bluuebunny/crossref_metadata_2025 huggingface dataset:
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 .
A phase I/II study of HB-201, an arenavirus-based cancer immunotherapy, alone, or in combination with anti-PD-1 in patients with HPV16+ cancers.
Authors: Burman Bharat , Niu Jiaxin , Leidner Rom S. , Wang Ding , Richardson Debra L. , Iacobucci Corinne , Hwang Andy , Qing Xiaoping , Matushansky Igor , Zamarin Dmitriy , Ho Alan Loh , Pfister David G. , Posner Marshall R.
Published: May 2020

TPS3171

Background: Human Papillomavirus 16 (HPV16) is linked to several cancer types; treatment options are limited for patients with HPV16+ recurrent or metastatic cancers. The generation and maintenance of the HPV16+ malignant state requires the stable expression of HPV16-specific E7 and E6 oncogenes, which can also serve as immunogenic tumor-associated antigens. HB-201 is a replication-competent live-attenuated vector based on the arenavirus LCMV encoding a non-oncogenic E7 and E6 fusion protein. In preclinical models, both intravenously (IV) and intratumorally (IT) administered HB-201 demonstrate potent immunogenicity by induction of HPV16-specific cytotoxic T cells and associated efficacy. Methods: This is a first in human, Phase I/II study of HB-201 monotherapy or in combination with PD-1 immune checkpoint inhibitor (anti-PD-1) in HPV16+ confirmed recurrent/metastatic cancers. Phase I consists of 2 treatment groups, each conducted with a 3+3 dose escalation design. Group 1 is enrolling patients with HPV16+ head and neck squamous cell carcinoma who will receive HB-201 IV only. Group 2 is enrolling HPV16+ cancer patients with a safely accessible tumor site who will receive HB-201 IT for the first dose, followed by HB-201 IV for subsequent doses (IT-IV). HB-201 will be administered every 21 days. The Phase II component will be conducted with the recommended Phase II doses (RP2Ds) defined in Phase I and will consist of 3 groups: Group A (HB-201 IV only), Group B (HB-201 IV plus anti-PD-1), and Group C (HB-201 IT-IV). Key eligibility criteria include age > 18, ECOG performance status 0-1, confirmed HPV16+ recurrent or metastatic cancer, disease progression from at least 1 systemic standard of care therapy, and measurable disease per RECIST v1.1. The Phase I primary objective is to determine RP2Ds for IV and IT HB-201. The Phase II primary objective is to assess antitumor activity. Secondary endpoints for both phases include safety, tolerability, overall survival, progression-free survival, and duration of response. Exploratory objectives include characterization of immunogenicity of HB-201 and biomarkers associated with immune or antitumor response. Enrollment to Groups 1 and 2 began in December 2019. Clinical trial information: NCT04180215 .
Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-PD-1 therapy.
Authors: Shen Colette , Frakes Jessica , Weiss Jared , Caudell Jimmy J. , Hackman Trevor G , Akulian Jason A. , El-Haddad Ghassan , Hu Yun , Dixon Robert , Pearson Alexander T. , Barsoumian Hampartsoum B. , Cortez Maria Angelica , Jameson Katherine LaRoque , Said Patricia , Welsh James William , Seiwert Tanguy Y.
Published: May 2020

TPS3173

Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: This trial [NCT03589339] is a multicenter, open-label, phase I study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2. Clinical trial information: NCT03589339 .
A phase I/II, two-part, multicenter, first-in-human study of DS-7300a in patients with advanced solid malignant tumors.
Authors: Bendell Johanna C. , Doi Toshihiko , Patel Manish R. , Piha-Paul Sarina Anne , Sen Shiraj , Shimizu Toshio , Cheng Ben , Mekan Sabeen F. , Myobatake Yusuke , Okuda Yasuyuki , Serbest Gul , Johnson Melissa Lynne
Published: May 2020

