bluuebunny/crossref_metadata_2025 huggingface dataset:
Progress report of a cross-organ and biomarker-based platform study: BELIEVE trial NCCH1901.
Authors: Ando Yayoi , Shimoi Tatsunori , Sunami Kuniko , Okita Natsuko Tsuda , Mori Mikio , Shibata Taro , Nakamura Kenichi , Yamamoto Noboru
Published: June 2023

TPS1611

Background: Cancer Genomic Medicine (CGM) has been developing and more patients have received the comprehensive genomic profiling (GCP) test under national healthcare system in Japan. However, the number of patients who could receive the genomically matched therapy based on the results of CGP tests was limited. To improve the drug accessibility, we initiated a cross-organ, biomarker-based clinical trial (NCCH1901, the BELIEVE trial). It was a platform trial and could be considered as the Japanese counterpart to the National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) study in the United States. Methods: It was a multi-institutional joint research nationwide led by NCCH with a master’s protocol. Several drug cohorts were pre-established, allowing patients to participate in molecularly targeted treatments recommended as a result of CGP test. All drugs were provided for free from the pharmaceutical companies. The objective of this trial was to administer off-label drugs for the respective genomic abnormalities and collect efficacy and safety data for patients of the drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. This trial has been conducted under both of the Japanese Clinical Trial Act and the patient-proposed healthcare services which enable patients to receive unapproved, off-label drugs partially covered by National Health Insurance. The protocol and the informed consent forms were approved by the National Cancer Center Hospital (NCCH) certified review board and the Ministry of Health, Labour and Welfare (MHLW). The trial was registered in the Japan Registry of Clinical Trials (jRCTs031190104). As of January 31, 2023, we have 20 drug cohorts and the planned number of enrollments for each cohort was 50 with the target lesions and 30 without the target lesions. There were more than 500 patients so far. The most common cancer was brain tumours, followed by carcinoma of endocrine organs and the colorectal cancer. BRAF mutation and ERBB2 amplification were the frequent genomic abnormalities registered in this trial. Five drug cohorts have already finished recruiting and 2 drug cohorts assessed their efficacies. We are still continuing to discuss several pharmaceutical companies to increase the drugs cohorts in this platform. This trial is now recruiting the patients and is contributing significantly to increase the treatment opportunity for the cancer patients. Clinical trial information: jRCTs031190104 .
Phase 3 TRIDENT study (EF-32): Tumor treating fields (TTFields; 200 kHz) concomitant with chemoradiation, and maintenance TTFields therapy/temozolomide in newly diagnosed glioblastoma.
Authors: Shi Wenyin , Roberge David , Kleinberg Lawrence , Jeyapalan Suriya A. , Goldlust Samuel Aaron , Nagpal Seema , Lustgarten Leonardo , Combs Stephanie E , Nishikawa Ryo , Reardon David A. , Grossman Rachel , Glas Martin
Published: June 2023

TPS2083

Background: Tumor Treating Fields (TTFields) therapy, a noninvasive and locoregional antimitotic cancer treatment modality, is approved for newly diagnosed (nd), recurrent glioblastoma (r) GBM and mesothelioma. In patients with ndGBM, progression-free survival (PFS) and overall survival (OS) were significantly improved with TTFields therapy/temozolomide (TMZ) vs TMZ alone in the pivotal EF-14 study, leading to FDA approval in ndGBM. To avoid potential impedance of radiotherapy (RT), TTFields therapy was administered following RT/TMZ; however, preclinical studies have demonstrated that TTFields therapy enhances the therapeutic effect of RT. Methods: TRIDENT (EF-32; NCT04471844), a phase 3, global, randomized study, will evaluate TTFields therapy concomitant with RT/TMZ in patients ≥18 years of age (≥22 years in the US) with histologically-confirmed ndGBM, ≥3 months life expectancy, and ≥70 Karnofsky performance status. Patients will be stratified on the basis of MGMT promoter methylation status and extent of resections. Approximately 950 patients will be assigned 1:1 to continuous TTFields therapy (200 KHz, ≥18 h/day) concomitant with RT/TMZ (experimental arm) or RT/TMZ alone (control arm). Patients in the experimental arm will receive TTFields therapy continuously from the first day of chemoradiation. Patients in the control group will begin TTFields at the same time as maintenance TMZ, approximately one month after completion of chemoradiation. TTFields therapy will continue in both treatment groups until second disease progression (PFS2) or 24 months (if clinically able). The primary endpoint is median OS, and secondary endpoints include PFS, 1- and 2-year survival rates, objective response rate, PFS2, 6- and 12-month PFS rates, safety, and quality of life (EORTC QoL questionnaires). The ability of TTFields therapy to extend OS in a dose-dependent manner is an exploratory endpoint. The sample size is powered for a hazard ratio of < 0.8 with a 5% type I error. The hypothesis that first-line TTFields therapy/RT/TMZ can significantly improve OS vs RT/TMZ will be tested using a stratified log-rank test. The study is expected to enroll patients at 150 sites, with enrollment currently open in 9 countries. Clinical trial information: NCT04471844 .
Efficacy and safety study of neoadjuvant efineptakin alfa (NT-I7) and pembrolizumab in recurrent glioblastoma.
Authors: Webb Mason , Burns Terry C , Twohy Erin , Sener Ugur , Kizilbash Sani Haider , Ruff Michael W. , Uhm Joon H. , Galanis Evanthia , D'Andre Stacy D. , Riviere-Cazaux Cecile , Lee Byung Ha , Flickinger Lynn M. , Parney Ian F. , Campian Jian Li
Published: June 2023

