bluuebunny/crossref_metadata_2025_split huggingface dataset:
BDB001, an intravenously administered toll-like receptor 7 and 8 (TLR7/8) agonist, in combination with pembrolizumab in advanced solid tumors: Phase 1 safety and efficacy results.
Authors: Patel Manish R. , Tolcher Anthony W. , Rasco Drew W. , Johnson Melissa Lynne , Alistar Angela Tatiana , Li Lixin , Chung Alexander H. , Andtbacka Robert H.I. 
Published: June 2021

2512 Background: BDB001 is an intravenously administered TLR 7/8 dual agonist immune modulator capable of reprogramming dendritic cells to produce antitumor activities. BDB001 monotherapy has demonstrated favorable tolerability and robust systemic immune activation leading to durable clinical responses in a phase I dose escalation trial. Here, we report on the safety and efficacy of BDB001 in combination with pembrolizumab in a phase I dose escalation trial in advanced solid tumors (NCT03486301). Methods: BDB001-101 is a phase 1, open label, dose escalation/expansion trial of BDB001 (IV, Q1W) in combination with pembrolizumab (IV, Q3W) in patients with advanced solid tumors. The primary endpoint was safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics and pharmacodynamic profiling of immune activation. Results: Twenty-three subjects with 13 different tumor types were enrolled across 4 dose levels. Sixty one percent were female, median age was 63 years (range, 33-86), median number of prior therapies was 3 (range, 1-8), and 48% of tumors had progressed on prior anti-PD-(L)1 therapy. Overall, BDB001 in combination with pembrolizumab was well tolerated and dose-limiting toxicities were not observed. The most common treatment related adverse events (TRAEs) were fever (39.1%), fatigue (39.1%), chills/rigor (34.8%), pruritus/rash (21.7%), and nausea (13.0%). Most of these TRAEs were grade 1 or 2 and transient. Only 3 (13.0%) subjects experienced grade 3 TRAEs of fatigue, rash, stomatitis, and alkaline phosphatase elevation. There were no grade 4 or 5 TRAEs. Pharmacodynamic evaluation of plasma cytokine levels showed robust increases in interferon gamma and interferon inducible protein-10 (IP-10) at BDB001 Dose Level 3 and 4. Preliminary efficacy evaluation of the 14 subjects treated at Dose Level 3 and 4 showed durable and deep clinical responses in 4 (29%) subjects with anti-PD-(L)1 mAb refractory melanoma, hepatocellular carcinoma, cholangiocarcinoma, and platinum-resistant ovarian carcinoma. The responses were observed by the initial efficacy assessment at 9-weeks, with some seen as early as 4-weeks. In addition, 4 (29%) subjects had stable disease for a disease control rate of 57%. To date, median time on treatment is 14.4 weeks (range, 6.0 – 42.1+) with 3 subjects still active on treatment. Conclusions: Intravenously administered BDB001 in combination with pembrolizumab is well tolerated. Rapid and deep clinical responses were observed, supported by robust systemic immune activation. BDB001 in combination with pembrolizumab is a promising novel therapeutic option for patients with advanced solid tumors and is being evaluated in an ongoing dose expansion trial. Clinical trial information: NCT03486301.
Anakinra (AKR) prophylaxis (ppx) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) receiving orvacabtagene autoleucel (orva-cel).
