Citations

AbstractPurposePepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high‐affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low‐affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T‐cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto‐oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma.Experimental designPepinemab was administered intravenously on Days 1 and 15 of a 28‐day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2‐stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood.ResultsPepinemab (20 mg/kg) was well tolerated and no dose‐limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults.ConclusionsPepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response.Clinical trial registryThis trial is registered as NCT03320330 at Clinicaltrials.gov.DisclaimerThe content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

Upamostat is an orally available small-molecule serine protease inhibitor that is a highly potent inhibitor of trypsin 1, trypsin 2, trypsin 3 (PRSS1/2/3), and the urokinase-type plasminogen activator (uPA). These enzymes are expressed in many cancers, especially during tissue remodeling and subsequent tumor cell invasion. Opaganib (ABC294640), a novel, orally available small molecule is a selective inhibitor of the phosphorylation of sphingosine to sphingosine-1-phosphate (S-1-P) by sphingosine kinase 2 (SPHK2). Both sphingosine kinase 1 (SPHK1) and SPHK2 are known to regulate the proliferation-inducing compound S-1-P. However, SPHK2 is more critical in cancer pathogenesis. The goal of this project was to investigate the potential antitumor effects of upamostat and opaganib, individually and in combination, on cholangiocarcinoma (CCA) xenografts in nude mice. PAX165, a patient-derived xenograft (PDX) from a surgically resected CCA, expresses substantial levels of SPHK2, PRSS1, PRSS2, and PRSS3. Four groups of 18 mice each were treated with upamostat, opaganib, both, or vehicle. Mouse weights and PAX165 tumor volumes were measured. Tumor volumes in the upamostat, opaganib, and upamostat plus opaganib groups were significantly decreased compared to the control group.

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]

AbstractBackgroundRamucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR‐2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min) ≥ 50 µg/mL was established.ProceduresThis phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned.ResultsTwenty‐nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1–21] years; 22 were evaluable for the PK endpoint. Dose‐limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin ≥ 50 µg/mL.ConclusionRamucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.

Abstract Introduction: Irinotecan is an inhibitor of the topoisomerase I enzyme that is essential in DNA transcription, replication, and repair. It is considered a “backbone” regime in colorectal cancer in adults and in pediatric gliomas to which other antineoplastic agents are added to improve the outcome. It is used as well in the treatment of many other types of adult and pediatric cancers. Irinotecan acts as a prodrug of SN-38 which has approximately 100-1000-fold greater cytotoxic activity. The metabolic and pharmacokinetic behavior of irinotecan is very complex and currently not completely elucidated. Clinical data have shown high variability in treated patients in the efficacy, toxicity, and pharmacokinetic profile of the drug. To increase safety and efficacy, a physiologically based pharmacokinetic modeling (PBPK) approach was used to predict the optimal dose for treatment initiation. Methods: Clinical data were used in combination with measured physicochemical and blood-binding data to inform the model. Hence a middle-out approach was used to build the parent model for a population of adult cancer patients. While the default Sim-Cancer population available within the Simcyp Simulator (v21) was used, the unbound fraction in plasma for the healthy population was incorporated into the PBPK model. By using the reverse translational tool and a retrograde approach, the irinotecan metabolism was described by incorporating CYP3A (Km 14.4±1.6 μM, Vmax 14.7± 0.6 pmol/min/mg protein) and an additional clearance. This additional clearance was then explained by scaled esterases (CES1 and CES2) enzyme kinetic from in vitro data. Besides the clinical study that was used to build the model, other independent intravenously administered irinotecan studies were used for verification. Results: The model predicted the plasma concentration of the parent drug and its metabolite (SN-38) in good agreement with observed data from the clinical study that was used to build the model, as well as from several clinical studies that were not used to build the initial model, covering a dose range of 50-750 mg/m2. Conclusion: We developed a PBPK model that accurately predicts the pharmacokinetic behavior of irinotecan and its metabolite (SN-38) in an adult cancer population. Future directions involve the adaption of the model to the pediatric cancer population to predict the optimal dose for initiation of first-in-human Phase I studies and to identify potential drug interactions and unanticipated toxicities when this “backbone” regimen is combined with other investigated anticancer agents. This will then lead to an increase in individualized treatment. Citation Format: Kristina Zoran Denic, Sibylle Neuhoff, Joel Reid, Rachel Kudget. A physiologically based pharmacokinetic modeling approach for predicting the exposure of irinotecan and its active metabolite (SN-38) in cancer patients [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 A140.

