An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Phase 1 dose escalation study of MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2631-2631
Author(s):  
Sekwon Jang ◽  
John D. Powderly ◽  
Alexander I. Spira ◽  
Ouiam Bakkacha ◽  
Deryk Loo ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Multiple Tumor ◽  
Melanoma Patients ◽  
Tumor Types

2631 Background: MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody (mAb). B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Studies demonstrate that B7-H3 is a significant factor in progression and events of metastasis of multiple tumor types, including melanoma. Methods: This phase 1 study characterizes safety, maximum tolerated or maximum administered dose, pharmacokinetics, immunogenicity, and tumor response per RECIST v1.1 of MGC018 in a 3+3+3 dose escalation design in patients with advanced solid tumors. MGC018 was administered intravenously (IV) every 3 weeks. Results: The study enrolled 29 patients of multiple tumor types, which included 3 melanoma patients refractory to ≥2 prior lines of checkpoint therapy. The study completed 5 of 6 planned dose cohorts (0.5 mg/kg - 4 mg/kg) as of the data cutoff of 21 January 2021. The final cohort of 4 mg/kg has 3 patients with ongoing treatment and follow-up at the date of submission. Dosing MGC018 IV every 3 weeks resulted in minimal serum accumulation. At least 1 treatment emergent adverse event occurred in 29 patients (100.0%); most common (≥25%) were anemia, neutropenia, fatigue, hyperpigmentation, infusion related reaction, nausea, and palmar plantar erythrodysesthesia. Two dose-limiting toxicities occurred; one grade 4 neutropenia (2 mg/kg) and one grade 3 fatigue lasting 7 days (4 mg/kg). No febrile neutropenia was reported. The 3 melanoma patients had reductions in target lesion sum of 24.4%, 27.5%, and 35% (unconfirmed partial response) and remain on treatment as of the data cutoff. The recommended phase 2 dose was determined to be 3 mg/kg. Conclusions: Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma. Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks. The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer. Clinical trial information: NCT03729596.

FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3157-TPS3157 ◽  
Author(s):  
David Michael Hyman ◽  
Lipika Goyal ◽  
Petros Grivas ◽  
Funda Meric-Bernstam ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Tumor Type ◽  
Phase 2 ◽  
Alternative Treatment Option

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.

Phase I/II dose-escalation and expansion study of FLX475 alone and in combination with pembrolizumab in advanced cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3163-TPS3163
Author(s):  
John D. Powderly ◽  
Bartosz Chmielowski ◽  
Julie R. Brahmer ◽  
Sarina Anne Piha-Paul ◽  
Samantha Elizabeth Bowyer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Dose Escalation ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Safety Data ◽  
Receptor Occupancy ◽  
Phase 2 ◽  
Open Label

TPS3163 Background: Regulatory T cells (Treg) can dampen anti-tumor immune responses in the tumor microenvironment (TME). The predominant chemokine receptor on human Treg is CCR4, the receptor for the chemokines CCL17 and CCL22, which are produced by tumor cells, tumor-associated macrophages and dendritic cells, as well as by effector T cells (Teff) in the setting of an inflammatory anti-tumor response. Preclinical studies with orally-available CCR4 antagonists have demonstrated potent inhibition of Treg migration into tumors, an increase in the intratumoral Teff/Treg ratio, and anti-tumor efficacy as a single agent and in combination with checkpoint inhibitors. In a first-in-human trial conducted in healthy volunteers, the oral CCR4 antagonist FLX475 was demonstrated to be well tolerated with outstanding PK properties. A robust PD assay measuring receptor occupancy on circulating Treg demonstrated the ability to safely achieve exposure levels predicted to maximally inhibit Treg recruitment into tumors via CCR4 signaling. These human PK, PD, and safety data have enabled a streamlined design of a Phase 1/2 study of FLX475 in cancer patients both as monotherapy and in combination with checkpoint inhibitor. Methods: This clinical trial is a Phase 1/2, open-label, dose-escalation and cohort expansion study to determine the safety and preliminary anti-tumor activity of FLX475 as monotherapy and in combination with pembrolizumab. The study is being conducted in 2 parts, a dose-escalation phase (Part 1) and a cohort expansion phase (Part 2). In Part 1 (Phase 1) of the study, at least 3 to 6 eligible subjects are being enrolled in sequential cohorts treated with successively higher doses of FLX475 as monotherapy (Part 1a) or in combination with pembrolizumab (Part 1b). In Part 2 (Phase 2) of the study, expansion cohorts of both checkpoint-naïve and checkpoint-experienced patients with tumor types predicted to be enriched for Treg and/or CCR4 ligand expression (i.e. “charged tumors”) -- including both EBV+ and HPV+ tumors and NSCLC, HNSCC, and TNBC -- will be enrolled using a Simon 2-stage design. As of February 4, 2020, Phase 1 dose escalation has been completed and a recommended Phase 2 dose chosen for both FLX475 monotherapy and combination therapy with pembrolizumab. Enrollment into Phase 2 expansion cohorts has been initiated. Clinical trial information: NCT03674567 .

