreatic tumor induced immune suppression while allowing the expansion of tumor specific effector T cells, hereby possibly shifting the pancreatic tumor microenvironment into a more immune permissive state. The addition of immune enhancing therapies to IRE might work synergistically and could potentially induce a clinically significant treatment effect. This study protocol describes the rationale and design of the PANFIRE-III trial that aims to assess the safety of the combination of IRE with IMO-2125 (toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma.Irreversible electroporation (IRE) is a novel image-guided tumor ablation technique with the ability to generate a window for the establishment of systemic antitumor immunity. IRE transiently alters the tumor’s immunosuppressive microenvironment while simultaneously generating antigen release, thereby instigating an adaptive immune response. Combining IRE with immunotherapeutic drugs, i.e., electroimmunotherapy, has synergistic potential and might induce a durable antitumor response. The primary objective of this study is to assess the safety of the combination of IRE with IMO-2125 (a toll-like receptor 9 ligand) and/or nivolumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In this randomized controlled phase I clinical trial, 18 patients with mPDAC pretreated with chemotherapy will be enrolled in one of three study arms: A (control): nivolumab monotherapy; B: percutaneous IRE of the primary tumor followed by nivolumab; or C: intratumoral injection of IMO-2125 followed by percutaneous IRE of the primary tumor and nivolumab. Assessments include contrast enhanced computed tomography (ceCT), 18F-FDG and 18F-BMS-986192 (PD-L1) positron emission tomography (PET)-CT, biopsies of the primary tumor and metastases, peripheral blood samples, and quality of life and pain questionnaires. There is no curative treatment option for patients with mPDAC, and palliative chemotherapy regimens only moderately improve survival. Consequently, there is an urgent need for innovative and radically different treatment approaches. Should electroimmunotherapy establish an effective and durable anti-tumor response, it may ultimately improve PDAC’s dismal prognosis.

Pharmacokinetics and safety evaluation of oral Palonosetron in Chinese healthy volunteers: A phase 1, open-label, randomized, cross-over study

PurposePalonosetron hydrochloride is a specific 5-HT3 receptor antagonist, used to prevent chemotherapy-induced nausea and vomiting (CINV), and is a known chemical entity currently registered in the oral and IV forms in several countries worldwide. MethodsSingle-center, single-dose, 3-treatment, open-label, randomized, 3-period, phase-I cross-over study, conducted in 18 individuals (16 males and 2 females). The primary objective was to assess the pharmacokinetic profile of Palonosetron 0.25, 0.5 and 0.75mg, after a single, oral administration in Chinese male and female healthy volunteers. ResultsAfter administration of a single oral dose of 0.25mg, 0.5mg, or 0.75mg palonosetron in Chinese male and female healthy subjects, plasma palonosetron concentrations reached maximum values (Cmax) of 673 ± 151 pg/mL, 1330 ± 258 pg/mL, and 1990 ± 490 pg/mL, respectively, at 3-5 h (tmax). The plasma elimination half-life for 0.25, 0.5 and 0.75 mg of palonosetron was 41.8±9.72 hours, 44.6±8.59 hours and 42.3±8.51 hours, respectively. Single oral doses of 0.25mg, 0.5mg, or 0.75mg palonosetron were safe and well tolerated among all the 18 subjects involved. ConclusionsThe PK of palonosetron was found to be linear in the dose range of 0.25 to 0.75 mg. Oral palonosetron in doses up to 0.75 mg was well tolerated in healthy Chinese subjects. The PK and safety data obtained from this study were similar to previous phase I studies with IV palonosetron.

Tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534, a potent G protein-coupled receptor 40 (GPR40) agonist, at single- and multiple-ascending oral doses in healthy Chinese subjects

SHR0534 is being developed for type-2 diabetes mellitus. Herein the tolerability, safety, pharmacokinetics and pharmacodynamics of SHR0534 in healthy Chinese subjects were assessed in a phase-I, randomized, double-blind, placebo-controlled, single- and multiple-ascending dose study. Forty subjects were randomized 4:1 to receive SHR0534 at the dose of 10, 25, 50 or 100 mg, or placebo, and another eleven subjects were allocated to either the 5 mg group or the placebo group at an 8:3 ratio. All subjects received a single dose on day 1, followed by a 9-day washout and once-daily administrations for 14 consecutive days. Serial samples were collected, and vital signs, electrocardiograms, laboratory tests, urinalysis and adverse events (AEs) were recorded. All doses of SHR0534 were safe and well tolerated with infrequent, generally mild-to-moderate AEs and no serious AEs in the study. SHR0534 was absorbed with a T max of approximately 4 hours, and systemic exposure increased with dose. Accumulation was minimal (2- to 3-fold) and steady state was reached after seven days of dosing. For pharmacodynamics, no significant hypoglycaemic effects were seen in healthy adults. Good pharmacokinetics and safety were demonstrated but no obvious effect was found.