Objective CYP2C9 and CYP2C19 are highly polymorphic pharmacogenes that encodes enzymes that metabolize a large number of clinically relevant drugs. While the majority of variability in drug metabolism can be explained by a few common alleles, identification of gene sequence variation that alters enzyme activity and incorporation of that information into pharmacogenomic rules for clinical decision support might lead to improved therapy. Using sequence data derived from the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment (RIGHT Protocol), we sought to identify variants of unknown significance (VUSs) for CYP2C9 and CYP2C19, and to characterize the function of the encoded enzymes. Methods Targeted next‐generation sequencing for 84 pharmacogenes using the PGRN‐Seq v1.0 capture reagent was performed with DNA samples from 1013 RIGHT Protocol participants. Plasmids containing VUSs were created using site directed mutagenesis and were transiently expressed in COS‐1 cells. Initial determination of enzyme activity was performed using fluorogenic substrates. Enzyme kinetic parameters (Km and Vmax) for each of the variant allozymes were determined using liquid chromatography mass spectrometry with tolbutamide (CYP2C9) and mephenytoin (CYP2C19) as prototypic substrates. We also compared our results with in silico functional predictions by SIFT and Polyphen. Results Seven VUSs were identified for each gene, none of which had been functionally characterized. There were significant positive correlations between protein content and fluorometric enzyme activity for all variants for both CYP2C9 (P<0.05) and CYP2C19 (P<0.005). Notably, CYP2C9 V237L and CYP2C19 A173V activity was much lower than predicted based on protein content. The substrate intrinsic clearance of CYP2C9 variants P73L , S115R , V237L [6.23E‐05±1.08E‐05; 2.55E‐05±4.1E‐06; 7.28E‐05±2.4E‐05 (uL/mg protein/min)], and CYP2C19 variants V113I , A173V , R186C and R186H [2.49E‐04±2.78E‐05; 1.80E‐05±2.19E‐06; 2.33E‐05±9.2E‐06;1.45E‐04±1.2E‐05 (uL/mg protein/min)] were less than 25% of their respective WT enzyme . Conclusion Sequencing of CYP2C9 and CYP2C19 from 1013 subjects identified low frequency variants that had not been functionally characterized. In silico predictions which showed variable results, can be helpful but are not always accurate, hence functional validation is necessary for VUSs requiring protein expression and determination of kinetic parameters. Efforts to identify variation in diverse populations is resulting in a very large number of VUSs, so there is a need for the application of high throughput mutagenesis approaches and functional characterization methods to help pharmacogenomics contribute to precision medicine. Support or Funding Information NIH RO1 GM28157 and the Mayo Center for Individualized Medicine Pharmacogenomics Program.

AbstractBackgroundDespite recent approval of several new agents, relapsed acute lymphoblastic leukemia (ALL) remains challenging to treat. Sapanisertib (MLN0128/TAK‐228) is an oral TORC1/2 inhibitor that exhibited preclinical activity against ALL.MethodsWe conducted a single‐arm multi‐center Phase II study of sapanisertib monotherapy (3 mg orally daily of the milled formulation for 21 days every 28 days) in patients with ALL through the Experimental Therapeutics Clinical Trials Network (NCI‐9775).ResultsSixteen patients, 15 of whom were previously treated (median 3 prior lines of therapy), were enrolled. Major grade 3–4 non‐hematologic toxicities included mucositis (3 patients) and hyperglycemia (2 patients) as well as hepatic failure, seizures, confusion, pneumonitis, and anorexia (1 patient each). Grade >2 hematological toxicity included leukopenia (3), lymphopenia (2), thrombocytopenia, and neutropenia (1). The best response was stable disease in 2 patients (12.5%), while only 3 patients (19%) were able to proceed to Cycle 2. Pharmacokinetic analysis demonstrated drug exposures similar to those observed in solid tumor patients. Immunoblotting in serially collected samples indicated limited impact of treatment on phosphorylation of mTOR pathway substrates such as 4EBP1, S6, and AKT.ConclusionIn summary, single‐agent sapanisertib had a good safety profile but limited target inhibition or efficacy in ALL as a single agent. This trial was registered at ClinicalTrials.gov as NCT02484430.