TPS2085

Background: Glioblastoma (GBM) is the most common and aggressive form of brain tumor in adults. Despite maximal surgical resection, irradiation, and chemotherapy, median overall survival (OS) remains at only 30 weeks for recurrent GBM (rGBM) patients, emphasizing the need for novel treatments. GBM tumors are immunologically ‘cold,’ in that they have an immune-suppressive microenvironment with a low number of tumor-infiltrating lymphocytes (TIL). Interleukin 7 (IL-7) plays a key role in T cell development and survival. The physiological level of IL-7 increases to stimulate T cell expansion in lymphopenic condition. Previous studies have shown that lymphopenic GBM patients have shorter survival. However, their IL-7 levels are unexpectedly low. Efineptakin alfa (NT-I7), a long-acting IL-7, has been shown to increase effector CD8 T cells and reduce suppressor T-regulatory cells in murine GBM models, with subsequently improved OS. Further, we recently completed a Phase I study which showed that NT-I7 is safe, well- tolerated, and increased absolute lymphocyte counts (ALC) in newly diagnosed GBM patients. Phase II dosing was determined through this Phase I study reaching maximum tolerated dose. Thus, we hypothesized that NT-I7 may reverse GBM-associated immune suppression and potentiate the effect of an immune checkpoint inhibitor, leading to an increase in TILs and improved survival. Our preliminary data suggests that combining NT-I7 with pembrolizumab, an anti-PD-1 antibody, improves survival in murine glioma models. The purpose of this study is to evaluate the safety and efficacy of combining NT-I7 and pembrolizumab in rGBM patients. Methods: This is an open-label single arm one-stage Phase II study of NT-I7 and pembrolizumab as neoadjuvant and adjuvant therapy with surgery for adult patients with rGBM. We plan to enroll 30 evaluable patients, including a 6-patient safety run-in. Key eligibility criteria include candidates willing to undergo clinically indicated resection or biopsy, age ≥ 18 years, Karnofsky performance status ≥ 70, and dexamethasone dose > 2 mg/day ≤ 2 days prior to registration. The primary endpoint is a 9-month OS rate. Secondary endpoints include progression-free survival, objective response rate, changes in ALC, and adverse events profile. The correlative endpoints include studies to assess the anti-glioma immune response, changes in T cell subsets, T cell effector function, cytokine analysis, and immunohistochemical analysis of GBM tissue. Longitudinal cerebrospinal fluid proteomics is optional. This study opened on 1/20/2023. Two of the planned 30 patients had been enrolled by submission on 2/14/2023. Clinical trial information: NCT05465954 .
Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma.
Authors: Liu Jiajian
Published: June 2023

TPS2663

Background: Cancer immunotherapies targeting PD-1 or PD-L1 have been proven effective in causing durable antitumor immune responses with less toxicity in many types of tumors. However, the response rate of anti-PD-1/PD-L1 treatments is far from satisfactory and most patients show primary or acquired resistance to the treatments. Tim-3, one of the next generation of immune checkpoint targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Biopharma Co., Ltd. for the patients who are resistant to or refractory from PD-1/PD-L1 treatments. It blocked the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways simultaneously, showed better T/DC cell activity and in vivo anti-tumor efficacy compared to Tim-3 and PD-1 antibody combination in preclinical studies. Methods: This is a FIH, multicenter, non-randomized, open label, phase 1 study of LB1410 in Participants With Advanced Solid Tumor or Lymphoma（Keyplus-001）. The planned sample size is approximately 100 patients in two parts: part 1 dose escalation will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, EC etc. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status 0-1，histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies or lymphoma for which standard treatment fails, or no standard treatment is available, or standard treatment is not applicable at this stage. Exclusion criteria include pregnancy, lactation, or breastfeeding, ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB1410. Besides, the pharmacodynamics (PD) biomarkers related to LB1410 treatment, clinical activity will be explored. This clinical trial is in progress; cohorts 1 to 5 in dose escalation part have been completed. Clinical trial information: NCT05357651 .
A phase 1 first-in-human clinical trial of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, in advanced solid tumors.
Authors: Rodon Ahnert Jordi , Gruber Joshua James , Telli Melinda L. , Mita Monica M. , Mita Alain C. , Kim Joseph W. , Villalona-Calero Miguel Angel , Patel Meera , Yadav Shalini S. , Sharma Padmanee , Haber Tom , Symons Jessica Lauren , Seet Qihui , Dharmadhikari Bhushan , Thakkar Dipti , Kwek Kon Yew , DiMascio Leah , Rowinsky Eric Keith , Ingram Piers , Boyd-Kirkup Jerome Douglas
Published: June 2023

