8002 Background: Tec is the first BCMA-directed bispecific antibody approved for the treatment of triple-class exposed RRMM. Tal, a bispecific antibody targeting the novel myeloma antigen GPRC5D, has shown promising efficacy in pts with RRMM. Simultaneously targeting 2 validated myeloma target antigens, using tec + tal in combination may lead to improved outcomes by overcoming resistance mechanisms, such as antigen escape. Here, we report the first results from the phase 1b RedirecTT-1 trial (NCT04586426) in pts with RRMM. Methods: Enrolled pts had MM per International Myeloma Working Group 2016 criteria; were RR or intolerant to the last line of therapy (LOT); were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy; and had measurable disease. The primary objectives are to evaluate safety and to identify a recommended phase 2 regimen (RP2R) for the combination. Responses were investigator assessed. AEs were graded per CTCAE v5.0. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. Results: As of Dec 12, 2022, 63 pts received tec + tal. Median (range) age was 67 y (39–81); median (range) prior LOT was 5 (1–11); 33% (15/45) had high-risk cytogenetics; 78% (49/63) were triple-class refractory; 63% (40/63) were penta-drug exposed; and 43% (27/63) had extramedullary disease (EMD; all bone independent). Median (range) duration of follow-up was 14.4 mos (0.5–21.9). The most common treatment-emergent AEs were CRS (81%; grade [gr] 3, 3%, no gr 4), neutropenia (76%; gr 3/4, 75%), and anemia (60%; gr 3/4, 43%). Dose-limiting toxicities (DLTs) were reported at dose level 1 (gr 3 herpetic stomatitis) and dose level 3 (gr 3 AST/ALT elevation). One ICANS event was reported at dose level 3. No DLTs were reported at the RP2R. Across all dose levels, overall response rate (ORR) was 84% (52/62) among all evaluable pts and 73% (19/26) among evaluable pts with EMD; rate of CR or better (≥CR) was 34% (21/62) and 31% (8/26), respectively. At the RP2R, ORR was 92% (12/13) among all evaluable pts and 83% (5/6) among evaluable pts with EMD; rate of ≥CR was 31% (4/13) and 33% (2/6), respectively. Median duration of response has not been reached. Updated data, with 19 additional pts at the RP2R, will be presented. Conclusions: In this first combination study of a BCMA- and GPRC5D-targeted bispecific antibody, tec + tal at the RP2R has a manageable safety profile consistent with each of the monotherapies. A 92% ORR was observed in pts with advanced RRMM at the RP2R, and an ORR of 83% was achieved in pts with EMD, a high-risk population with unmet need, supporting further evaluation of the combination. Clinical trial information: NCT04586426 .
2057 Background: Temozolomide (TMZ) transiently upregulates NKG2D ligands targeted by innate immune effector cells. Lymphodepletion impairs this immune response, however, genetic modification of ex vivo expanded γδ T cells with an MGMT-expressing lentivector confers resistance to TMZ, allowing concurrent chemotherapy and γδ T cell infusion, thereby targeting the tumor when NKG2DL are maximally expressed. This Drug Resistant Immunotherapy (DRI) is currently being evaluated in a Phase 1 first in human study (NCT04165941) and interim safety and biologic correlative analysis are detailed here for the first dosing cohort. Methods: Adults with newly diagnosed, untreated glioblastoma (GBM), adequate organ function, and a KPS≥70% will be enrolled. Subjects undergo subtotal resection and placement of a Rickham reservoir followed 3-4 weeks by apheresis from which γδ T cells are expanded, transduced with an MGMT-expressing lentivector, harvested, and cryopreserved. Standard of care induction TMZ/radiation therapy is initiated followed by 6 cycles of maintenance TMZ. Intravenous TMZ (150mg/m2) and intracranial dosing of 1 x 107 γδ T cells occur on day 1 of each maintenance cycle. Daily oral TMZ 150mg/m2 follows for Days 2-5. Dose level 1 (DL1) subjects receive 1 fixed dose of γδ T cells and DL2 receive 3 doses administered on Day 1 of each of first 3 cycles of TMZ dependent on absence of dose limiting toxicity. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted at specific time points from peripheral blood and cerebral spinal fluid collected from the Rickham. Results: Six subjects (4 females, 2 males) have been enrolled in DL1. All subjects were IDH1-WT with 5 subjects MGMT unmethylated and 1 methylated. Of these, 1 generated inadequate gd T cells and 2 withdrew consent prior to DRI treatment. For the 3 that received DRI, treatment-related adverse events with maximum CTCAE Grade 3 occurred in 1 subject; UTI, dehydration, and thrombocytopenia. The most common Grade 1/2 events included: fever, leukopenia, nausea, and vomiting which were attributable to TMZ or radiotherapy. Circulating T cells remained below normal range throughout maintenance phase in 2/3 subjects. NK and gd T cell numbers remained within low normal range for 3/3 and 2/3 subjects, respectively. Serum Th1 (IFNg, IL-2, TNFa) and Th2 (IL4, IL5, IL-10) cytokines were within clinical range although TNFa remained elevated from the gdT cell infusion through day +30 in 2 subjects. Conclusions: Administration of MGMT-gene modified gdT cells and TMZ as DRI is feasible in lymphodepleted subjects during TMZ maintenance phase and sufficiently safe to warrant further investigation at additional doses. Clinical trial information: NCT04165941.