TPS3646

Background: B7 homologue 3 (B7-H3) is a protein that is overexpressed in various cancer types, including lung, head and neck squamous cell carcinoma, prostate, esophageal, and breast. B7-H3 overexpression is associated with poor prognosis because it promotes increased invasive and metastatic potential of cancer cells (Dong P, et al. Front Oncol. 2018;8:264). Currently, no B7-H3–targeted cancer therapies are approved. DS-7300a is an antibody-drug conjugate composed of a humanized anti–B7-H3 IgG1 monoclonal antibody (MABX-9001a) conjugated to a drug linker that releases its payload upon internalization by cancer cells. The payload, DXd, is an exatecan derivative that inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA for replication and transcription. DS-7300a induced apoptosis in cancer cells in vitro and showed potent antitumor activity in xenograft models of various types of solid tumors in vivo. Methods: This phase 1/2, multicenter, nonrandomized, open-label, first-in-human study of DS-7300a is ongoing in the United States and Japan in patients with selected advanced solid tumors (NCT04145622). This study has 2 parts: dose escalation (part 1) and dose expansion (part 2). Primary objectives are to evaluate the safety, tolerability, and antitumor activity of DS-7300a and to determine the maximum tolerated dose or recommended dose for the expansion part. Secondary objectives include the pharmacokinetic characterization of DS-7300a, determination of the total levels of anti–B7-H3 antibody and the drug component (DXd), and assessment of the incidence of anti-drug antibodies against DS-7300a. Key inclusion criteria are age ≥ 18 years (United States) or ≥ 20 years (Japan), an ECOG performance status of 0 or 1, ≥ 1 measurable lesion according to RECIST 1.1 as assessed by the investigator, and consent to provide pre- and on-treatment tissue samples (mandatory if clinically allowed and not contraindicated). Key exclusion criteria include prior treatment with orlotamab, enoblituzumab, other B7-H3–targeted agents, or an antibody-drug conjugate that is conjugated with a topoisomerase I inhibitor. Dose expansion will start with 3 cohorts, including patients with selected advanced solid tumors. In both parts, DS-7300a will be administered intravenously on day 1 of each 21-day cycle. During dose escalation, the starting dose of DS-7300a is 0.8 mg/kg. This trial is currently in the dose-escalation part. Clinical trial information: NCT04145622 .
A basket trial of trastuzumab deruxtecan, a HER2-targeted antibody-drug conjugate, for HER2-amplified solid tumors identified by circulating tumor DNA analysis (HERALD trial).
Authors: Yagisawa Masataka , Nakamura Yoshiaki , Yoshino Takayuki , Komatsu Yoshito , Kadowaki Shigenori , Muro Kei , Sunakawa Yu , Satoh Taroh , Nishina Tomohiro , Esaki Taito , Fujii Satoshi , Ono Hiromi , Tomita Daiki , Fujishiro Noriko , Hirano Nami , Fuse Nozomu , Sato Akihiro , Ogawa Gakuto , Nomura Shogo , Taniguchi Hiroya
Published: May 2020