TPS2664

Background: V-domain Ig Suppressor of T-cell Activation (VISTA), is an immune checkpoint regulator found on tumor, myeloid, and other immune cells. Its presence has been shown to enhance tumor growth, create an immunosuppressive microenvironment, and may potentially contribute to developing resistance to anti-CTLA-4 and anti-PD-1/PD-L1 therapies. Therefore, VISTA represents a promising therapeutic target. HMBD-002, a non-depleting, high-affinity IgG4 monoclonal antibody against VISTA, has demonstrated significant inhibition of tumor growth in preclinical studies, both as a monotherapy and in combination with pembrolizumab. HMBD-002 acts by increasing T-cell activity and reprogramming the suppressive tumor microenvironment to a proinflammatory antitumor phenotype. Cancer types including triple-negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC), which exhibit high expression levels of VISTA in the TME, provide a rational basis for exploring these indications in clinical studies. Methods: This phase 1/2, open-label, multi-center trial is being conducted in two parts to evaluate the safety, pharmacokinetics, and antitumor activity of HMBD-002, an IgG4 monoclonal antibody targeting VISTA, as a monotherapy and in combination with pembrolizumab. The dose-escalation stage (Part 1) will follow a standard 3 + 3 study design with weekly dosing and adaptive dose-escalation increments to determine the recommended phase 2 dose (RP2D) for subsequent disease-directed studies. Monotherapy escalation cohorts 1-4 have been completed without dose-limiting toxicities (DLTs). The dose-expansion stage (Part 2) will evaluate the antitumor activity of HMBD-002 alone and combined with pembrolizumab in patients with TNBC and NSCLC, as well as a wide range of VISTA-expressing malignancies. Exploratory analyses will be conducted to assess treatment-induced immunological changes both systemically and within the tumor microenvironment. Longitudinal blood samples will be evaluated using single-cell mass cytometry (CYTOF) and multiplex cytokine analysis. Pre and on-treatment tumor tissue samples will be assessed for VISTA & PD-L1 expression using IHC. Additionally, tumor tissues will be evaluated using multiplex immunofluorescence, and gene-expression profiling. Biomarker correlations with clinical outcomes may lead to the identification of predictive markers of response to HMBD-002. Clinical trial information: NCT05082610 .
Phase I study of NEROFE and doxorubicin in KRAS-mutated ST2-positive solid tumors.
Authors: Weinberg Benjamin Adam , Wang Hongkun , Reuss Joshua E. , Boikos Sosipatros Alexandros , Walsh Elaine M. , Kim Chul , He Aiwu Ruth , Noel Marcus Smith , Gramza Ann Wild , Gibney Geoffrey Thomas , Liu Stephen V. , Macke Laura Ann , Montcalm Jennifer E. , Bouker Kerrie , Ohana Joel , Sandler Uziel , Devary Yoram
Published: June 2023

TPS2667

Background: KRAS-mutated tumors are notoriously difficult to treat clinically with targeted therapies. Recent advances targeting KRAS G12C with sotorasib and adagrasib are encouraging but limited to a small subset of patients. NEROFE is a 14 amino acid peptide which inhibits suppression of tumorigenicity 2 (ST2; member of the interleukin 1 [IL-1] receptor family and IL-33 receptor), a novel immune checkpoint present on tumor cells and tumor-associated macrophages. ST2 blockade with NEROFE has been shown to transform an immunosuppressive tumor microenvironment into an immune-stimulatory microenvironment. NEROFE also has been shown to induce microRNA miR-217 which downregulates KRAS and MAPK1/2 gene expression in preclinical models. When combined with low-dose doxorubicin, NEROFE has a synergistic effect on inducing apoptosis in KRAS-mutated, ST2-positive cell lines and xenograft models. Methods: This is a phase I trial of NEROFE given at 48 mg/m2 (dose level [DL] -1), 96 mg/m2 (DL1), 192 mg/m2 (DL2), or 288 mg/m2 (DL3) IV weekly with doxorubicin 8 mg/m2 IV weekly. A standard 3+3 dose escalation/de-escalation is used. The primary objective is to determine the recommended phase II dose. Patients are eligible if they have an advanced solid tumor with a KRAS mutation and ST2-positivity (via immunohistochemistry [IHC], centrally confirmed with pre-screening allowed). Patients must have measurable disease amenable to serial biopsy. Patients must have had progression or intolerance to all standard therapies or must decline available standard therapy. Pharmacokinetic profiles will be analyzed from serial blood draws pre- and 1, 2, 4, 6, and 24 hours post-infusion on cycle 1 day and cycle 2 day 1. Pre- and on-treatment tumor biopsies are mandatory. Correlative studies include IHC for ST2 expression, immune cell infiltration and blood-based analyses of KRAS mRNA, miR-217, and cytokines. Enrollment to DL1 began in Q1 2023 (NCT05661201). Clinical trial information: NCT05661201 .
GNC-038, a tetra-specific antibody, in patients with R/R non-Hodgkin lymphoma or acute lymphoblastic leukemia: A phase 1 study design and rationale.
Authors: Wang Jianxiang , Qi Junyuan , Li Wenyu , Zhai Zhimin , Li Ping , Zou Wen , Ding Muran , Yang Xue , Wang Rong , Guo Wanjing , Xiao Sa , Khalili Jahan S. , Zhu Hai , Olivo Martin Sebastian , Zhu Yi
Published: June 2023

