bluuebunny/crossref_metadata_2025_split huggingface dataset:
First-in-human phase I study of the bifunctional EGFR/TGFβ fusion protein BCA101 in patients with EGFR-driven advanced solid cancers.
Authors: Janku Filip , Hanna Glenn J. , Carvajal Richard D. , Paik Paul K. , Hernando-Calvo Alberto , Gillison Maura L. , Fu Siqing , Wheler Jennifer J. , Bohr David , Reiners Ralf , Tan Seng-Lai , Bilic Sanela , Bedard Philippe L. 
Published: June 2021

3074 Background: Therapeutic targeting of EGFR has demonstrated efficacy in common advanced malignancies such as colorectal cancer (CRC), squamous cell of the head and neck (SCCHN), and non-small cell lung cancer (NSCLC). TGFβ has pro-tumorigenic effects on migration, invasion and tumor-specific immunosuppression, which may enhance the oncogenic effects of activated EGFR. Inhibition of EGFR signaling can lead to TGFβ upregulation as a resistance mechanism. BCA101 is a bifunctional recombinant fusion protein consisting of a chimeric anti-EGFR antibody and an extracellular domain (ECD) of human TGFβRII which demonstrated anti-tumor activity in several preclinical models. Methods: Patients with EGFR-driven advanced solid cancers refractory to standard therapies received BCA101 at escalating doses from 64 mg to 1000 mg intravenously (IV) weekly across 6 dose levels using a 3+3 design to determine dose limiting toxicities (DLT, established within 21 days of initial dosing), maximum tolerated dose (MTD) and/or recommended dose (RD). Secondary endpoints include detailed pharmacokinetic (PK), pharmacodynamic (PD) studies in serial tumor and/or blood samples and assessment of anti-tumor activity. Results: As of 2/11/2021, 21 patients received single agent BCA101 at 64 (n = 3), 240 (n = 7), 500 (n = 2), 750 (n = 3), 800 (n = 3) or 1000 (n = 3) mg IV weekly, including patients with CRC (n = 6), SCCHN (n = 5) uveal melanoma (n = 2), ovarian cancer (n = 2), glioblastoma multiforme (n = 2), conjunctival melanoma, chordoma, pancreatic cancer and anal squamous cell carcinoma (all n = 1). These patients had 1-7 prior lines of antineoplastic therapy (median 4), including 3 patients with prior EGFR inhibitor exposure. Adverse events (AE) related to BCA101 observed in > 1 patient included grade (G) 1-2 rash (n = 9), G 1-2 lipase elevation (n = 2). G3 vitreous hemorrhage at the 240 mg dose level has been the only DLT. The MTD has not been reached and the RD will be based on safety, exposure and pending PD data. Saturation of the clearance was observed at doses above 500mg. Dose proportional increase in Cmax and AUC were observed with doses of 750-1000mg. Best RECISTv1.1 response was stable disease (SD) in 3/10 evaluable patients, with 1 patient on drug ≥4 months. Conclusions: BCA101 is well tolerated at biologically active doses. BCA101 is now being tested in combination with the PD-1 antibody pembrolizumab in patients with SCCHN and anal carcinoma. Clinical trial information: NCT04429542.
A phase 2 study of defactinib (VS-6063) in patients with NF2 altered tumors: Results from NCI-match (EAY131) subprotocol U.
