bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II study of pembrolizumab plus SurVaxM for glioblastoma at first recurrence.
Authors: Ahluwalia Manmeet Singh , Peereboom David M. , Ciolfi Marci , Schilero Cathy , Hobbs Brian , Ciesielski Michael J , Fenstermaker Robert Alan 
Published: May 2020

TPS2581 Background: Glioblastoma is the most common primary malignant brain tumor with median survival of approximately 15-16 months. Following first recurrence, progression free survival at six months ~15%. There is no therapy in recurrent glioblastoma associated with any survival benefit and there is an urgent need for better therapeutic options. Immunotherapy is one promising option for patients with cancer. This is being explored in glioblastoma and a number of forms of active specific vaccination and immune checkpoint based approaches have been devised and are being investigated in glioblastoma. Methods: Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor. Survivin is a 16.5 kDa intracellular protein that belongs to the inhibitor of apoptosis protein (IAP) family. SurVaxM is a 15 amino acid antigenic peptide that targets surviving capable of binding several human MHC class I molecules. Primary Objective is to assess clinical activity of Pembrolizumab and SurVaxM in patients with recurrent glioblastoma using progression free survival at 6 months (PFS-6) as determined using RANO criteria. Secondary Objective(s) includes safety and tolerability of combination, response rates, progression free survival and overall survival. Exploratory Objective include measuring cellular and humoral immune responses during concurrent administration of Pembrolizumab and SurVaxM. This is a phase II study of two arms in patients with recurrent glioblastoma. Arm A is patients with first recurrence of glioblastoma who have failed prior chemotherapy and radiation but have not received any immunotherapy. Arm B is an exploratory arm of glioblastoma patients who have failed prior anti-PD1 therapy. This clinical trial will enroll 41 patients with glioblastoma at first recurrence (bevacizumab naïve) in arm 1.This will include a 6-patient toxicity/safety run-in. There will an exploratory cohort of 10 patients who have failed prior PD1 blockade for a total of 51 patients in 2 arms. Key inclusion criteria include diagnosis of glioblastoma, Age ≥18 years old, Previous first line treatment with at least radiotherapy with or without temozolomide and Documented first recurrence of GBM and Karnofsky performance status of 70 and normal organ function. Key exclusion criteria include more than one recurrence of GBM, presence of extracranial metastatic or leptomeningeal disease, patients with > 1 cm midline shift on imaging. Patients must not require > 10 mg daily of prednisone equivalent. Clinical trial information: NCT04013672 .
Bgb-A425, an investigational anti-TIM-3 monoclonal antibody, in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in patients with advanced solid tumors: A phase I/II trial in progress.
Authors: Desai Jayesh , Meniawy Tarek , Beagle Brandon , Li ZheZhen , Mu Song , Wu John , Denlinger Crystal S. , Messersmith Wells A. 
Published: May 2020

TPS3146 Background: While immune surveillance plays a critical role in preventing tumor proliferation and metastasis, tumors develop resistance mechanisms to suppress and/or escape the immune system. T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and programmed cell death protein-1 (PD-1) function as immune checkpoint receptors on tumor-infiltrating lymphocytes. Overlap in expression and function suggests TIM-3 and PD-1 cooperate to maximize effector T-cell exhaustion, leading to a decreased antitumor immune response. Although blockade of TIM-3 alone is unlikely to result in an efficacious antitumor immune response, combined TIM-3/PD-1 blockade may enhance the antitumor properties of anti-PD-1 therapies alone. BGB-A425 is an investigational IgG1-variant monoclonal antibody against TIM-3. Tislelizumab, an anti-PD-1 antibody, was engineered to minimize binding to FcɣR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This phase 1/2 study will assess the safety/tolerability, pharmacokinetic (PK) profile, and antitumor activity of BGB-A425 in combination with tislelizumab in patients with advanced solid tumors. Methods: This is an open-label phase 1/2 study (NCT03744468) of BGB-A425 in combination with tislelizumab in patients with histologically/cytologically confirmed advanced, metastatic, unresectable solid tumors. Phase 1 will determine the recommended phase 2 dose (RP2D) for combination treatment; phase 2 will assess the antitumor effects of the combination in select tumor types. In phase 1, up to 42 patients will be enrolled into sequential cohorts of increasing doses of intravenous (IV) BGB-A425 in combination with tislelizumab 200 mg IV, based on a 3+3 study design. During Cycle 1, patients will receive BGB-A425 alone on Day 1 followed by tislelizumab alone on Day 8. If no dose-limiting toxicities are observed, patients will receive both BGB-A425 and tislelizumab sequentially on Day 29 and every 21 days thereafter. Once the RP2D is determined, the combination therapy will be evaluated in up to 120 patients with select tumor types in phase 2. Safety/tolerability profile and RP2D determination (phase 1) and objective response rate per RECIST v1.1 (phase 2) are primary objectives; secondary objectives include antitumor activity, PK profile, and immunogenicity of combination therapy. Clinical trial information: NCT03744468 .