TPS3650

Background: Trastuzumab deruxtecan, a new HER2-targeting antibody-drug conjugate, has been approved for unresectable or metastatic HER2-positive breast cancer by the Food and Drug Administration. In a phase I/II trial, trastuzumab deruxtecan showed a manageable safety profile and antitumor activity in HER2-positive various cancer types. In addition, a tissue-based HER2 test occasionally cannot identify accurate HER2 status due to spatial and temporal intratumoral heterogeneity, leading to potentially missing an opportunity for responders to receive benefit from anti-HER2-targeted therapy. Circulating tumor DNA (ctDNA) analysis can detect comprehensive somatic genome alterations by assessment of spatial and temporal intratumoral heterogeneity with minimal invasiveness. Methods: We designed an investigator-initiated multicenter phase II basket trial to evaluate efficacy and safety of trastuzumab deruxtecan in advanced solid tumor malignancies with HER2 amplification identified by Guardant360, a 74-gene sequencing ctDNA panel, as a part of the Nationwide Cancer Genome Screening Project (GOZILA study, UMIN000029315). The key eligibility criteria are as follows: 1) Histopathologically confirmed advanced solid tumor malignancy; 2) Identified HER2 amplification by Guardant360; 3) Failed prior standard therapy. The participants will receive intravenously 5.4 mg/kg of trastuzumab deruxtecan every 3 weeks. The primary endpoint is objective response rate (ORR). The planned sample size is 55-65. A Bayesian model considering the potential heterogeneity across cancer types will be applied to detect ORR of 5% versus 25% to a certain level while maintaining the false-positive error rate in each cancer type at 10%. Furthermore, tumor tissue, ctDNA and circulating tumor cells are serially collected and analyzed to investigate the predictive biomarkers and resistance mechanisms. The trial was activated in late 2019. At the time of the abstract submission, 2 patients have been enrolled. This trial is granted by AMED under Grant Number JP18lk0201084. Clinical trial information: JapicCTI-194707 .
Randomized phase II trial of topotecan plus M6620 (VX-970) versus topotecan alone in patients with relapsed small-cell neuroendocrine cancers including small cell lung cancer.
Authors: Takahashi Nobuyuki , Vilimas Rasa , Nichols Samantha , Sciuto Linda , Webb Santhana , Steinberg Seth M. , Pommier Yves , Thomas Anish
Published: May 2020

TPS3653

Background: Ataxia telangiectasia and Rad3-related (ATR) is an essential kinase that senses stressed replication forks and orchestrates the multifaceted replication stress response. Cancer cells under replication stress are particularly susceptible to ATR inhibition. Small-cell neuroendocrine cancers (SCNCs) are highly aggressive and arise in multiple tissues, most commonly lung (SCLC). We hypothesized that SCNCs are under replication stress and that exacerbating this stress could selectively kill SCNC by replicative damage. Based on promising data from a single-arm study, this study seeks to evaluate the improvement of progression free survival (PFS) by adding M6620 to topotecan in patients with SCNC. Methods: This study is an investigator-initiated, multicenter, open-label randomized phase 2 clinical trial. Key inclusion criterion are patients at age ≥18 with SCNCs that had relapsed after at least one prior chemotherapy, ECOG PS ≤ 2, and adequate organ function. Patents with asymptomatic brain metastasis, irrespective sensitivity with prior platinum-based chemotherapy, and previously treated with immune checkpoint inhibitors are eligible. The primary cohort consists of 54 patients with SCLC randomized 2:1 to receive either topotecan in combination with M6620 or topotecan alone. Topotecan is administered 1.25 mg/m2 intravenously over 30 minutes every 23 hours on day 1 through 5, pegfilgrastim 6 mg subcutaneously on day 6 and M6620 is administered at 210 mg/m2 intravenously over 60 minutes on day 2 and day 5 if the patient is randomized to the combination arm, in 21-day cycles. Patients randomized to the topotecan alone arm can cross-over to the combination arm at disease progression. An exploratory cohort will enroll 20 patients with SCNC. Primary endpoint is PFS improvement with the combination compared with topotecan alone. Secondary endpoints are ORR and overall survival. To evaluate the genomic features associated with clinical outcomes and to gain insight into the underlying mechanisms of ATR inhibitor response, we require mandatory biopsy before starting treatment. Clinical trial information: NCT03896503 .
A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors.
Authors: Schram Alison M. , Drilon Alexander E. , Macarulla Teresa , O'Reilly Eileen Mary , Rodon Jordi , Wolpin Brian M. , Ou Sai-Hong Ignatius , Kim Dong-Wan , Yang James C. , Lam Justina Yick Ching , Varga Andrea , De Langen Joop , Witteveen Petronella , Boni Valentina , Cerea Giulio , Duruisseaux Michaël , Liu Stephen V. , Wasserman Ernesto , Tabernero Josep
Published: May 2020