Authors: Costa Luciano J. , Mailankody Sham , Shaughnessy Paul , Hari Parameswaran , Kaufman Jonathan L. , Larson Sarah Marie , Dingli David , Lee Kelvin , Conte Kristin , DeVries Todd , Piasecki Julia , Li Meng , Dubowy Ronald L. , Htut Myo 
Published: June 2021

2537 Background: Orva-cel is a B-cell maturation antigen–targeted chimeric antigen receptor (CAR) T cell therapy being evaluated in the phase 1/2 EVOLVE study (NCT03430011) in pts with RRMM who had at least 3 prior lines of therapy (Tx). We previously reported safety and efficacy in the phase 1 study and established the recommended dose (RD) of orva-cel as 600 × 106 CAR+ T cells (Mailankody et al, ASCO 2020). Cytokine release syndrome (CRS), a dominant toxicity of CAR T cell therapy, is mediated in part by IL-1. We explore the role of ppx with AKR, an IL-1 signaling inhibitor, on reducing the incidence of grade (G) ≥2 CRS after orva-cel treatment at the RD. Methods: Fourteen pts were enrolled sequentially for AKR ppx and treated with orva-cel at the RD. The non-AKR ppx control group comprised the remainder of the phase 1 pts receiving orva-cel at the RD (n = 19). The median follow-up (range) was 3.0 mo (1.8–6.2) for the AKR ppx group and 8.8 mo (5.3–12.2) for the non-AKR ppx group. AKR was administered as 100 mg SC the night before orva-cel infusion, 3 h before the infusion (Day 1), and q24 h on Days 2–5. Dosing was increased to q12 h if CRS developed. CRS was graded by Lee (2014) criteria. Tocilizumab (T) and steroids (S) were used per protocol-specified treatment management guidelines. Results: Disease characteristics and outcomes are shown in the table. In AKR ppx and non-AKR ppx groups, median number of prior regimens was 6 and 5, and bridging Tx was used in 57% and 68% of pts, respectively. The total frequency of CRS was similar in the 2 groups, but with less G 2 in the AKR ppx pts; relative risk (95% CI) = 0.54 (0.21, 1.38). No G ≥3 CRS was seen in either group. The incidence of neurological events (NE), G ≥3 infection, and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) was similar. T and S use was numerically lower with AKR ppx. Orva-cel expansion kinetics were similar in the 2 groups. All pts had a 2-month efficacy assessment, with ORR in 100% of AKR ppx and 95% of non–AKR ppx pts. Conclusions: In this nonrandomized evaluation of AKR ppx with orva-cel treatment, the incidence of G ≥2 CRS was lower in pts receiving AKR ppx. The use of AKR ppx produced no adverse effect on the incidence of NE, infection, or MAS/HLH, nor on orva-cel expansion or disease response. These results warrant further study of AKR ppx in CAR T cell therapy. Clinical trial information: NCT03430011. [Table: see text]
Preliminary analysis of a phase 1/2 study of NEXI-001 donor-derived multi-antigen-specific CD8+ T-cells for the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT).
Authors: Al Malki Monzr , Vasu Sumithira , Modi Dipenkumar , Perales Miguel-Angel , Bui Donna , Edavana Vineetha , Kim Sojung , Suarez Lauren , Oelke Mathias , BednÃ¡rik Dan , Knight Robert D. , Varela Juan Carlos 
Published: June 2021

2538 Background: Allogeneic HCT is a potentially curative therapy for many patients with AML that relies on a graft-versus-leukemia (GvL) effect. Patients who relapse after allogeneic HCT have a poor prognosis and few treatment options. Donor lymphocyte infusion (DLI) can achieve a GvL effect in some patients, however, efficacy is frequently associated with the development graft-versus-host disease (GVHD). There is a substantial need for treatment approaches that enhance the benefit of GVL while decoupling toxicities associated with GVHD. Methods: We report ongoing results from a first-in-human study (NCT04284228) of a non-genetically engineered, donor-derived adoptive cellular therapy product, NEXI-001, which contains multiple populations of CD8+ T cells that recognize different HLA 02.01-restricted peptides from the WT1, PRAME, and Cyclin A1 antigens. NEXI-001 contains T cell memory subtypes that combine anti-tumor potency with long-term persistence. Results: At the time of this analysis, 7 patients with relapsed AML after allogeneic HCT were enrolled. Five Patients were treated with single infusions of NEXI-001 at three different dose levels: 50, 100 and 200 million. Currently, the median follow-up is 5 months. Significantly, GVHD, cytokine release syndrome, neurotoxicity, or NEXI-001-related adverse events were not observed. NEXI-001 treatment resulted in reductions in red blood cell and platelet transfusions and increased donor chimerism. Decreases in myeloblasts in bone marrow and peripheral blood and reduction in the size of an extramedullary myeloid sarcoma were suggestive of an anti-leukemia effect (Table). Correlative studies indicate that NEXI-001 CD8+ cells undergo a rapid proliferation after infusion and are also associated with a robust hostlymphocyte recovery that occurs as quickly Day 3 after infusion. NEXI-001 infused CD8+T cells are detectable by multimer staining in peripheral blood of patients and proliferate over time. TCR sequencing analyses determined that infused NEXI-001 cells contain T cell clones that were undetectable in the peripheral blood of patients at baseline but were detected in blood and bone marrow and persist over time. Conclusions: NEXI-001 has the potential to enhance GvL effect without the associated toxicities of GVHD, cytokine release syndrome, and neurotoxicity. Due to these encouraging results, the trial will proceed with an evaluation of repeated NEXI-001 dosing Clinical trial information: NCT04284228. [Table: see text]
Assessment of cancer-specific microbiome signature of response to immune checkpoint inhibitors.