Abstract WSD0922-Fu is an oral, CNS-penetrant, small molecule EGFR inhibitor which potently inhibits EGFR aberrations specific to non-small cell lung cancer (NSCLC) and high-grade astrocytoma (HGA). MC1914 (NCT04197934) is a first-in-human phase 1 trial in patients with EGFR aberrant recurrent HGA and NSCLC. Adult patients with either recurrent EGFR mutant NSCLC with CNS metastases or recurrent EGFR aberrant HGA were enrolled and treated across six cohorts (40 mg once daily to 320 mg twice daily, 28-day cycles) to determine the maximum tolerated dose (MTD). 25 patients (17 HGA, 8 NSCLC) were enrolled (median age = 57 years; 24% female; 36% ECOG 0). All patients with HGA received prior radiation and temozolomide. All patients with NSCLC had previous disease progression on EGFR inhibitor therapy (prior osimertinib 88%). The median duration of WSD0922-Fu exposure among all patients was 55 days (range 3 to &gt;279 days) [NSCLC median = 131 days; HGA median = 51 days]. Common treatment-related adverse events are comparable to other EGFR inhibitors (fatigue, acneiform rash, diarrhea, nausea, pruritis). At Cycle 1 Day 15 for patients treated at MTD (160 mg twice daily), the mean terminal elimination half-life (%CV) in the plasma was 31.6 h (102%) (median 14.5 h). The mean Cmax, Tmax, oral clearance at steady state, and AUC (0-12 h) (%CV) were 4513 ng/mL (50%), 2.0 hr (69%), 6.9 L/hr/m2 (42%), and 28084 h*ng/mL (52%), respectively. Among patients with NSCLC treated at MTD or higher dose levels and with available response data, 100% (5/5) of patients demonstrated clinical benefit (SD + PR) while 60% of patients had partial responses. Intracranial and extracranial efficacy was concordant. Furthermore, prolonged stable disease (9 cycles) was observed in a patient with EGFRvIII mutant GBM. Expansion cohorts are in progress to optimize WSD0922-Fu dose and schedule for future phase 2 development.

AbstractBackgroundOutcomes for children with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are poor, and new therapies are needed. Pevonedistat is an inhibitor of the NEDD‐8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, with protein degradation regulating cell growth and survival.ProcedureWe evaluated the feasibility, toxicity, and pharmacokinetics (PK) of pevonedistat (20 mg/m2 days 1, 3, 5) in combination with azacitidine, fludarabine, cytarabine (aza‐FLA) in children with R/R AML and MDS (NCT03813147). Twelve patients were enrolled, median age was 13 years (range 1–21). Median number of prior chemotherapeutic regimens was two (range one to five), and two (25%) patients had prior hematopoietic cell transplantation. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy‐related AML (n = 1).ResultsOverall, three of 12 (25%) patients experienced DLTs. The day 1 mean ± SD (n = 12) Cmax, VSS, T1/2, and CL were 223 ± 91 ng/mL, 104 ± 53.8 L/m2, 4.3 ± 1.2 hours, and 23.2 ± 6.9 L/h/m2, respectively. T1/2, VSS, and Cmax, but not CL, were significantly different between age groups. The overall response rate was 25%, with n = 3 patients achieving a complete remission with incomplete hematologic recovery (CRi).ConclusionsPevonedistat 20 mg/m2 combined with Aza‐FLA was tolerable in children with R/R AML with similar toxicity profile to other intensive AML regimens. However, within the confines of a phase 1 study, we did not observe that the pevonedistat + Aza‐FLA combination demonstrated significant anti‐leukemic activity.