INTRODUCTION: HAPLO BMT combined with cyclophosphamide infusion on days +3 and +4 following BMT (PTCy) for patients that lack an HLA-matched donor provides effective graft versus host disease (GVHD) prophylaxis but with a heightened risk of disease recurrence likely due to prolonged immunodeficiency. Multiple studies have shown that increases in circulating donor-derived gamma delta (γδ) T cells during the early post-transplant period is strongly associated with significant improvement in disease-free survival (DFS). We developed a clinical protocol to engineer this effect by infusing escalating doses of ex vivo expanded and activated donor γδ T cells (EAGD) during this period of immunodeficiency as prophylaxis against disease recurrence. As innate immune effectors γδ T cells immediately recognize and kill malignant cells in a broad-based non-MHC restricted manner and do not initiate GVHD. STUDY DESIGN AND METHODS: This single-center Phase I clinical trial of allogeneic haploidentical BMT + EAGD (NCT03533816), currently underway at the Kansas University Cancer Center, represents the first time BMT patients have received a large infusion of EAGD from a haploidentical donor during the early post-transplant time period. Subjects ≥18 years of age with AML, ALL, CML or MDS either in morphologic complete remission with high risk features, in first complete remission, or chronic phase (CML) eligible for BMT are enrolled in a 3 x 3 design with escalating EAGD doses from 1 x 106/kg to 3 x 106/kg to 1 x 107/kg. Subjects must have adequate organ function and a KPS ≥70. Any subjects with central nervous system neoplastic involvement, HIV infection, or a life expectancy <12 weeks are excluded. Haploidentical donors provide an initial non-mobilized leukapheresis product from which EAGD are manufactured and an unmanipulated bone marrow harvest as the source of hematopoietic stem cells. Closed system EAGD manufacturing is performed in the Miltenyi Prodigy® bioreactor by expansion of γδ T cells in conjunction with αβ T cell depletion. Specimens for composition, viability, sterility, identity, and purity are obtained prior to cryopreservation and results obtained prior to infusion. Subjects undergo standard of care conditioning therapy with fludarabine and cyclophosphamide followed by BMT and post-BMT cyclophosphamide (Cy). The EAGD product is thawed and infused directly within 5 days of neutrophil engraftment (ANC >500/mL for 3 consecutive days). Peripheral blood is collected at screening, pre and post EAGD infusion, then monthly thereafter through Day 100 with additional samples collected every 6 months through 1 year and annually thereafter. Biologic parameters include leukemia phenotype and genomics, multiparameter peripheral blood immunophenotyping, single-cell and serum Th1/Th2/Th17 cytokine analysis, and immunogenomics for both peripheral blood and the EAGD cell product. Primary endpoints include the following safety assessments; laboratory parameters, viral monitoring, physical exams, acute and chronic GVHD, as well as biopsy pathology. Relapse and overall survival will be measured as secondary endpoints. Descriptive statistics under each specific dose will be used to summarize baseline characteristics, safety variables and efficacy outcomes. Kaplan-Meier curves and summary statistics will be used to summarize time-to-event outcomes. STATUS: To date, 3 female subjects (age range, 44 - 54) with AML have been enrolled with 2 subjects receiving the EAGD infusion. To have no treatment-related adverse events have been recorded Disclosures Lamb: In8bio: Current Employment, Current equity holder in private company. Beelen:In8bio: Current Employment, Current equity holder in publicly-traded company. Youngblood:In8bio: Current Employment, Current equity holder in publicly-traded company. McGuirk:Pluristem Ltd: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bellicum Pharmaceutical: Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding.