A phase I study of CD40 agonist ABBV-927 plus OX40 agonist ABBV-368 with or without the PD-1 inhibitor budigalimab in patients with advanced solid tumors.
Authors: Powderly John D. , Tolcher Anthony , LoRusso Patricia , Blaney Martha Elizabeth , Dacosta Daniel , Henner William R , McDevitt Michael Anthony , Miller Kathy D. , Golan Talia 
Published: May 2020

TPS3147 Background: CD40 is a key costimulatory molecule for both the innate and adaptive immune systems that is essential for T-cell activation and proliferation. OX40 is a costimulatory molecule that is involved in enhancing nascent immune responses and concomitantly acts to suppress regulatory T-cell activity. ABBV-927 and ABBV-368 are potent agonistic antibodies against CD40 and OX40, respectively. This open-label, Phase 1 study will evaluate the doublet combination of ABBV-927 and ABBV-368 and the triplet combination of ABBV-927, ABBV-368, and the programmed cell death protein-1 (PD-1) inhibitor budigalimab in patients with advanced solid tumors. Methods: For this study (NCT03893955), patients must be ≥18 y with an Eastern Cooperative Oncology Group performance status of 0-1. Patients must have an advanced solid tumor that has progressed on standard therapies. Disease-specific cohorts will include patients with non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Patients with NSCLC must have previously received a PD-1/PD-ligand 1 inhibitor and a platinum-based therapy and no more than one prior immunotherapy. Patients with TNBC must not have received immunotherapy. Patients with uncontrolled central nervous system metastases will be excluded. The recommended Phase 2 dose (RP2D) will first be identified with ABBV-927 + ABBV-368 in patients with solid tumors (Arm A) and will be expanded in disease-specific cohorts including TNBC. The RP2D of ABBV-927 + ABBV-368 + budigalimab will be identified in patients with NSCLC (Arm B). The primary endpoints are determination of the RP2D of ABBV-927 + ABBV-368, the RP2D of ABBV-927 + ABBV-368 + budigalimab, and overall response rate; duration of response, progression-free survival, safety, and pharmacokinetics are secondary endpoints. Screening began on 21 May 2019, and enrollment is ongoing. Clinical trial information: NCT03893955 .
Quilt-3.064: An open-label phase I study of PD-L1 t-haNK in subjects with locally advanced or metastatic solid cancers.