Authors: Sarfaty Michal , Desjardins Christopher A. , Giardina Paul , Bardhan Kankana , Pandian Swarna , Halley Keith , Halvorsen Elizabeth M. , Callahan Margaret K. , Postow Michael A. , Lee Chung-Han , Kotecha Ritesh , Kashani Daniel , Ratna Neha , Regazzi Ashley Marie , Henn Matthew R. , Hellmann Matthew D. , Iyer Gopa , Ford Christopher B. , Peled Jonathan U. 
Published: June 2021

2574 Background: Clinical and preclinical experiments suggest that the gut microbiome can affect outcome in cancer patients treated with immune checkpoint inhibitors (ICI). Most data to date has been in melanoma, so the relationship of the gut microbiome with treatment outcome in other cancers is poorly understood. Here, we evaluated the microbiome composition in correlation to ICI response in patients with metastatic lung, urothelial, or renal cancer, as well as metastatic melanoma. Methods: Fecal microbiome samples were obtained from patients with metastatic melanoma, lung, urothelial, or renal cancer immediately before ICI therapy was initiated. Bacterial genomic DNA was isolated and profiled by whole metagenome sequencing. Sequence data were analyzed using a custom implementation of MetaPhlAn2. Response to ICI was defined as partial or complete response or remaining on therapy for more than 6 months. Results: Samples were prospectively collected from 94 patients, including metastatic melanoma (n = 17), lung (n = 44), urothelial (n = 23), or renal cancer (n = 10). Treatment included anti-PD(L)1 monotherapy (n = 51), anti-PD1 + anti-CTLA4 combination therapy (n = 17), or a combination of anti-PD1 and chemotherapy (n = 26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs NR, PERMANOVA, p = 0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p = 0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three cancer types (lung, urothelial and melanoma). One sample in this NR cluster was from a patient whose metastatic NSCLC was nonresponsive to pembrolizumab and carboplatin/pemetrexed. This microbiome sample was evaluated in vivo using subcutaneous MC38 and CT26 tumor models in germ-free mice. In contrast to mice colonized with stool from a healthy donor, mice colonized with stool from this patient yielded a nonresponsive result upon treatment with anti-PD1 or anti-PD-L1 in combination with anti-CTLA4. Conclusions: Analysis of the fecal microbiome composition from patients with metastatic lung, urothelial, renal cancer, and melanoma identified a cancer-specific signature of R and NR to ICI. Across three cancer types, a consistent signature of NR was identified and corroborated experimentally in preclinical models.
CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).
Authors: Lonardi Sara , Lugowska Iwona , Jackson Christopher G. C. A. , O'Donnell Anne , Bahleda Rastilav , Garrido Marcelo , Latten-Jansen Loes , Chacon Matias , Yimer Habte Aragaw , Camacho Trixia , Konduri Srivani , Aras Urvi , Sanghavi Kinjal , Vezina Heather , Dolfi Sonia , Alessi Federica , Harvey R Donald , Trigo José , Calvo Aitana 
Published: June 2021

2575 Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]
Phase I/II study of nivolumab plus vorolanib in patients with thoracic malignancies: Interim efficacy of the SCLC and primary refractory NSCLC cohorts, and safety data across all cohorts.