TAZ, a selective, oral EZH2 inhibitor, is in the phase 2 clinical investigation stage for the treatment of advanced solid tumors (AdvST) and B-cell non-Hodgkin lymphoma (NHL). Drug-drug interaction (DDI) potential of TAZ was investigated in study EZH-105, a phase 1, open-label, 2-part study in adults with AdvST or NHL. In Part A, patients received TAZ 400 mg twice-daily (BID) days 1-24, then 800 mg BID continuously. Moderate CYP3A inhibitor fluconazole 400 mg was administered once daily (QD) days 16-19. Serial blood samples for pharmacokinetic analysis were collected on days 15 and 19. Patients in Part B received TAZ 800 mg BID continuously starting day 2. The CYP2C8 probe repaglinide 0.25 mg and CYP2C19 probe omeprazole 20 mg were administered on day 1 and 1 hour following TAZ administration on day 16. Omeprazole 20 mg QD continued days 17-19. Serial blood samples were collected on days 1, 16, and 19. DDIs were evaluated based on AUC and Cmax. Other primary endpoints included safety of TAZ. As of August 14, 2018, 27 patients were enrolled (n=17 AdvST, n=10 NHL). Median age was 60 years. Preliminary pharmacokinetic results are displayed in the Table. Median treatment exposure was 70 days in Part A and 57 days in Part B. Two patients, both in Part B, discontinued due to treatment emergent adverse events (TEAEs). Grade ≥3 TEAEs were reported in 12 patients. The most frequent treatment-related TEAEs (any grade) included diarrhea (n=6), fatigue (n=6), and nausea (n=3). In conclusion, the likelihood of a clinically significant DDI in the presence of TAZ is minimal. Table.Preliminary study EZH-105 PK resultsPart A. The effect of fluconazole on TAZParameterTAZ alone Day 15 Mean (%CV)TAZ + fluconazole Day 19 Mean (%CV)TAZ, n=14Cmax, ng/ml426 (95)968 (80)AUC0-12h, ng*h/mL1590 (81)5180 (66)Part B. The effect of TAZ on REP and OMPREP + OMP Day 1 Mean (%CV)REP + OMP + TAZ Day 16 Mean (%CV)REP, n=12Cmax, ng/ml5 (109)10 (78)AUC0-7h, ng*h/mL9 (110)17 (65)OMP, n=12Cmax, ng/ml263 (266)220 (250)AUC0-7h, ng*h/mL677 (340)558 (231)Part B. The effect of OMP on TAZTAZ prior to OMP Day 16 Mean (%CV)TAZ + OMP Day 19 Mean (%CV)TAZ, n=9Cmax, ng/ml613 (91)663 (68)AUC0-12h, ng*h/mL2200 (58)2820 (62)AUC, area under the concentration curve; CI, confidence interval; Cmax, maximum plasma concentration; CV, coefficient of variation; REP, repaglinide; OMP, omeprazole; PK, pharmacokinetic; TAZ, tazemetostat. Citation Format: Jennifer E. Amengual, Gary K. Schwartz, Lora Inclan, Abhijeet Kumar, Patricia Robles-Medina, Shahnaz Singh-Kandah, Benjamin Suttle, Melissa Beelen, Daniel Persky. Drug-drug interaction potential of EZH2 inhibitor tazemetostat (TAZ) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT028.
TPS3150 Background: Temozolomide (TMZ) transiently upregulates GBM-specific stress-induced NKG2D ligands that are targeted by innate immune effector cells. Leveraging this effect is problematic, however, due to the lymphodepleting effects of TMZ.Genetic modification of ex vivo expanded and activated with an MGMT-expressing lentivector allows simultaneous chemotherapy and γδ T cell therapy that targets the tumor when NKG2DL are maximally expressed. We have termed this Drug Resistant Immunotherapy (DRI). Patient-derived xenograft mouse models of both primary and recurrent GBM treated with DRI have shown a significant survival advantage that were otherwise impervious to either cell therapy or TMZ. These preclinical findings and associated safety data provide the rationale to initiate a Phase I trial of DRI in primary GBM. Methods: This first in human study will evaluate the safety and optimal dosing frequency of the DRI with TMZ (NCT04165941).Eligibility criteria include the following: GBM eligible for resection, ≥18y, adequate organ and marrow function, and KPS≥70. Six to 12patients with newly diagnosed GBM are being enrolled in a 3 + 3 design into 1 of 2 fixed dose levels (DL) of DRI. Following tumor resection and immediately prior to induction chemo/radiotherapy, an apheresis product is collected and γδ T cells expanded in Zoledronic Acid (Novartis) and rhIL-12 (Miltenyi) and transduced with a P140K-MGMT lentivector (Miltenyi Lentigen, Gaithersburg, MD), harvested, and cryopreserved. At initiation of maintenance phase TMZ therapy, patients receive 150mg/m2 intravenous TMZ concurrently with intracranial injection of 1 x 107 γδ T cells (DL1) delivered through a Rickham reservoir previously inserted into the tumor cavity at resection. The patient then receives 4 daily doses of oral TMZ followed by 24d rest. Treatment cycles escalate from 1 to 3 (DL2) DRI doses following a safety observation period and absence of dose limiting toxicity. Maintenance TMZ treatment will continue for 6 cycles. Safety evaluations consist of routine laboratory analyses, clinical measurements (physical exams, vital signs), neurological function and evidence DRI γδ T cell related toxicity. Peripheral blood will be obtained for comprehensive immuno-phenotyping and T cell function analysis. Clinical benefit of DRI will be characterized by evaluating responses (CR, PR, SD and PD) and determining progression-free, median, and overall survival. As of February 2020, enrollment into DL 1 is ongoing. Clinical trial information: NCT04165941 .
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.