TPS3654

Background: NRG1 fusions are oncogenic drivers across various cancers. NRG1 fusion proteins bind to HER3, leading to HER2/HER3 heterodimerization, increased downstream signaling, and tumor growth. Clinical responses to anti-HER3 antibodies or HER2 tyrosine kinase inhibitors have been reported. In contrast to these agents, MCLA-128 is a HER2/HER3 bispecific antibody that blocks both NRG1 binding and HER2/3 dimerization. Two patients with chemotherapy-resistant ATP1B1-NRG1-positive pancreatic KRAS-wild-type adenocarcinomas who received MCLA-128 through FDA-approved single-patient Investigational New Drug (IND) applications showed significant tumor shrinkage and durable tumor marker (CA-19-9) response. These data support the evaluation of MCLA-128 in NRG1 fusion-positive tumors using a basket approach. Methods: This is a global, open-label, multicenter phase 2 basket trial of MCLA-128 in patients with solid tumors harboring NRG1 gene fusions. Main eligibility criteria are locally advanced unresectable or metastatic cancers harboring an NRG1 fusion, and failure under prior standard therapy appropriate for the tumor type and disease stage. Genomic screening of tumor tissue is done at a local laboratory (with post-hoc central confirmation) or central laboratory (RNA sequencing). Three NRG1 fusion-positive tumor cohorts are being evaluated: pancreatic cancer, NSCLC, and other solid tumors. The sample size for the first two cohorts is up to 25 patients; the basket group may enroll up to 40 patients. The primary endpoint for all cohorts is investigator-assessed objective response rate (RECIST v1.1). The key secondary endpoint is duration of response. Other secondary endpoints include progression-free and overall survival. Eligible patients receive a bi-weekly dosing regimen of 750 mg of MCLA-128 (2-hour infusion), every 2 weeks, in 4-week cycles. The study is actively accruing patients in North America, Europe, and Asia. Previously presented at ESMO 2019, 685TiP, Schram et al.-Reused with permission. Clinical trial information: NCT02912949 .
Trial in progress: A phase Ib study of AMG 510, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101).
Authors: Fakih Marwan , Durm Greg Andrew , Govindan Ramaswamy , Falchook Gerald Steven , Soman Neelesh , Henary Haby Adel , Hong David S.
Published: May 2020

TPS3661

Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation has been identified as a driver oncogenic mutation in several solid tumors (eg, non-small cell lung cancer [NSCLC], colorectal cancer [CRC]). Development of therapies targeting KRASG12C has been unsuccessful. AMG 510 is a specific and irreversible small molecule inhibitor of KRASG12C. A first-in-human clinical trial of AMG 510 monotherapy in patients with KRAS p.G12C mutant solid tumors is currently ongoing. AMG 510 in combination with additional anticancer therapies may lead to enhanced antitumor efficacy. This study is a master protocol designed to evaluate multiple investigational regimens of AMG 510 in patients with KRAS p.G12C mutant solid tumors. Here, we present two combination cohorts of AMG 510 with a mitogen-activated protein kinase kinase (MEK) inhibitor and an investigational anti-programmed cell death protein-1 (PD-1) therapy, respectively. Additional combination cohorts will be presented at the meeting. Methods: This is a phase 1b, open-label study evaluating AMG 510 in combination with a MEK inhibitor or an investigational anti-PD-1 therapy in pts with KRAS p.G12C mutant solid tumors. The dose exploration phase (part 1; n=20) will evaluate the safety and tolerability of AMG 510 in combination with the MEK inhibitor or anti-PD-1 therapy; this will be followed by a dose expansion phase (part 2; n=40) to verify the safety and tolerability profile of AMG 510 combination therapies and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic malignancy with KRAS p.G12C mutation identified through molecular testing and at least one or multiple lines of prior systemic therapy (eg, ≥2 for advanced/metastatic colorectal cancer). Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic parameters of combination regimens, disease control rate, duration of response, progression-free survival, and duration of stable disease (measured by computed tomography or magnetic resonance imaging and assessed per RECIST 1.1). The study began enrolling pts in December 2019 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04185883 .
A multicenter phase Ib/II study of DNA-PK inhibitor peposertib (M3814) in combination with capecitabine and radiotherapy in patients with locally advanced rectal cancer.
Authors: Romesser Paul Bernard , Holliday Emma B. , Philip Tony , Sarholz Barbara , Kuipers Mirjam , Rodriguez-Gutierrez Almudena , Diaz-Padilla Ivan , Miller Eric David
Published: May 2020