TPS2668

Background: Bispecific T cell engagers can mediate single antigen-specific cell cytolysis, but cannot preempt clonal relapse, or modify the immunosuppressive cancer cell surfaceome. The first-in-class octavalent, CD19xCD3x4-1BBxPD-L1 tetra-specific antibody, GNC-038, functions as a CD19-specific T cell engager by mediating direct antitumor activity, but further, GNC-038 overcomes inhibition of T cells by PD-L1 based on its 4 binding sites. The antitumor activity of GNC-038 is mediated by activating CD3 and 4-1BB signaling on T cells and targeting high expression of CD19 or PD-L1 on tumor cells. Preclinical studies showed GNC-038 has robust anti-tumor activity. Considering its favorable tolerance and pharmacokinetics in cynomolgus monkeys, we developed a phase I study to investigate GNC-038 for the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL) and relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: Patients diagnosed with relapsed/refractory non-Hodgkin lymphoma or acute lymphoblastic leukemia are currently being enrolled in this phase I study to evaluate the safety, tolerability and pharmacokinetics of GNC-038. This study will be conducted in two phases, dose-escalation (Ia) and dose-expansion (Ib). During the dose escalation phase, R/R-NHL patients will receive GNC-038 (0.016-6 μg/kg/d) as continuous intravenous (cIV) infusion for 8 weeks. Further escalation will be conducted with step-up dosing: cIV infusion of 3.6 μg/kg/d GNC-038 will be administered during week 1 followed by higher doses on subsequent weeks (9, 13.5, 20.25 or 30 μg/kg/d). R/R-ALL patients will receive GNC-038 by cIV infusion for 8 weeks (0.016-16 μg/kg/d). During the dose-expansion phase, one or more dosages will be chosen for further investigation in specific indications. The primary endpoints are dose limiting toxicity (DLT), maximum tolerated dose (MTD), treatment emergent adverse events (TEAE) and recommended phase 2 dose (RP2D). Secondary endpoints are adverse events (AEs), pharmacokinetics, objective response rate (ORR), duration of response (DOR), progression free survival (PFS) and overall survival (OS). Exploratory endpoints are biomarker assessment, anti-drug antibody (ADA) and pharmacodynamics. The dose expansion phase (Ib) has been initiated. Clinical trial information: NCT04606433 .
High-dose vitamin C to enhance neoadjuvant immune checkpoint therapy in mismatch repair proficient colon cancer: The ALFEO pilot study.
Authors: Sartore-Bianchi Andrea , Amatu Alessio , Di Nicolantonio Federica , Troiani Teresa , Tosi Federica , Napolitano Stefania , Martini Giulia , Bencardino Katia , Bonazzina Erica , Carnevali Pietro , Forti Edoardo , Mutignani Massimo , Vanzulli Angelo , Ghezzi Silvia , Scaglione Francesco , Marsoni Silvia , Bardelli Alberto , Ciardiello Fortunato , Ferrari Giovanni , Siena Salvatore
Published: June 2023

TPS2675

Background: Most colon cancer (CC) patients can be treated with upfront curative surgery; however, relapse often occurs and the disease becomes deadly. Neoadjuvant chemotherapy does not jeopardize timing or quality of surgery and enhances relapse-free outcomes in proficient mismatch-repair (pMMR) CC (Morton et al, J Clin Oncol 2023). In the same setting, the use of immune checkpoint inhibitors (ICIs) with a single dose of ipilimumab (Ipi) and two doses of nivolumab (Nivo) proved to be feasible without delaying surgery and resulting in 23% major pathological responses (mPR) (Chalabi et al, ASCO 2022). We have previously shown that high dose vitamin C (HDVitC) triggers tumor infiltration and activation of CD8+ T cells in mouse tumors, enhancing efficacy of ICIs in pMMR CC preclinical models (Magrì et al, Sci Transl Med 2020). Methods: ALFEO is an open-label pilot trial of neoadjuvant CC treatment to test whether HDVitC can enhance the efficacy of ICIs in this setting. Main inclusion criteria are pMMR CC stage cT4N0/TxN1-2/[cM1 liver-limited disease with favorable oncological criteria candidate for upfront surgery on both T and M after multidisciplinary team evaluation]. Patients will receive Nivo i.v. 3 mg/kg D1 and D15, Ipi i.v. 1 mg/kg D 1 and VitC 70 g/ m2 D1-3 and 15-17. Tumor assessment will be performed at D21-28, followed by surgery within D28. Primary objective is activity of Nivo/Ipi + HDVitC; secondary objective is safety; exploratory objectives are correlation between efficacy and pharmacodynamic including tumor microenvironment changes. Primary endpoint is mPR rate. Considering the proof-of-principle nature of the trial, a design with a boundary for early stopping (both futility/utility and toxicity) and a fixed maximum sample size of 24 patients has been chosen. mPR for the Ipi/Nivo has been set at 23% (H0), while H1 at 75%. A Bayesian hypothesis test-based design (Zhou et al, Pharm Stat 2021) will be used for decision-making. Su. Clinical trial information: ECTR2022-502101-15-00 .
Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.
Authors: Jain Prantesh , Hutson Alan , Janes Cayla , Bruno Debora S. , Durm Greg Andrew , Sangal Ashish , Mehrotra Bhoomi , Crombet Ramos Tania , Leon Kalet , Dy Grace K.
Published: June 2023