Authors: Jackman David Michael , Jegede Opeyemi , Zauderer Marjorie Glass , Mitchell Edith P. , Zwiebel James , Gray Robert James , Li Shuli , McShane Lisa , Rubinstein Lawrence , Patton David R , Williams Paul M. , Hamilton Stanley R. , Conley Barbara A. , Arteaga Carlos L. , Harris Lyndsay , O'Dwyer Peter J. , Chen Alice P. , Flaherty Keith 
Published: June 2021

3087 Background: The NCI-MATCH trial assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to targeted therapies based on genetic alterations identified in tumor biopsies. Neurofibromatosis 2 (NF2)-inactivated tumors demonstrate increased sensitivity to FAK inhibition in preclinical models. Arm U evaluated the FAK inhibitor defactinib in pts with NF2 altered tumors. Methods: Patients found to harbor an inactivating NF2 mutation on NGS were assigned to the ARM U substudy MATCH. Defactinib 400 mg was given by mouth twice daily until progression or intolerable toxicity. The primary endpoint was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival (PFS), and 6-month PFS. Results: Of 5,548 cases with sufficient tissue for genomic analysis, 51 pts were found to have NF2 alterations (< 1% of the total analyzed). While NF2 alterations are known to occur more commonly in meningiomas and mesotheliomas, alterations were also detected in an array of other tumor types, including renal cell carcinomas and ovarian cancers. Thirty-five pts were ultimately enrolled; 33 patients were started on therapy, with 2 of those determined to be ineligible for outcome analysis. All pts had received at least one prior therapy, with 52% (16/31) having received 3 or more prior lines of therapy. Median follow-up was 35.9 months. ORR [90% CI] was 3% (1/31, [0.16, 14.86]), with the one partial response in a pt with choroid meningioma. Of the twelve pts whose best response was stable disease (39%, 12/31), 8 demonstrated some degree of tumor shrinkage (Table) with a disease control rate of 42% (13/31). Median PFS was 1.9 months for the 31 eligible pts who received study treatment, with median PFS of 9.3 months for the 9 patients who had a best response of stable disease or better. Six pts achieved a PFS of greater than 5.5 months. Among all treated pts (n=33), the most common treatment-related toxicities were fatigue (36%), nausea (33%), and hyperbilirubinemia (27%). There were no grade 4 or 5 toxicities; 27% of pts had grade 3 toxicities. No correlation could be made between clinical outcomes and tumor histology or specific NF2 genotype. Conclusions: Defactinib monotherapy had limited clinical activity in this cohort of previously treated patients with solid tumors exhibiting NF2 loss. Clinical trial information: NCT04439331. [Table: see text]
A phase I study of a TGF-β receptor I kinase inhibitor YL-13027 in patients with advanced solid tumors.
Authors: Li Jin , Liu Tianshu , Bao Hanying , Xu Zusheng , Shu Yang , Zheng Binghua 
Published: June 2021

3098 Background: Transforming growth factor beta (TGF-β) is upregulated in the majority of tumors, promoting tumor cell proliferation, differentiation, and, modulation of the tumor microenvironment. YL-13027, a small molecule inhibitor of type 1 receptor of TGF-β, is a potent highly selective oral agent that downregulates TGFbR1-dependent pathways in tumor cells. YL-13027 dosed into tumor bearing animals drives tumor growth inhibition and interruption of metastasis. In this first-in-human phase1 study, we characterized the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK) and preliminary efficacy of YL-13027 in patients with advanced solid tumors. Methods: YL-13027 tablets were administered orally, twice daily under fasted conditions for 28 days, for at least two 28 day cycles until disease progression, unacceptable toxicity or withdrawal from the study. Starting with an initial dose of 60 mg, dose escalation in a 3+3 design, and pre-determined PK assessments were applied. Adverse events (AEs) were graded by NCI-CTCAE v5.0. PK analysis was performed using a non-compartmental method. Efficacy was evaluated according to RECIST1.1. Results: As of January 18th 2021, thirteen patients were enrolled sequentially to Cohort-1 (60 mg, n = 2), Cohort-2 (120 mg, n = 1), Cohort-3 (180 mg, n = 3), Cohort-4 (240 mg, n = 4) and Cohort-5 (300 mg, n = 3), having gastrointestinal (n = 9), esophageal (n = 1), gallbladder (n = 1), lung (n = 1) and breast (n = 1) carcinomas. These patients had prior systemic antitumor standard therapies, including multi-line chemotherapy, radiation therapy, molecular targeted therapy, immunotherapy, or surgery. Twelve patients completed the cycle 1 safety observation period, with no cardiovascular toxicities or other DLTs observed. The MTD was not reached. Twelve patients experienced AEs possibly related to YL-13027. The most frequent related TEAEs (all grades/grade ≥3) were gamma-glutamyltransferase increased (38.5%/7.7%), haemoglobin decreased (38.5%/0%), blood alkaline phosphatase increased (23.1%/7.7%), aspartate aminotransferase increased (23.1%/0%) and blood phosphorus decreased (23.1%/0%). A maximum YL-13027 plasma concentration was reached within 2h post dose, and the mean elimination half-life was 4.2h in the steady state. Six subjects were evaluable for efficacy. One triple-negative breast cancer (TNBC) subject (Cohort-4) acquired a Partial Response (38.8% reduction of the target lesion), with the response exceeding 4 cycles, and YL-13027 treatment is continuing. The TNBC patient’s tumor profile indicated genomic mutations of EGFL7p.Q256H(13.50%), TP53p.E51*(10.90%) and NF1p.L21V(8.70%) from the initial tumor specimen at diagnosis. Conclusions: YL-13027 is well tolerated and further clinical investigation is warranted. Clinical trial information: NCT03869632.