Authors: Wong Selina K. , Whisenant Jennifer G. , Bestvina Christine M. , Berry Lynne D , Owonikoko Taofeek K. , Sanborn Rachel E. , Lammers Philip Edward , El Osta Badi Edmond , Ramalingam Suresh S. , Carlisle Jennifer W , Steuer Conor Ernst , Borghaei Hossein , Selvaggi Giovanni , Shyr Yu , Wakelee Heather A. , Horn Leora , Beckermann Katy 
Published: June 2021

2578 Background: Combination strategies to improve the efficacy of single agent immune checkpoint inhibitors (ICIs) are increasingly being explored, with one strategy being the addition of vascular endothelial growth factor (VEGF) inhibition. Having shown promise in the treatment of hepatocellular carcinoma and renal cell carcinoma, NCT03583086 is a multi-institutional, phase I/II study of combination vorolanib and nivolumab in both naïve and refractory thoracic tumors that progressed on at least one prior line of platinum-based chemotherapy. Though structurally similar to the tyrosine kinase inhibitor, sunitinib, vorolanib was designed to have a more favorable safety profile with comparable efficacy. Here we present safety data across all cohorts and interim efficacy analyses of the SCLC and NSCLC with primary resistance to ICI-based therapy cohorts, both of which have now completed enrolment. Methods: The maximum tolerated dose determined in phase I was vorolanib 200mg daily and nivolumab 240mg q2 weeks. Phase II uses a two-stage MinMax design across 5 cohorts with objective response rate (ORR) as the primary endpoint: NSCLC (ICI naïve, primary refractory, and acquired resistance), SCLC, and thymic carcinoma. Primary refractory is defined as radiographic progression of disease within 12 weeks of ICI initiation. Results: As of January 2021, 75 patients have been enrolled across all cohorts. Stage 1 of the SCLC and primary refractory NSCLC cohorts have completed accrual at 18 and 15 patients, respectively. In the SCLC cohort, disease-control rate (DCR) was 7% and no objective responses were achieved among 14 evaluable patients. In the primary refractory NSCLC cohort, DCR was 57% and ORR 7% (1 partial response) among 14 evaluable patients. A total of 140 treatment-related adverse events (TRAEs) have been reported, 13 (9%) were grade 3 and there were no grade 4/5 events. Fatigue (9%), nausea (6%), diarrhea (6%), ALT elevation (5%), and AST elevation (5%) were the most common all grade TRAEs. The most common grade 3 TRAEs were ALT elevation and hypertension. Conclusions: This therapeutic strategy of nivolumab plus vorolanib appears to be a well-tolerated combination with a manageable safety profile. Adding VEGF inhibition may offer additional disease control in the setting of NSCLC with primary resistance to ICIs, but neither the SCLC or primary refractory NSCLC cohorts achieved the pre-determined target number of objective responses for progression to stage 2 of the study. Enrolment in the other 3 cohorts as well as exploratory correlatives are ongoing. Clinical trial information: NCT03583086.
First-in-human, phase I study of PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in biochemical relapse (BCR) and metastatic castration-resistant prostate cancer (mCRPC).
Authors: Autio Karen A. , Higano Celestia S. , Nordquist Luke T. , Appleman Leonard Joseph , Zhang Tian , Zhu Xinhua , Babiker Hani M. , Vogelzang Nicholas J. , Prasad Sandip , Schweizer Michael Thomas , Billotte Stephane , Binder Joseph , Cavazos Nora , Li Ruifeng , Chan Kam , Cho Helen , Dermyer Michael , Hollingsworth Robert , Kern Kenneth Alan , Petrylak Daniel P. 