TPS2677

Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 > 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 < 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression <50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .
A phase I trial of diphencyprone for cutaneous neurofibromas in adult patients with neurofibromatosis type 1.
Authors: Poplausky Dina , Young Jade N , Block Brandon , Cabral Patricia , Rivera-Oyola Ryan , Estrada Yeriel , Singer Giselle K , Wong Vicky K. , Correa Da Rosa Joel , Brown Rebecca M , Gulati Nicholas
Published: June 2023

TPS2678

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic tumor predisposition syndrome affecting about 1 in 2500 people. Affected patients develop a variety of skin findings including café-au-lait macules, axillary freckling, and cutaneous neurofibromas (cNFs). These patients also have an increased risk of malignant tumors including gliomas and soft tissue sarcomas. However, the cNFs, of which a patient can have thousands, are often cited as the most burdensome sign. Despite their benign nature, these tumors can be physically bothersome and cause significant emotional distress. To date, there are no effective pharmacotherapies for these tumors. This is a single-center, phase I, open label trial to evaluate the safety, tolerability, and efficacy of diphencyprone (DPCP), a topical hapten that induces a delayed-type hypersensitivity skin reaction, for the treatment of cNFs in adults with NF1. Methods: This trial is enrolling NF1 patients aged 18 and older with at least four cNFs greater than 4mm. Subjects taking systemic immunosuppressants, those with underlying immunodeficiency or uncontrolled intercurrent illnesses, and those who are pregnant or nursing are excluded from the study. DPCP 0.04% ointment is administered topically once weekly to up to 20 cNFs in a localized area for 10 weeks. The primary endpoint is to determine the safety and tolerability of DPCP ointment in the treatment of cNFs. Adverse events are graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. To assess subjective tolerability, subjects score their symptoms, including pain, stinging, burning, and pruritus from 0 (none) to 3 (severe). Efficacy and tumor regression are assessed using the Response Evaluation Criteria in Solid Tumors guidelines in conjunction with photographs and manual tri-axial tumor measurements. Additionally, qualitative assessments are made by the study team using 3D whole-body photography. One treated tumor is tracked throughout the study with optical coherence tomography (OCT) imaging. Skin biopsies of a cNF and surrounding tissue are collected at baseline, on Day 17 after treatment initiation, and four weeks post-treatment for exploratory endpoints. Quantitative RT-PCR and single-cell RNA sequencing studies will assess gene expression changes in immune and tumor cell-related genes pre- and post-treatment with DPCP. Immunohistochemistry and proteomic profiling will be performed to characterize changes in the tumor microenvironment. Genetic testing for the NF1 germline mutation will be correlated with treatment response. Enrollment is ongoing with a target of 20 participants. Since September 2022, the study has enrolled 12 patients and five have completed the study. Clinical trial information: NCT05438290 .
XMT-1660: A phase 1b trial of a B7-H4 targeted antibody drug conjugate (ADC) in breast, endometrial, and ovarian cancers.
Authors: Hamilton Erika P. , Chaudhry Arvind , Spira Alexander I. , Adams Sylvia , Abuhadra Nour , Giordano Antonio , Parajuli Ritesh , Han Hyo S. , Weise Amy M. , Marchesani Aubri , Gupta Divya , Josephs Kate , Kalinsky Kevin
Published: June 2023