Trial in progress: A phase 1-2 multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of ABN401 in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3157-TPS3157
Author(s):  
Dae Ho Lee ◽  
Aflah Roohullah ◽  
Byoung Chul Cho ◽  
Charlotte Rose Lemech ◽  
Paul L. de Souza ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Locally Advanced ◽  
Local Therapy ◽  
Tumor Type ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Open Label

TPS3157 Background: c-MET (hepatocyte growth factor (HGF) receptor) overexpression, either by gene amplification, or mutation is associated with oncogenic transformation in numerous malignancies including lung, gastric, skin, renal, colorectal, and pancreatic cancers. ABN401 inhibits the activation of c-MET by reversibly interfering with the binding of c-Met tyrosine kinase to adenosine triphosphate (ATP) and blocking the receptor's downstream signaling that has demonstrated efficacy in NSCLC and gastric cancer in mouse xenograft and PDx models. This clinical trial is in progress in patients with advanced cancers. Methods: ABN401 is being evaluated in an open-label, non-randomized, dose-escalation (phase 1) study in patients with advanced solid tumors, and dose-expansion (phase 2) in patients with targeted indications and c-MET biomarker expression (NCT04052971). The phase 1 explores ascending daily doses of oral ABN401 monotherapy in 21-day cycles to identify the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). A preplanned extension (pilot expansion) study has been initiated based on predefined positive efficacy signals at intermediate doses up to 10 NSCLC patients who have c-MET alteration. Once RP2D is determined, the phase 2 expansion of up to 10-29 patients in four specific tumor-type cohorts is planned, utilizing a Simon's optimal two-stage design to evaluate the clinical activity of ABN401. ABN401-001 study began enrolling patients in August 2019 and is ongoing in Korean and Australia. Dose escalation up to cohort 4 has been completed, enrollment to cohort 5 began in November 2020. AEs are assessed according to CTCAE v5. Tumor response is determined according to RECIST 1.1 criteria and safety findings reviewed by the DRC, which will determine the RP2D and MTD. Key Phase 1 eligibility criteria include 1) histological or cytological diagnosis of melanoma or any type of carcinoma or sarcoma and 2) refractory metastatic disease, or refractory locally advanced disease not amenable to local therapy. For the extension (pilot expansion) study, patients must have NSCLC with MET exon 14 skipping, MET amplification and/or c-MET overexpression. An exploratory study is being conducted for co-development of a companion diagnostic (CDx) system including a CTC device and ddPCR kit through liquid biopsy. Clinical trial information: NCT04052971.

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

A phase 1/2 trial of ORIN1001, a first-in-class IRE1 inhibitor, in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3080-3080
Author(s):  
Nashat Y. Gabrail ◽  
Erika P. Hamilton ◽  
Anthony D. Elias ◽  
Mothaffar F. Rimawi ◽  
Chao Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Pharmacokinetic Analysis ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Duration Of Treatment ◽  
Open Label

3080 Background: ORIN1001 is a first-in-class small molecule with a novel, unique enzyme and mode of inhibition that selectively inhibits Inositol Requiring Enzyme 1α (IRE1) RNAse and blocks X-Box Binding Protein 1 (XBP1) activation in the endoplasmic reticulum (ER). IRE1α/XBP1 has been implicated in a host of pathologies, and molecules that modulate it are under intense investigation for the treatment of oncologic, metabolic, neurodegenerative and other diseases. ORIN1001 has demonstrated preclinical anti-tumor activity alone and in combination with standard of care across multiple animal models including breast, prostate, lung, liver, pancreatic, brain, colon, ovarian, esophageal, and hematologic cancers and is now undergoing first-in-human testing. Methods: A phase 1, open label, 3+3 dose escalation trial is testing ORIN1001 administered PO daily to patients (pts) with advanced solid tumors (single agent) or relapsed refractory breast cancer (in combination with Abraxane). The phase 1 dose escalation part of the trial evaluates the safety, tolerability, pharmacokinetics and preliminary efficacy of ORIN1001. After identification of the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) for the single agent, the dose expansion part of the trial will test ORIN1001 in combination with Abraxane. Results: As of Jan 25, 2021, 22 patients with advanced cancer have received ORIN1001 dosed at 100mg, 200mg or 300mg per day in 21-day continuous cycles with a median age of 61 (range 42-77). The pts had received a median of 4 prior line of treatments. Two DLTs were observed at 200 mg with thrombocytopenia and rash. MTD has not been reached. Common (>15%) treatment-emergent adverse events (TEAEs) included nausea, vomiting, rash, fatigue, and hypokalaemia. The vast majority of these events were Grade 1-2 in severity. Seven (32%) pts had at least 1 TRAE grade≥ 3, the most frequent of which were thrombocytopenia (N=3) and rash (N=3). Preliminary pharmacokinetic analysis showed ORIN1001 exposure to increase in a dose proportional manner. Mean t1/2 at steady state was 18 hrs. Thirteen pts were evaluated for preliminary efficacy. Best response, per RECIST 1.1, was stable disease (SD) in 8 pts while 5 pts had progressive disease (PD). For 2 ongoing patients with advanced liver or colorectal cancer, duration of treatment has exceeded 300 days and 570 days, respectively. Conclusions: To date, the phase 1 part of the first-in-human trial has demonstrated a reasonable safety and pharmacokinetic profile for ORIN1001 at 100mg and 200mg dose levels. While efficacy data have yet to mature, chronic dosing achieved in pts with heavily treated advanced solid tumors, suggests clinical potential for in the setting of advanced solid cancers. The phase 2 part of the trial testing ORIN1001 in combination with Abraxane is currently enrolling pts with advanced breast cancer. Clinical trial information: NCT03950570.