TPS4117

Background: Preoperative chemo-radiotherapy with or without sequential chemotherapy, followed by surgical intervention, is standard of care for patients with locally advanced rectal cancer (LARC). However, 1/3 of these patients still develop distant metastases, indicating the need for more effective therapies. DNA-dependent protein kinase (DNA-PK) regulates a key DNA damage repair pathway for double-strand break repair. Peposertib (M3814), a potent, selective, orally administered DNA-PK inhibitor, has been shown to potentiate the effect of ionizing radiation in a human colon cancer xenograft model and several colon cancer cell lines. Peposertib is being investigated in several different trials across multiple indications. This Phase Ib/II study (NCT03770689) aims to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of the neoadjuvant treatment combination of peposertib, capecitabine, and radiotherapy (RT) in patients with LARC. Methods: Patients aged ≥18 years with histologically confirmed and resectable Stage II/III rectal adenocarcinoma are eligible. Induction chemotherapy is permitted, but residual disease must first be documented by MRI, digital rectal examination and endoscopy. Patients who received other anticancer therapies or those with prior pelvic RT are excluded. During open-label Phase Ib (open), 18–30 patients (n = 3 per cohort) are due to receive peposertib + capecitabine (orally, 825 mg/m2 twice daily [BID]) + RT (45–50 Gy), 5 days/week. Peposertib 50 mg once daily (QD) is the starting dose. Additional dose levels will be between 100─800 mg QD. Dose escalation is determined by the safety monitoring committee and guided by a Bayesian 2-parameter logistic regression model. At Phase II (planned), 150 patients will be randomized (1:1) to receive oral capecitabine (825 mg/m2 BID) + RT (45–50 Gy), with either oral peposertib (recommended phase II dose [RP2D]) or placebo, QD for 5 days/week. Primary objectives are to define a maximum tolerated dose and RP2D (Phase Ib), and to evaluate the efficacy of peposertib + capecitabine + RT in terms of pathological/clinical complete response (Phase II). Secondary objectives include assessment of antitumor activity (Phase Ib), quality of life outcomes (Phase II), and PK of peposertib, and the safety and tolerability of the combination therapy (both phases). One patient has received peposertib 50 mg QD and six patients have received peposertib 100 mg QD. Patients are currently receiving peposertib 150 mg QD. Clinical trial information: NCT03770689 .
NIVACOR: Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line chemotherapy for advanced colorectal cancer RASm/BRAFm patients.
Authors: Damato Angela , Iachetta Francesco , Normanno Nicola , Bergamo Francesca , Maiello Evaristo , Zaniboni Alberto , Antonuzzo Lorenzo , Nasti Guglielmo , Tonini Giuseppe , Bordonaro Roberto , Di Fabio Francesca , Romagnani Alessandra , Berselli Annalisa , Pinto Carmine
Published: May 2020