Authors: Seery Tara Elisabeth , Kistler Mira , Lee John H. , Soon-Shiong Patrick 
Published: May 2020

TPS3152 Background: Tumor cells can escape immunosurveillance through upregulation of PD-L1, which inhibits the proliferation and antitumor activity of T cells. T cells genetically altered to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens have mediated potent responses in patients with hematologic cancers, but have shown limited efficacy in solid tumor cancers and can be associated with severe toxicity, ie, cytokine release syndrome (CRS). Like T cells, NK cells can be genetically modified to express CARs that can specifically recognize and lyse cancer cells. Unlike T cells, NK cell cytotoxicity does not require prior sensitization and is not HLA-restricted, making NK cells an attractive choice for clinical immunotherapy. In addition to their innate cytotoxicity, NK cells mediate antibody-dependent cellular cytotoxicity (ADCC) via expression of CD16. PD-L1 t-haNK is an off-the-shelf, human, allogeneic, NK cell line engineered to express a CAR targeting PD-L1. It can be easily and continuously expanded in culture and preclinical in vitro and in vivo studies have demonstrated effective PD-L1 CAR–mediated antitumor activity against PD-L1+ MDSCs. PD-L1 t-haNK has also been engineered to express the high-affinity variant of the Fcγ receptor (FcγRIIIa/CD16a 158V), and thus has enhanced CD16-targeted ADCC capabilities, particularly when combined with a monoclonal antibody. As such, a dual-targeted NK approach may be more effective at potentiating antitumor activity and reversing suppression in multiple cancers that express PD-L1 in the tumor microenvironment. Methods: This is a dose-escalation study of PD-L1 t-haNK in subjects with locally advanced or metastatic solid cancers, regardless of PD-L1 expression. Dose escalation will involve a standard 3 + 3 design. The primary objectives are to determine safety, maximum tolerated dose (MTD), and designate a recommended phase 2 dose. Secondary objectives include estimates of preliminary efficacy by objective response rate, progression-free survival, and overall survival. Subjects in Cohort 1 will receive ~2 × 109 PD-L1 t-haNK cells twice per week and assessed for dose-limiting toxicities (DLTs). If no DLTs occur, the dose may increase to ~4 × 109 cells twice per week in Cohort 2. Dose expansion will occur when the MTD has been determined. PD-L1 t-haNK is administered by IV infusion in an outpatient setting. Enrollment in Cohort 1 has been completed (N = 6, > 100 doses total) without DLTs or CRS. Enrollment into Cohort 2 began December 2019. Clinical trial information: NCT04050709 .
First-in-human phase I/II clinical trial of ONC-392: Preserving CTLA-4 immune tolerance checkpoint for safer and more effective cancer immunotherapy.
Authors: Rolfo Christian Diego , Bentzen Soren , Devenport Martin , Liu Yang , Zheng Pan 
Published: May 2020

TPS3159 Background: A major paradigm in cancer immunotherapy is to use checkpoint inhibitors to break regulatory mechanisms that guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example to establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Our recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The irAEs are attributable to inactivation of the CTLA-4 checkpoint, while the CITE is effective through selective depletion of regulatory T cells (Treg) in the tumor microenvironment. We hypothesize that a safer and more effective CTLA-4-targeting immunotherapy should preserve the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg-depletion in tumor microenvironment. In preparation to test this ground-breaking hypothesis clinically, we have generated a next generation of anti-CTLA-4 antibody that preserves the CTLA-4 immune checkpoint by avoiding lysosomal degradation of CTLA-4. The new antibody, ONC-392, has dramatically lower irAEs in a humanized mouse model and significantly more potent activity in depleting tumor-infiltrating Tregs, resulting in more effective CITE. Methods: This is an open label Phase IA/IB clinical study to test the safety, pharmacokinetics (PK), and efficacy of ONC-392 as a single agent and in combination with Pembrolizumab in advanced solid tumors and non-small cell lung cancer patients. The study consists of two linked parts: Part A is a dose-finding rapid titration study, with ONC-392 as a single agent in patients with advanced disease of various histology. The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M), Part B is a Phase IA/IB trial of ONC-392 in combination with a standard dose of 200 mg Pembrolizumab in patients with NSCLC. The trial consists of a dose-finding, dose escalation or de-escalation, Phase IA component aimed at defining the recommended phase II dose for ONC-392 in combination with a standard dose of Pembrolizumab (RP2D-C), then progressing into two parallel, single arm, Phase IB expansion cohorts to test for safety and initial efficacy in two groups of patients with NSCLC: Stage IV NSCLC anti-PD(L)1 immunotherapy naïve with PD-L1-positive (PD-L1 TPS ≥ 1%); Stage IV NSCLC refractory/resistant to anti-PD(L)1 immunotherapy. Clinical trial information: NCT04140526 .