scholarly journals Preliminary Efficacy of the Anti-Insulin–Like Growth Factor Type 1 Receptor Antibody Figitumumab in Patients With Refractory Ewing Sarcoma

2011 ◽  
Vol 29 (34) ◽  
pp. 4534-4540 ◽  
Author(s):  
Heribert Juergens ◽  
Najat C. Daw ◽  
Birgit Geoerger ◽  
Stefano Ferrari ◽  
Milena Villarroel ◽  
...  
Keyword(s):  
Growth Factor ◽  
Dose Escalation ◽  
Ewing Sarcoma ◽  
Phase 1 ◽  
Strong Association ◽  
Single Agent ◽  
Objective Response ◽  
Primary Phase ◽  
Insulin Like Growth Factor ◽  
Phase 2

Purpose Patients with Ewing sarcoma (ES) with metastases and those who relapse fare poorly and receive therapies that carry significant toxicity. This phase 1/2 study was conducted to evaluate the efficacy of figitumumab in advanced ES. Patients and Methods Patients with sarcoma 10 to 18 years old were enrolled in two dose escalation cohorts (20 and 30 mg/Kg intravenously every 4 weeks) in the phase 1 portion of the study. Patients with ES 10 years old or older were enrolled in the phase 2 portion of the study. The primary phase 2 objective was objective response rate (ORR). Results Thirty-one patients with ES (n = 16), osteosarcoma (n = 11), or other sarcomas (n = 4) were enrolled in the phase 1 portion of the study. Dose escalation proceeded to 30 mg/kg every 4 weeks with no dose-limiting toxicity identified. In the phase 2 portion of the study, 107 patients with ES received figitumumab at 30 mg/kg every 4 weeks for a median of 2 cycles (range, 1 to 16). Sixty three percent of phase 2 patients had received at least three prior treatment regimens. Of 106 evaluable patients, 15 had a partial response (ORR, 14.2%) and 25 had stable disease. Median overall survival was 8.9 months. Importantly, patients with a pretreatment circulating free insulin-like growth factor (IGF) -1 lower than 0.65 ng/mL (n = 14) had a median OS of 3.6 months, whereas those with a baseline free IGF-1 ≥ 0.65 ng/mL (n = 84) had a median OS of 10.4 months (P < .001). Conclusion Figitumumab had modest activity as single agent in advanced ES. A strong association between pretreatment serum IGF-1 and survival benefit was identified.

A phase 1/2 study with open-label, dose escalation phase followed by single-arm expansion at the maximum tolerated dose to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 injection alone and in combination with cetuximab in adults with advanced solid tumors and head and neck cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3156-TPS3156
Author(s):  
Alberto Bessudo ◽  
Ezra E.W. Cohen ◽  
Rodolfo Gutierrez ◽  
Daniel H. Johnson ◽  
Ari Rosenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Head And Neck ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Standard Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Neoplastic Disease ◽  
Dual Inhibitor ◽  
Pdx Models