TPS3154

Background: Breast cancer (BC) is the most commonly diagnosed cancer and one of the leading causes of cancer death in women. Despite significant therapeutic advances, the majority of patients with unresectable or recurrent/metastatic disease eventually develop resistance to available standard of care (SOC) therapies. High B7-H4 expression has been observed in several cancers including breast, endometrial, and ovarian, with limited expression in normal tissue. As a member of the CD28/B7 family of cell surface proteins, it promotes tumorigenesis by suppressing anti-tumor immunity. XMT-1660 is a B7-H4-directed Dolasynthen antibody drug conjugate designed with a precise, optimized drug-to-antibody ratio and a DolaLock microtubule inhibitor payload with controlled bystander effect. In the preclinical setting, XMT-1660 has demonstrated anti-tumor activity in TNBC and ER+/HER2- patient-derived xenograft mouse models, which included tumors from heavily pre-treated patients (Collins et al, AACR 2022). Increased anti-tumor activity tended to be more frequent in preclinical models with higher B7-H4 expression, providing rationale for a Ph1 clinical trial. Methods: The Ph1 trial includes a first-in-human open-label dose escalation (DES) portion followed by dose expansion (EXP) evaluating XMT-1660 in patients with BC, EC, and OC following progression on SOC as applicable (i.e., CDK4/6i + ET; platinum-based chemotherapy). In the DES, Bayesian Optimal Interval (BOIN) design will be used to determine the MTD. Patients will receive XMT-1660 IV Q3 weeks. Primary endpoints in DES are to assess safety and determine a recommended phase 2 dose (RP2D) and assessment of preliminary efficacy as a secondary endpoint. In parallel with DES, optional backfill cohorts will enroll patients into tumor-type specific cohorts (TNBC, HR+/HER2- BC, EC, or OC) at a selected dose level from DES and can be initiated at multiple dose levels simultaneously. In the EXP portion, cohorts enrolling TNBC, ER+/HER2- BC, EC/OC are planned and additional patients may be enrolled based on emerging data. The primary endpoint of EXP is to assess safety and tolerability, overall response rate, disease control rate, and duration of response. Secondary endpoints include pharmacokinetic analysis and assessment of antidrug antibodies. Patients are not selected by B7-H4 status, but baseline tumors samples are collected for retrospective tumor tissue evaluation. The trial is currently enrolling patients. NCT05377996. Clinical trial information: NCT05377996 .
Phase 1/2 study of PRO1184, a novel folate receptor alpha-directed antibody-drug conjugate, in patients with locally advanced and/or metastatic solid tumors.
Authors: Call Justin A , Orr Douglas W. , Anderson Ian Churchill , Richardson Debra L. , Chen Zhu , Ma Sharon , Hunder Naomi N. H. , Hamilton Erika P.
Published: June 2023

TPS3157

Background: PRO1184 is an antibody-drug conjugate (ADC) directed to folate receptor alpha (FRα), a cell surface antigen overexpressed in multiple cancers including ovarian, endometrial, lung, mesothelioma, and breast cancer. PRO1184 consists of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies demonstrated that the hydrophilic linker confers excellent physicochemical properties and pharmacokinetic (PK) profiles across a range of payload mechanisms and is superior to conventional linkers on these critical parameters for ADCs. In addition, exatecan is broadly active in many tumor types, is membrane permeable, and is not a substrate of multidrug resistance efflux pumps. It may thus lend a robust bystander effect and induce deeper or more durable responses in refractory tumors. Preclinical studies further established that PRO1184 exerts potent antitumor activity in mouse xenograft models with high, moderate, and low FRα expression, consistent with the inherent potency and expected bystander activity of the exatecan payload. PRO1184 is stable in plasma and retains the excellent PK properties and bioactivity of the unconjugated parent antibody. The preliminary safety profile of PRO1184 was more favorable than a benchmarking deruxtecan-based ADC in cynomolgus monkeys. PRO1184 is thus a promising development candidate with a potentially large therapeutic index to benefit a broad population of patients with FRα-expressing solid tumors. Methods: PRO1184-001 is an ongoing, phase 1/2, open-label dose escalation and expansion study. Eligible patients are adults with metastatic or unresectable solid tumors, including ovarian, endometrial, non-small cell lung, breast cancer, or mesothelioma. Patients must have measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, or mRECIST 1.1 for pleural mesothelioma. Patients must also have previously received therapies known to confer clinical benefit unless considered ineligible, refused by the patient, or not available in the region. PRO1184 is given by intravenous infusion on Day 1 of a 21-day cycle and treatment may continue until disease progression, unacceptable toxicity, or other reason for discontinuation. The primary objectives are to evaluate the safety and tolerability of PRO1184 and to identify the maximum tolerated dose, if reached, and recommended phase 2 dose (RP2D). Part A of the study consists of a dose escalation phase and Part B consists of 4 FRα-expressing tumor specific expansion cohorts treated at the RP2D. PK, immunogenicity, and antitumor activity will also be evaluated. The study is currently enrolling at sites in the US, with future enrollment in China planned (NCT05579366). Clinical trial information: NCT05579366 .
FRONTIER: FAPi radioligand open-label, phase 1 study to evaluate safety, tolerability and dosimetry of [Lu-177]-PNT6555—A dose escalation study for treatment of patients with select solid tumors.
Authors: Bodei Lisa , Kavan Petr , Liberman Moishe , Taunk Neil , Metser Ur , Juneau Daniel , O'Reilly Eileen Mary , Ma Junsheng , Cioci Richard , Abdul Razak Albiruni Ryan
Published: June 2023