TPS4118

Background: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has been shown to be one of the therapeutic regimens in first line with the highest activity profile in patients (pts) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Tumors co-opt the PD-1/PD-L1 signaling pathway as one key mechanism to evade immune destruction. Anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which are only about 5% among all mCRC. Nowadays, there are no data demonstrating anti-PD1 activity in stable and proficient (MMRp/MSS) disease. Another critical therapeutic target is the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis; his inhibition with bevacizumab increase immune cell infiltration, giving a strong rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on evidence, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts with mCRC all- RAS/BRAF mutant regardless of microsatellite status. Methods: This is a prospective, open-label, multicentric phase II trial where pts with mCRC RAS/BRAF mutant in first line will receive nivolumab in combination with FOLFOXIRI/Bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR) and our hypothesis is that the treatment is able to improve the ORR from 66% to 80%. Secondary endpoints include overall survival, safety, time to progression, duration of response. Collateral translational studies evaluate the tumor mutational burden, and genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 4 of planned 70 pts have been enrolled. Clinical trial information: EudraCT Number: 2018-002893-38. Clinical trial information: NCT04072198 .
Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).
Authors: Morris Van K. , Yothers Greg , Kopetz Scott , Jacobs Samuel A. , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Wolmark Norman , George Thomas J.
Published: May 2020

TPS4121

Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint across all US and Canadian cooperative groups. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103 .
Phase III study of first-line zolbetuximab + CAPOX versus placebo + CAPOX in Claudin 18.2+/HER2−advanced or metastatic gastric or gastroesophageal junction adenocarcinoma: GLOW.
Authors: Shah Manish A. , Ajani Jaffer A. , Al-Batran Salah-Eddin , Bang Yung-Jue , Catenacci Daniel , Enzinger Peter C. , Ilson David H. , Kim Sunnie , Lordick Florian , Shitara Kohei , Van Cutsem Eric , Arozullah Ahsan , Park Jung Wook , Xu Rui-hua
Published: May 2020

TPS4648

Background: Gastric cancer is the fourth leading cause of cancer death worldwide. Capecitabine + oxaliplatin (CAPOX) is a standard first-line treatment for advanced gastric cancer. Claudin (CLDN)18.2 has emerged as a promising targetable biomarker. In healthy tissue, CLDN18.2, a tight junction protein, is confined to gastric mucosa (ie, cells in the pit and base regions of gastric glands). Upon malignant transformation, structural loss in gastric or gastroesophageal junction (G/GEJ) adenocarcinoma cells may allow antibodies more access to previously unavailable CLDN18.2. Zolbetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to CLDN18.2 and mediates cell death through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Results of a phase 2 study (NCT01630083) showed prolonged survival of patients with CLDN18.2-positive (CLDN18.2+) advanced G/GEJ adenocarcinoma treated with zolbetuximab + epirubicin, oxaliplatin, and capecitabine (EOX) vs EOX alone. Methods: This phase 3, double-blind, placebo-controlled study (NCT03653507) will enroll ~500 adult patients from global sites. Patients are required to have CLDN18.2+/HER2− locally advanced unresectable or metastatic G or GEJ adenocarcinoma that is radiographically evaluable per RECIST v1.1. Patients are not permitted to have received prior treatment with chemotherapy for advanced or metastatic G or GEJ adenocarcinoma. Patients will be randomly assigned 1:1 to receive either zolbetuximab plus CAPOX or placebo plus CAPOX. Randomization will be stratified by region (Asia vs non-Asia), number of metastatic sites (0 to 2 vs ≥3), and prior gastrectomy (yes vs no). Zolbetuximab will be administered at a loading dose of 800 mg/m2 IV on Cycle 1 Day 1 followed by 600 mg/m2 IV every 3 weeks. Central testing of tumor tissue will determine CLDN18.2 and HER2 status (if unknown); patients will be considered CLDN18.2+ if ≥75% of tumor cells demonstrate moderate-to-strong membranous immunohistochemical staining. The primary objective is to compare progression-free survival between treatment arms. Secondary endpoints are overall survival; objective response rate; duration of response; and the safety/tolerability, pharmacokinetics, and immunogenicity of zolbetuximab. As of January 31, 2020, 127 sites were active and open to enrollment. Clinical trial information: NCT03653507 .