TPS3156 Background: NT219 is a small molecule, dual inhibitor of insulin receptor substrates (IRS) 1/2 and signal transducer and activator of transcription 3 (STAT3), effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. Patient derived xenograft (PDX) models have shown that inhibition of both IRS and STAT3 is essential to overcome targeted epidermal growth factor receptor inhibitor (EGFRi) resistance, and NT219 has demonstrated efficacy as monotherapy and in combination with immune oncology therapies. Particularly, both pathways have been found to be relevant in resistance to cetuximab in head and neck squamous cell carcinoma (HNSCC) PDX models. Methods: This phase 1/2 study (Clinical trial: NCT04474470) began in September 2020. The phase 1 component has a dose escalation arm of NT219 as a single agent at doses ranging between 3mg/kg and 50mg/kg in adult subjects with recurrent and/or metastatic solid tumors enrolled in sequential dose cohorts of 3 to 6 subjects, in a conventional 3+3 design aiming to establish the safety of single agent NT219. Following the conclusion of follow up on the third dose cohort, an additional dose-escalation arm of NT219 in combination with standard dose cetuximab will be opened in patients with recurrent and/or metastatic HNSCC and colorectal cancer, aiming to establish the safety of NT219 when combined with cetuximab. In the expansion phase, 29 patients will be enrolled at the recommended phase 2 dose in combination with standard dose cetuximab in patients with recurrent/metastatic HNSCC. The primary objectives of the trial are safety, tolerability, MTD, and RP2D and preliminary efficacy of NT219 alone and in combination with cetuximab. Measurements of STAT3 and IRS1/2 phosphorylation in biopsy specimens and TILs will be evaluated as potential biomarkers. NT219 provides a first-in-class treatment for patients with resistant neoplastic disease. The current trial will provide important data in patients with recurrent/metastatic cancers, particularly, HNSCC on the effects of the inhibition of STAT3 and IRS1/2 pathways as a novel therapeutic approach. Clinical trial information: NCT04474470.

Phase I study of LBL-007, a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2523-2523
Author(s):  
Yuankai Shi ◽  
Suxia Luo ◽  
Huan Zhou ◽  
Shengyu Zhou ◽  
Shan An ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Objective Response ◽  
Human Study ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Tumor Immune Escape

2523 Background: LAG-3 is an immune checkpoint receptor expressed on activated T cells to negatively regulate these cells, resulted in tumor immune escape. LBL-007, a novel anti-LAG-3 antibody, was developed by screening of a human antibody phage display library and demonstrated specific binding to human LAG-3, stimulation of IL-2 release and blockage of LAG-3 binding to its ligands including MHC II. It has shown that LBL-007 significantly inhibited tumor growth in a mouse MC38 tumor model in hLAG-3 knock-in mice with more pronounced tumor inhibition when combined with an anti-PD-1 antibody. Methods: A phase I, multicenter, open-label and first-in-human study was conducted to evaluate the safety, tolerability, and PK in patients with advanced solid tumors. The dose escalation phase was designed with 6 dose cohorts of LBL-007 at 0.05, 0.25, 1, 3, 6 and 10 mg/kg (iv every 2 weeks), using a modified 3+3 design. Key inclusion criteria included: age≥18 years, histologically/cytologically confirmed advanced solid tumors, failed ≥2 lines of prior standard therapies, ECOG of 0-1, and adequate hematologic, renal, hepatic, and cardiac function. Patients who received anticancer or immunotherapy 4 weeks from first dose of LBL-007 were excluded. The primary endpoints were tolerability and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Any potential efficacy was assessed by objective response rate (ORR) evaluated by CT/MRI per RECIST 1.1. Results: From March 12th, 2020 to Feb 9th, 2021, 17 patients were evaluated in this study. There were no dose limiting toxicities (DLTs) at any dose cohorts, and patients were tolerated very well. Overall, there were 129 adverse events (AEs), and 8 events were serious adverse event (SAE), of which 5 were defined as suspected unexpected serious adverse reaction (SUSAR), but most unlikely treatment related AEs (TRAEs). All AEs regardless of attribution included anemia, hypocalcemia, and flu related respiratory infection, etc. The most common AEs were anemia (14, 10.9%), hypocalcemia (6, 4.7%) and thrombocytopenia (4, 3.1%). Totally, there were 8 patients without disease progression, defined as SD at the first evaluation and sustained for 3.5-9 months. The target lesions in 2 of these 8 patients were reduced by 18.9% and 23.2% (both in esophagus cancer). The progression-free survival of these 2 patients was 4.4 and 9.0 months, respectively. Patients are also being enrolled into the indication exploratory phase (3 and 6 mg/kg), testing the combination therapy with an anti-PD-1 antibody in patients with melanoma and other solid tumors. Conclusions: The dose escalation part of the study revealed tolerability of LBL-007 with an impressive safety profile, and potentially some encouraging signs of anti-tumor activities. Clinical trial: Chinaclinicaltrials.org.cn (1900025904). Clinical trial information: CTR20210196.

scholarly journals CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

2021 ◽  
Vol 9 (7) ◽  
pp. e002446
Author(s):  
Rachel E Sanborn ◽  
Omid Hamid ◽  
Elisabeth GE de Vries ◽  
Patrick A Ott ◽  
Javier Garcia-Corbacho ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Phase 1 ◽  
Objective Response ◽  
Tolerability Profile ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Anal Squamous Cell Carcinoma ◽  
Grade 3

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

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