A phase Ib trial of ERK inhibition with ulixertinib combined with palbociclib in patients (Pts) with advanced solid tumors.
Authors: Raybould Alison L. , Burgess Brian , Urban Clarissa , Naim Rashid , Lee Michael Sangmin , McRee Autumn Jackson 
Published: June 2021

3103 Background: Activating KRAS mutations are the most frequently detected aberrant oncogenes in pancreatic adenocarcinoma. Combination strategies to target the downstream RAF-MEK-ERK effector pathway are a rational approach. Preclinical data with ERK and CDK4/6 inhibition in both pancreatic cancer cell lines and xenografts demonstrates synergistic cell death and tumor growth suppression. Ulixertinib (BVD-523) is an oral small molecule inhibitor of ERK1/2. This phase 1b study evaluated the safety, pharmacokinetics, and early clinical efficacy of ulixertinib when combined with the oral CDK4/6 inhibitor palbociclib in pts with advanced solid tumors. Methods: Using a 3+3 design, pts received ulixertinib at a starting dose of 300mg (range 300-600mg) twice daily continuously with palbociclib at a starting dose of 75mg (range 75-125mg) on D1-21 out of a 28 day cycle. The primary objective was to establish the maximum tolerated dose (MTD) of the combination. Secondary objectives included characterizing safety and estimating progression free survival (PFS). Dose limiting toxicities (DLTs) were evaluated during the first cycle of treatment. Adverse events were graded by CTCAE v4.03. Response was evaluated after 2 cycles (8 weeks) by RECIST 1.1 criteria. Results: 26 pts were enrolled (13 colorectal, 9 pancreas, 2 melanoma, 1 cholangiocarcinoma, 1 GIST); 16 were evaluable for response. The MTD of the combination was ulixertinib 450mg BID and palbociclib 125mg daily. DLTs included grade 3 fatigue, grade 3 acute kidney injury and grade 3 hyponatremia (Table). Due to toxicity in cohort 3, the protocol was amended to include two additional cohorts (2A and 2B) with a reduced dose of ulixertinib and increasing doses of palbociclib. The most common treatment-related adverse events (TRAEs) (all grades) were fatigue (70%), rash (62%) and nausea (54%). The most common laboratory TRAEs were decreased lymphocyte count (77%), decreased WBC count (73%) and anemia (65%). Grade 3 TRAEs were decreased WBC count, decreased lymphocyte count, anemia and fatigue. No grade 4/5 TRAEs were reported. Three pts demonstrated stable disease (SD). For this heavily pre-treated pt population, PFS was 2.05 months (95% CI 1.87, not determined). PK analysis for ulixertinib and palbociclib was linear and consistent with previously reported data; no drug-drug interactions were observed. Conclusions: The MTD of this phase Ib study of advanced solid tumor pts was ulixertinib 450mg BID combined with palbociclib 125 mg daily. At this dosing, 2 pts demonstrated SD, one with pancreatic cancer and one with cholangiocarcinoma. An expansion cohort of metastatic pancreatic cancer pts is ongoing. Clinical trial information: NCT03454035. [Table: see text]
Inhibition of histone lysine demethylases with TACH101, a first-in-class pan-inhibitor of KDM4.