Published: June 2021

2612 Background: Therapeutic vaccines targeting PC-associated antigens represent attractive approaches in combination with immune checkpoint inhibitors (ICI). Safety/antitumor activity of PF-06753512 (PrCa VBIR) was evaluated in a phase I, dose-escalation and expansion study in patients (pts) with BCR prior to ADT and in pts with mCRPC either prior to or after failure of novel hormone therapy. PrCa VBIR consists of: 1) priming immunization with a replication-deficient adenoviral vector (AdC68) expressing PSA, prostate-specific membrane antigen and prostate stem cell antigen; 2) boosts with plasmid DNA (pDNA) encoding the same antigens by IM electroporation; 3) ICI given subcutaneously, including anti CTLA-4 antibody tremelimumab (TRM) and anti PD-1 antibody sasanlimab (SSL). Methods: AdC68 ± ICI(s) were given on months (mos) 1 and 5 and pDNA ± ICI(s) on mos 2–4 and 6–8. After 8 mos, maintenance pDNA + ICI(s) were given every 1 or 2 mos. In Part A (6 escalation cohorts), pts with mCRPC received AdC68 (4 or 6x10e11 viral particles) + pDNA 5 mg ± ICIs (TRM alone 80 mg; TRM 40 or 80 mg + SSL 130 or 300 mg). In Part B (3 expansion cohorts), pts with mCRPC received AdC68 6x10e11 + pDNA 5 mg + TRM 80 mg + SSL 300 mg; pts with BCR received similar vector and pDNA + TRM 80 mg ± SSL 130 mg. Primary objectives: Assess overall safety (CTCAE v4.03), determine expansion dose. Secondary objectives: Anti-tumor activity (RECIST v1.1, Prostate Cancer Working Group 3, PSA 50 response) and immune response. (Note: Database remains open, some queries pending). Results: As of Sept 15, 2020, 91 pts were treated in dose-escalation (n=38) and expansion (n=53; BCR=35, mCRPC=18). Immune responses (ELISpot) were positive in some pts. Grade (G) 3 or 4 treatment-related adverse events (TRAEs) developed in 38.5% (35/91) of pts. G5 TRAEs occurred in 2 pts (n=1 G4 myasthenia gravis + G5 pulmonary embolism; n=1 G5 myocarditis). irAEs were more frequent in BCR compared to mCRPC. See the table for efficacy data. Conclusions: Vaccination with PrCa VBIR had a manageable safety profile. TRAEs increased when 2 ICIs were given. Some pts with BCR experienced durable PSA-50 responses without ADT; patients with mCRPC had few objective tumor responses, but had prolonged median rPFS. PrCa VBIR appears to stimulate antigen-specific immunity and results in noticeable antitumor activity, particularly in androgen sensitive disease. Clinical trial information: NCT02616185. [Table: see text]
Long-term follow up of patients with mesothelioma treated with dendritic cell therapy in three phase I trials.
Authors: Dumoulin Daphne W , Cornelissen Robin , Bezemer Koen , Baart Sara , Aerts Joachim 
Published: June 2021

2618 Background: Immunotherapy targeting PD-(L)1 has become indispensable in the treatment of many malignant tumors. Recently, checkpoint inhibition using anti-PD-1 in combination with anti-CTLA-4 was proved to be effective in patients with malignant pleural mesothelioma (MPM). However, the minority of patients benefit from this treatment. The lack of immunotherapy efficacy in the majority of patients with mesothelioma can be explained by the fact that mesothelioma is a tumor with an “immune-desert” phenotype, meaning a non-inflamed tumor characterized by low T-cell infiltration. By administration of dendritic cells (DCs), which were cultured, activated, and exposed to antigens ex-vivo, this “immune-desert” phenotype might be turned into an “inflamed” phenotype. Previously, we performed and published three phase I trials using activated DCs, which support this concept. Here, we report the long-term survival of the patients treated with DCs in these three phase 1 studies. Methods: We collected the survival data of the phase 1 trials using DC therapy in patients with MPM. In the first two trials, DCs loaded with autologous tumor lysate were used, while in the third allogeneic tumor lysate was used to load the DCs (Mesopher). Results: Between 2006 and 2015, in the three studies combined, 29 patients with MPM were treated with DC vaccination. At data cut-off, the median OS was 27 months (95% confidence interval (CI): 21 – 47 months). OS at 2 years was 55.2% (95% CI: 39.7%-76.6%), OS at 5 years was 20.7% (95% CI: 10.1%-42.2%). Conclusions: The long-term follow up of MPM patients treated with DC vaccination in the three separate phase 1 trials show a promising signal, with a 2-year OS of over 50% and a 5-year OS of over 20%. In addition, 2 patients are alive after 10 years of treatment. In our opinion, these findings show the potency of DC vaccination therapy in long-term activation of the immune system. DC vaccination therapy in patients with MPM is currently being investigated in a large, randomized phase II-III trial (NCT03610360) and in pancreatic cancer. Additional biomarker studies, as well as treatment combinations with for example ICI, could further improve the outcomes of DC-vaccination therapy. Clinical trial information: NCT02395679. [Table: see text]