TPS3161

Background: Fibroblast activation protein alpha (FAP) is a 170 kDa transmembrane glycoprotein expressed during development, active tissue remodeling, and cancer. Overexpression on cancer-associated fibroblasts in the tumor microenvironment, and on some cancer cells of mesenchymal origin, leads to the presence of FAP in > 90% of epithelial tumors, making FAP a compelling anti-cancer target. PNT6555, a potent FAP-targeting compound with rapid clearance from normal tissues and prolonged tumor retention in preclinical models1, is a radioligand consisting of a DOTA chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid) and a FAP-targeting moiety (Bz-D-Ala-boroPro) connected via an aminomethyl linker. The corresponding gallium-68 and lutetium-177 chelates constitute the imaging and therapeutic theranostic pair of PNT6555 under evaluation in this phase I study. Methods: FRONTIER (NCT05432193) is a multicenter, open-label, multi-dose phase I study of PNT6555 in participants with pancreatic ductal adenocarcinoma, esophageal cancer, colorectal cancer, melanoma skin cancer, cholangiocarcinoma, or soft tissue sarcoma solid tumors with FAP over-expression. The primary aim is to evaluate the safety and tolerability of [Lu-177]-PNT6555 in order to determine a recommended phase II dose (RP2D). Dosimetry, pharmacokinetics, and tumor and immune responses will also be assessed for [Lu-177]-PNT6555, as well as safety, tolerability, and diagnostic performance of [Ga-68]-PNT6555 PET/CT. Key eligibility criteria include being refractory to prior treatment with no alternative available therapeutic options, having adequate organ function, and being FAP-positive on [Ga-68]-PNT6555 PET/CT scan, defined as ≥50% of lesions with an SUVmax of ≥1.5x the liver SUVmean. [Ga-68]-PNT6555 will be dosed at 120 - 220 MBq (3.2 - 5.9 mCi), with PET/CT initiated 90 (±30) min later. FAP-positive participants will receive [Lu-177]-PNT6555 once every 6 weeks for up to 6 cycles. Starting at 4 GBq (108 mCi) ±10%, [Lu-177]-PNT6555 may be escalated by 4 GBq, with a maximum planned dose of 12 GBq. De-escalation by 2 GBq may also occur. Dose finding will be guided by the modified toxicity probability interval (mTPI-2) statistical design with a targeted toxicity rate of 30%. The planned total sample size is 30, with targets of 3-12 DLT evaluable patients per dose level. Cohort 1 has been completed without a DLT. Enrollment to cohort 2 began in January 2023. 1. Hallet R, et al. Pre-clinical characterization of the novel fibroblast activation protein (FAP) targeting ligand PNT6555 for the imaging and therapy of cancer. Presented at SNMMI Annual Meeting April 2022; Vancouver, BC, Canada. Clinical trial information: NCT05432193 .
A phase 1, open-label, first-in-human study of TAS2940 in patients with advanced solid tumors.
Authors: Rodon Ahnert Jordi , Spigel David R. , Kremer Jill , Jin Leah , Benhadji Karim Adnane , Gil Maciej , Besse Benjamin
Published: June 2023

TPS3165

Background: Aberrant expression and signaling of the ERBB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), has a role in the pathogenesis of solid tumors such as breast cancer (BC), non–small cell lung cancer (NSCLC), and glioblastoma (GBM). Although therapies that target HER2 are effective in early and advanced HER2-overexpressing BC, many patients develop resistance despite tumor dependence on HER2 at the time of progression. Approximately 4% of patients with NSCLC have HER2 mutations, mostly presenting as exon 20 insertions (ex20ins); however, approved HER2/EGFR tyrosine kinase inhibitors (TKIs) have limited efficacy in patients with NSCLC and HER2 ex20ins. Many patients with NSCLC or BC develop brain metastases, and EGFR alterations, including EGFRvIII mutations, are common in GBM. There is therefore a need for a brain-penetrable TKI with activity against tumors harboring HER2/EGFR alterations. TAS2940 is a potent, selective, and orally bioavailable pan-ERBB inhibitor that has shown promising preclinical efficacy against cancers with a variety of HER2/EGFR mutations and amplifications. Further, TAS2940 inhibited tumor growth and induced tumor regression in a dose-dependent manner in nude mice intracranially implanted with NCI-N87, a HER2-overexpressing human gastric cancer cell line. Methods: TAS2940-101 (NCT04982926) is an open-label, phase 1, first-in-human trial to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of TAS2940 in patients with advanced solid tumors and HER2/ EGFR aberrations. Eligible patients are aged ≥18 years, have non-measurable (Part 1) or measurable (Part 1 and 2) disease per RECIST 1.1 or RANO criteria, ECOG performance status 0/1, and adequate organ function. Patients with non-stable brain metastases are excluded. Part 1 (dose escalation) will use a Bayesian optimal interval design with a starting dose of 15 mg/kg orally QD (planned dose levels: 15, 30, 60, 120, 240 and 480 mg). Once the recommended phase 2 dose is determined, Part 2 (dose expansion) will enroll patients with NSCLC (Cohort A), HER2+ BC (Cohort B), recurrent/refractory GBM (Cohort C), or other solid tumors with EGFR/ HER2 aberrations (Cohort D). The primary objectives are the maximum tolerated dose of TAS2940 in Part 1 and antitumor activity in Part 2. Secondary objectives include antitumor activity in Part 1. The safety and PK profile of TAS2940 will be assessed in both parts. Approximately 142 patients will be enrolled, comprising ~42 in Part 1 and ~100 in Part 2. As of January 24, 2023, 15 patients have been enrolled. No dose-limiting toxicities have been reported with dose escalation up to 240 mg QD. Recruitment is ongoing. Clinical trial information: NCT04982926 .
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 , Puhalla Shannon L , Lucas Peter C. , Iqbal Atif , Boland Patrick M , Deming Dustin A. , Scott Aaron James , Lim Howard John , Hong Theodore S. , Wolmark Norman , George Thomas J.
Published: June 2023