Authors: Chandhasin Chandtip , Yoo Sanghee , Del Rosario Joselyn , Chen Young K , Stafford Jeffrey , Perabo Frank , Clarke Michael F. 
Published: June 2021

3105 Background: The KDM4 family of histone lysine demethylases consists of four main isoforms (KDM4A, B, C, D), all of which have been identified as key oncogenic drivers. They function as epigenetic regulators and control transitions between transcriptionally silent and active chromatin states via removal of methyl marks on histone H3K9 and histone H3K36. KDM4 isoforms play an important role in the epigenetic dysregulation in various cancers and is linked to more aggressive disease and poorer clinical outcomes. Functional redundancy and cross-activity have been observed across KDM4 family members, thus, selective inhibition of one isoform appears to not be effective. TACH101 is a novel, first-in-class pan inhibitor of KDM4 that simultaneously targets multiple isoforms of KDM4. Here we present data that show TACH101 has promising pre-clinical and pharmacologic properties as a cancer therapeutic. Methods: TACH101 was evaluated in in vitro and in vivo studies including cell-proliferation assays in multiple cancer cell lines, apoptotic and cell cycle analyses, and efficacy studies in various xenograft tumor models and patient-derived organoid models. Results: In vitro, TACH101 was broadly effective in killing 67% (200 out of 300) of cancer cell lines screened. TACH101 demonstrated potent increase of H3K36me3 levels (EC50 < 0.001 mM, HTRF) in KYSE-150 cell line engineered to overexpress KDM4C and potent anti-proliferative activity in multiple cell lines in OncoPanel. TACH101 treatment increased cancer cell population in S-phase in multiple cancer cell lines indicating cell-cycle arrest. TACH101 induced apoptosis in human colorectal (HT-29), esophageal (KYSE-150), and triple negative breast cancer (MDA-MB-231) cell lines with EC50s ranging from 0.033-0.092 µM. In vivo, TACH101 triggered effective tumor control in xenograft models including colorectal, esophageal, gastric, breast, and lymphoma with tumor growth inhibition of up to 100%. Further evaluation using a panel of patient-derived colorectal models and patient-derived organoids showed a strong correlation of TACH101 sensitivity with MSI-H status (IC50 ranges 1-150 nM). TACH101 also reduced tumorigenic potential by 4.4-fold as determined by FACS analysis using sorted CD44High EpCAM+ population in Limiting Dilution Assays in vivo, suggesting that reduction of cancer stem cells by TACH101 may be effective in therapy-resistant settings. Pharmacologic studies showed TACH101 demonstrated favorable cell permeability, good oral bioavailability, and high metabolic stability. Conclusions: Extensive preclinical work on TACH101 KDM4 inhibitor shows compelling data and broad applicability as a potential anti-cancer agent. Further evaluation is ongoing to advance the molecule into clinical trials.
Institutional experience with nab-sirolimus in patients with malignancies harboring TSC1 or TSC2 mutations.