A phase Ia/Ib dose-escalation study of intravenously administered SB 11285 alone and in combination with nivolumab in patients with advanced solid tumors.
Authors: Janku Filip , Strauss James , Karim Raghad , Olszanski Anthony J. , Luke Jason J. , Leach Kevin , Iyer Radhakrishnan , Abbas Atif 
Published: May 2020

TPS3162 Background: Activation of the Stimulator of Interferon Genes (STING) pathway in immune cells in the tumor microenvironment (TME) and tumor cells results in the induction of innate and adaptive immunity and subsequent activation of cytotoxic T cells and NK cells for durable anti-tumor responses. SB 11285 is a novel agonist of the STING pathway leading to the activation of tumor-resident APCs and priming of tumor antigen specific CD8+ T cells. In our preclinical studies using multiple tumor-derived cell lines, SB 11285 has been observed to cause the induction of cytokines, such as INF-b, INF- a, TNFa and others consistent with engagement of the STING target, as well as tumor cell death by STING-mediated apoptosis. SB 11285 reduced tumor volumes in multiple rodent tumor models when administered intravenously, intraperitoneally or intratumorally as monotherapy or in combination with checkpoint inhibitors such as anti-CTLA-4 or anti-PD-1 antibody. Systemic administration could additionally facilitate trafficking of newly activated CD8+T cells from periphery into the tumor site. Methods: This open-label, multicenter phase 1a/1b clinical trial (NCT04096638) aims to enroll approximately 110 patients in the dose escalation (Part 1) and expansion cohorts (Part 2). Part 1 of the trial is a dose escalation study with IV SB 11285 monotherapy followed by combination with the checkpoint inhibitor nivolumab. Part 1 Dose Escalation of the study will evaluate ascending doses of intravenously administered SB 11285 with respect to dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and the pharmacokinetic (PK)/pharmacodynamic profile as monotherapy and in combination with nivolumab. SB 11285, with a starting dose of 0.3μg/kg, will be administered as monotherapy weekly on Days 1, 8, 15, and 22 of repeated 28-day cycles in escalating doses and in combination with nivolumab administered on Q4W schedule. Part 2 Expansion Cohorts of the study will explore initial signs of efficacy in pre-specified tumor types (such as Melanoma, Head and Neck squamous cell carcinoma) using the recommended phase 2 dose (RP2D) of SB 11285 in combination with nivolumab. In addition, the biological effects of SB 11285 will be evaluated by changes in immune cell types and activation state, serum cytokines, and gene expression patterns indicative of activation of the immune compartment. The trial is being conducted at multiple sites in the U.S . Clinical trial information: NCT04096638 .
A phase I/II first-in-human study of a novel anti-MAGE-A4 TCR/anti-CD3 bispecific (IMC-C103C) as monotherapy and in combination with atezolizumab in HLA-A*02:01-positive patients with MAGE-A4-positive advanced solid tumors (IMC-C103C-101).