TPS3625

Background: Detection of circulating tumor DNA (ctDNA) shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells after surgical resection. For patients (pts) with colon cancer (CC), the detection of ctDNA is associated with persistent disease after resection and outperforms traditional clinical and pathological features in prognosticating risk for recurrence. However, for pts with stage II CC, there are currently no validated biomarkers predicting benefit in identifying pts whose residual disease cancer be cleared by adjuvant chemotherapy. 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 active surveillance (i.e., not needing 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 Guardant Reveal assay, 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. Enrollment continues across North America to the 1408-patient phase III endpoint. NCT#: 04068103. Support: U10CA180868, -180822; UG1CA189867; GuardantHealth. Clinical trial information: NCT04068103 .
The Ohio State University Guardant Shield Colorectal Cancer Screening Project.
Authors: Stanich Peter , DeGraffinreid Cecilia R , Washington Chasity M , Bhattacharyya Oindrila , Lontoc Angela , Paskett Electra D.
Published: June 2023

TPS3626

Background: Asymptomatic screening is an effective method for detecting early cancers when prognosis strongly depends on stage at time of diagnosis. Unscreened individuals often have a basic understanding of the importance and availability of colorectal cancer (CRC) screening but have concerns regarding the collection method of the currently available stool-based options or the invasiveness of direct visualization options that deter test completion. We hypothesize that offering a blood-based CRC screening test during a routine healthcare visit can increase screening adherence, especially within hard-to-reach populations and those hesitant about completing CRC screening. Methods: The Ohio State University Guardant Shield Colorectal Cancer Screening Project (NCT05716477) is a prospective study in the United States designed to recruit individuals who are currently engaging with mobile health clinics and are not up to date with CRC screening, with the aim of improving health in hard-to-reach populations. The study’s primary objective is to evaluate the acceptance of a commercially available blood-based CRC screening test (Shield, Guardant Health, USA) in individuals aged 45-84, who have existing appointments with a mobile health clinic, and are not up to date with guideline recommended CRC screening. The study team screens for eligibility criteria before the appointment and reaches out to the individual to begin the informed consent process. Positive blood-based test results will be triaged to colonoscopy for further evaluation. A post-study survey will be administered to consented individuals aimed to collect data on CRC screening knowledge which will be correlated to patient demographics and uptake. Acceptance will be defined as those approached and with completed specimen collection. Progress: The study initiated on October 25, 2022, with the first patient enrolled on December 20, 2022. Enrollment is expected to continue with a target enrollment of 300 individuals. Clinical trial information: NCT05716477 .
BREAKWATER: An open-label, multicenter, randomized, phase 3 study, with a safety lead-in (SLI), of first-line (1L) encorafenib (E) + cetuximab (C) ± chemotherapy (CT) vs standard-of-care (SOC) CT for BRAF V600E-mutant metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Yoshino Takayuki , Kim Tae Won , Wasan Harpreet Singh , Van Cutsem Eric , Ciardiello Fortunato , Maughan Timothy S. , Eng Cathy , Yaeger Rona , Desai Jayesh , Zhang Xiaosong , Usari Tiziana , Mori Ave , Tabernero Josep
Published: June 2023

TPS3627

Background: Globally, 8-12% of patients (pts) with mCRC have BRAF V600E mutations, which confer poor prognosis. Based on BEACON (NCT02928224), EC was approved for the treatment (tx) of previously treated pts with BRAF V600E-mutant mCRC. BREAKWATER (NCT04607421) is evaluating EC ± CT vs SOC CT in pts with BRAF V600E-mutant mCRC. In the BREAKWATER SLI (N = 57), EC + CT showed encouraging antitumor activity. Confirmed ORR by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 68.4% (46.0, 84.6) and 75.0% (46.8, 91.1) in 1L, and 37.5% (13.7, 69.4) and 44.4% (24.6, 66.3) in 2L. mPFS by BICR (95% CI) with EC + mFOLFOX6 and EC + FOLFIRI, respectively, was 11.1 months [mo] (8.5, NE) and NE (13.8, NE) in 1L, and 10.8 mo (4.3, NE) and 12.6 mo (6.9, NE) in 2L. These results support the continued evaluation of EC + CT. Based on the SLI, EC + mFOLFOX6 was selected for the phase 3 portion. Here we present the updated study design. Methods: BREAKWATER is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating 1L EC ± CT vs SOC CT alone in pts with BRAF V600E-mutant mCRC. Approximately 620 pts will be enrolled in the phase 3 portion and an additional 135 in cohort 3 (Table). Phase 3 and cohort 3 inclusion criteria are age ≥16 (or ≥18 based on country); no prior systemic tx for metastatic disease; measurable disease (RECIST 1.1); BRAF V600E-mutant mCRC (blood or tumor tissue); ECOG PS 0 or 1; and adequate bone marrow, hepatic, and renal function. Pts who received prior BRAF or EGFR inhibitors, those with symptomatic brain metastases (unless stable for ≥4 weeks prior to randomization), or with MSI-H/dMMR tumors (unless ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition) are excluded. Study treatments and endpoints are shown in the Table. Phase 3 enrollment began in November 2021. Clinical trial information: NCT04607421 . [Table: see text]