Authors: Dickson Mark Andrew , Ravi Vinod , Ganjoo Kristen N. , Iyer Gopa 
Published: June 2021

3111 Background: TSC1/ TSC2 genes are tumor suppressors in the mTOR pathway; mutated at low frequency across tumor types (̃1–2%). Retrospective analyses of patients (pts) with mTOR pathway mutations treated with everolimus did not show improved outcomes vs the wild type (Voss et al. Clin Cancer Res 2019. PMID 30327302). In NCT02201212, pts with TSC1/TSC2 mutations treated with everolimus had a 7% (2/30) response rate. In the AMPECT study, pts with advanced PEComa treated with a novel mTOR inhibitor (mTORi), nab-sirolimus ( nab-S, ABI-009), the subset of pts with TSC1/TSC2 mutations had a response rate of 64% (9/14) (Wagner et al. CTOS 2020. #3463014). In a xenograft model, nab-S showed significantly higher tumor accumulation, target suppression (pS6) and antitumor activity vs everolimus or sirolimus (Hou et al. AACR 2019. #348). In an expanded access program (NCT03817515), pts with advanced tumors bearing TSC1/ TSC2 mutations were treated with nab-S and outcomes in pts with malignancies other than PEComa are reported herein. Methods: Eligible pts (ECOG 0–2) received nab-S 100 mg/m2 IV, once weekly for 2 of every 3 weeks at 3 US sites between 7/2019 and 11/2020. Results: 7 pts with TSC1/ TSC2 mutations have been consecutively enrolled and are reported here. 6/7 pts had multiple prior therapies including 2 pts previously progressing on an mTORi. 4/7 pts had partial response (PR), all in mTORi naïve pts. 2/7 pts had stable disease (SD). In 2 pts previously treated with an mTORi, 1 had SD and 1 came off treatment after 1 cycle (CA125 ↑) with no follow-up scan. Treatment-related serious adverse events (SAEs; hyperglycemia and infection) and dose reduction were reported in 1 pt with metastatic angiosarcoma; SAEs resolved and the pt continued Rx. No other SAE or dose limiting event was reported Conclusions: Patients with various malignancies bearing TSC1 or TSC2 mutations, most with progression on multiple prior therapies, showed evidence of response and manageable toxicities during treatment with nab-S. A basket trial of nab-S in malignancies with TSC1/ TSC2 mutations is planned. Clinical trial information: NCT03817515. [Table: see text]
The next-generation pan-RAF inhibitor, KIN-2787, is active in class II and class III BRAF mutant models.
Authors: Franovic Aleksandra , Miller Nichol , Severson Paul , Kanouni Toufike , Timple Noelito , Jiang Ping , Murphy Eric , Martin Eric 
Published: June 2021

3116 Background: Oncogenic BRAF gene alterations, leading to aberrantly activated BRAF monomers (Class I mutations) or dimers (Class II and Class III mutations), are observed in approximately 6% of all human cancers. First-generation BRAF inhibitors targeting Class I BRAF mutants, including dabrafenib, encorafenib, and vemurafenib, provide significant clinical benefit to patients with BRAF V600 mutation-driven melanoma and select solid tumors as monotherapies or in combination with other targeted therapies. The currently approved BRAF inhibitors have not, however, proven to be effective in patients with Class II or III BRAF alterations which account for a large proportion (34%) of BRAF mutations. KIN-2787 is an orally available, potent and selective small molecule pan-RAF inhibitor specifically designed to inhibit Class II and III BRAF dimers, in addition to Class I mutants. Methods: The efficacy and tolerability of the pan-RAF inhibitor, KIN-2787, was evaluated in vitro and in vivo in Class I, II, and III BRAF mutation-driven human cancer models. Results: In biochemical assays, KIN-2787 showed low nanomolar to picomolar potency against RAF1, BRAF, and ARAF (IC50 0.06-3.46 nM) with minimal activity towards non-RAF kinases. In cell-based assays, KIN-2787 inhibited RAF activity, as measured by inhibition of downstream ERK phosphorylation (pERK), across multiple BRAF mutant cancer cell lines. Class II and III BRAF mutant cell lines were the most responsive when treated with KIN-2787 (IC50 < 50 nM); 19- and 7-fold more sensitive compared to cells harboring wild-type BRAF, respectively. Dose-dependent inhibition of A-375 (Class I), BxPC-3 (Class II), and WM3629 (Class III) BRAF mutant human xenograft tumor growth was attained with daily KIN-2787 treatment and was well-tolerated. A trend towards greater tumor responses was observed with twice daily (BID) compared to once daily (QD) dosing of KIN-2787; however, the two dosing regimens led to similar tumor growth inhibition (TGI) and regressions (mean TGI up to 101-118%; p ≤0.0001) at equivalent total daily doses. Furthermore, KIN-2787 led to a significant in vivo pharmacodynamic response using either regimen, however, prolonged target coverage, as measured by pERK, was achieved with BID dosing. The impact of KIN-2787 treatment on additional biomarkers, including transcriptional changes and MAPK pathway modulation in cell-based models and patient-derived samples, will be presented at the meeting. Conclusions: KIN-2787 is a next-generation pan-RAF inhibitor with pronounced in vitro and in vivo activity against human cancers driven by Class II and III BRAF mutations. A phase 1 dose escalation and expansion clinical trial evaluating the safety and efficacy of KIN-2787 monotherapy in patients with advanced or metastatic solid tumors harboring BRAF gene alterations, including Class II and III mutations, is expected to initiate in 2021.