Authors: Blumenschein George R. , Davar Diwakar , Gutierrez Rodolfo , Segal Neil Howard , Johnson Melissa Lynne , Dar Mohammed M. , Marshall Shannon 
Published: May 2020

TPS3165 Background: ImmTAC bispecifics are unique T cell receptor (TCR)/anti-CD3 bispecific molecules that are designed to redirect polyclonal T cells against intracellular antigens, in contrast to antibody-based therapies, which are limited to extracellular antigens. ImmTAC molecules recognize a specific peptide presented on defined Class I HLA molecules via an affinity enhanced, engineered, soluble TCR. Through the addition of an anti-CD3 scFv effector domain fused to the TCR targeting domain, ImmTAC molecules redirect T cell activity against cancer cells, regardless of the specificity of the T cell. IMC-C103C is an ImmTAC being investigated against MAGE-A4, which is among the most commonly expressed cancer testis antigens in solid malignancies, but with minimal to absent expression on normal tissues and/or hematopoietic cells. The most advanced ImmTAC in development, tebentafusp (IMCgp100), directed against melanocyte-associated lineage antigen gp100, has shown monotherapy activity in uveal melanoma and PD-1 refractory advanced cutaneous and uveal melanoma. Tebentafusp is being further evaluated in combination with durvalumab and tremelimumab. Methods: IMC-C103C-101 is a multi-center, open-label, Phase 1/2 first-in-human study of IMC-C103C as monotherapy and combination with atezolizumab in HLA-A*02:01-positive patients with MAGE-A4-positive advanced cancers. The study includes IMC-C103C monotherapy (Q1W) dose escalation, followed by expansion into indication specific arms to test for efficacy in defined patient cohorts. Concurrently, combinations with atezolizumab are planned. Primary objectives of dose escalation are to identify the MTD/RP2D, and characterize safety/tolerability. Secondary objectives include an assessment of efficacy (best overall response by RECIST v1.1), PK, PD, and ADA. IMC-C103C monotherapy dose escalation is in progress. Clinical trial information: NCT03973333 .
Phase I/II open label nonrandomized safety and efficacy study of the viral vectored ChAdOx1-MVA 5T4 immunotherapy in combination with PD-1 checkpoint blockade in intermediate-risk localized or locally advanced prostate cancer and advanced metastatic prostate cancer.
Authors: Tuthill Mark , Cappuccini Federica , Bryant Richard John , Poulton Ian , Pollock Emily , Carter Lucy , Verrill Clare , Meier Armin , Schmidt Günter , Catto James WF , Evans Tom , Gillessen Silke , Protheroe Andrew , Hamdy Freddie , Hill Adrian V.S. , Redchenko Irina 
Published: May 2020

TPS3170 Background: Antigen-specific immunotherapy (Sipuleucel-T) is licenced for the treatment for castrate resistant prostate cancer, but has modest clinical efficacy and is complex to administer to patients. New therapeutic antigen-specific approaches are required to generate and sustain therapeutic immune responses against tumour specific antigens in men with early and advanced prostate cancer. We have previously reported immunogenicity and efficacy data of a novel viral vectored vaccines-based immunotherapy based on two replication-deficient viruses, chimpanzee adenovirus (ChAdOx1) and MVA, targeting an oncofetal self-antigen 5T4, administered as a single agent and in combination with anti-PD-1 in mouse tumour models. We tested this immunotherapy alone in a first-in-human trial, VANCE (NCT02390063), in intermediate risk prostate cancer patients. Based on encouraging safety and exceptional T cell immunogenicity of the VANCE study, the phase I/II trial, ADVANCE (NCT03815942) is being undertaken to test the immunotherapy safety and efficacy in combination with PD-1 blockade in intermediate risk disease and metastatic prostate cancer. Methods: Study design: ADVANCE, an open label non-randomised phase I/II study, will recruit 12 patients with intermediate-risk prostate cancer patients (Gleason score ≤ 7, local tumour stage ≤T3c, PSA≤ 20 ng/ml) scheduled to undergo radical prostatectomy (Cohort 1) and 24 mCRPC patients with disease progression on anti-androgen therapy with either enzalutamide or abiraterone (Cohort 2). Cohort 1 will receive one cycle of ChAdOx1-MVA 5T4 immunotherapy and a single nivolumab infusion. Cohort 2 will receive 2 cycles of ChAdOx1-MVA 5T4 vaccination and three nivolumab infusions. Primary endpoint: Cohort 1 - PSA change from baseline to surgery, Cohort 2 – composite response rate measured as either ≥50% reduction of circulating tumour DNA or ≥50% serum PSA decrease from baseline at 24-week assessment and the maximal response rate. Secondary and exploratory endpoints include 5T4-specific immune response in the periphery, progression-free and overall survival and reduction of circulating tumour cells. 23 of planned 24 patients have been enrolled in Cohort 2. Enrolment to the Cohort 1 is ongoing. The data analysis is expected to be completed by Q4 2020 for Cohort 2. Clinical trial information: NCT03815942 .