Patients with advanced solid cancers treated with ERK inhibitors exhibit pseudo-progession in lymphatic nodes.
Authors: Abo-Zahrah Reem , Karp Daniel D. , Adat Abha , Yap Timothy A. , Fu Siqing , Rodon Ahnert Jordi , Piha-Paul Sarina Anne Anne , Tsimberidou Apostolia Maria , Naing Aung , Subbiah Vivek , Dumbrava Ecaterina Elena , Overman Michael J. , Patel Sapna Pradyuman , Amaria Rodabe Navroze , Westin Shannon Neville , Meric-Bernstam Funda , Janku Filip 
Published: June 2021

3138 Background: ERK1/2 signaling is often overactivated in cancer, especially in patients with molecular alterations activating the MAPK pathway. MAPK pathway inhibition can result in the increase of CD8+ and CD4+ T-cells and decreased expression of immunosuppressive cytokines. Methods: This is a retrospective study of 52 patients with advanced solid cancers and oncogenic alterations in the MAPK pathway, who were treated in phase I/II clinical trials with five different single agent ERK1/2 inhibitors at MD Anderson Cancer Center. We reviewed serial PET and/or CT imaging obtained before therapy, on therapy, and after therapy completion. We evaluated dynamic changes in the lymphatic nodes (LN) in the context of overall response per RECIST 1.1 and other outcomes. Results: Of the 52 patients, 19 (37%) patients were evaluated with serial PET/CT and 33 (63%) with serial CT imaging only. Of the 19 patients evaluated with PET/CT, 12 (63%) demonstrated increased FDG uptake in LN compared to pre-treatment imaging (LN enlargement, n = 9; no LN enlargement, n = 3) discrepant from the known target and non-target lesions. These 12 patients were on therapy with ERK inhibitors (11 at doses > recommended phase 2 dose [RP2D]) for a median of 3.6 months (range, 1.8-12 months) with a best response per RECIST 1.1. as follows: partial response, n = 1; stable disease (SD), n = 10; progressive disease (PD), n = 1. Of interest, in 6 of those 12 patients, FDG uptake in LN decreased or resolved after treatment discontinuation. Further, one patient had a biopsy of an emerged LN, which showed lymphocytic infiltrate without tumor cells. Of the 33 patients evaluated with CT only, 5 (15%) demonstrated increased size of LN discrepant from the known target and non-target lesions compared to pre-treatment imaging. These 5 patients were on therapy with ERK inhibitors (all at doses < RP2D) for a median of 1.4 months (range, 1.1-3.5 months) with a best response per RECIST 1.1. as follows: SD, n = 2; PD, n = 3. Of interest, in 2 of those 5 patients, size of LN decreased or resolved after treatment discontinuation. In addition, one patient had a biopsy of an emerged LN, which showed lymphoid aggerates without tumor cells. Conclusions: Our data suggest that treatment with ERK inhibitors can result in activation of the lymphatic nodes, which can manifest as pseudo-progression. This can lead to an inconclusive assessment of their therapeutic benefit and further suggests exploration of the potential synergistic effects with immune therapy.