Found 41 Presentations For Request "phase 1 study of the novel prodrug"
Presentation Topic- Developmental therapeutics
Filtered By
- Developmental therapeutics
527P - Phase I study of the novel prodrug MIV-818 in patients with hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA) or liver metastases (LM)
- Debashis Sarker (London, United Kingdom)
Abstract
Background
MIV-818 is an orally administered troxacitabine-based nucleotide prodrug currently undergoing phase 1 clinical trial (NCT03781934). It is rapidly metabolized by human hepatocytes, directing high levels of the chain-terminating nucleotide tri-phosphate to the liver, while minimizing exposure to other organs.
Methods
Patients (pts), ≥18 years, ECOG performance status < 1, adequate organ function, with advanced inoperable HCC, iCCA or LM from solid tumours of gastrointestinal origin were enrolled. MIV-818 as a single agent was administered as an inter-patient dose escalation 3+3 cohort design in the phase IB part of this trial reported here. The primary objective is to assess safety and tolerability. A key secondary objective was to evaluate the overall response rate based on RECIST v1.1. As exploratory objectives, on-treatment liver biopsies were collected to assess the pharmacokinetics and the pharmacodynamic effects of MIV-818.
Results
Nine evaluable pts (6M; 3F), median age = 64 years (range: 47-74) with HCC (5), mixed HCC/iCCA (1) iCCA (1) or LM (2) from GI tract solid tumours, previously treated with median 2 (1-7) lines of therapy, were included. Starting dose was 40 mg for 5 days in 21-day cycles. The most common treatment emergent AEs were those in the haematological system; raised LFTs and pruritus were also commonly reported. Out of 9 pts, one pt experienced a DLT (Maculopapular rash grade 3) during the first cycle of treatment. The longest duration of treatment was 9 cycles, seen in 1 pt. Tumour biopsies showed evidence of selective, drug-induced, DNA damage, measured as phosphorylation of histone H2AX, in tumour tissue with minimal or no impact of MIV-818 observed in healthy liver tissue.
Conclusions
MIV-818 had an acceptable safety and tolerability profile, with haematological suppression being the most common AE. Biomarker data of liver biopsies demonstrated a selective effect of MIV-818 on cancer cells. The study will now evaluate MIV-818 in combination with other agents in HCC patients.
Clinical trial identification
NCT03781934.
Legal entity responsible for the study
Medivir AB.
Funding
Medivir AB.
Disclosure
D. Sarker: Financial Interests, Personal, Advisory Board, null: Eisai; Financial Interests, Personal, Invited Speaker, null: MSD; Financial Interests, Personal, Advisory Board, null: Ipsen; Financial Interests, Personal, Advisory Board, null: Bayer; Financial Interests, Personal, Invited Speaker, null: Bayer; Financial Interests, Personal, Invited Speaker, null: AstraZeneca; Financial Interests, Personal, Invited Speaker, null: Eisai; Financial Interests, Personal, Other, Travel and conference fees: Ipsen; Financial Interests, Personal, Advisory Board, null: Surface Oncology; Financial Interests, Personal, Other, Travel and Conference Fees: MiNA Therapeutics; Financial Interests, Personal, Advisory Board, null: AAA; Financial Interests, Institutional, Invited Speaker, null: UCB; Financial Interests, Institutional, Invited Speaker, null: Eisai; Financial Interests, Institutional, Invited Speaker, null: MiNA Therapeutics; Financial Interests, Institutional, Invited Speaker, null: Medivir AB; Financial Interests, Institutional, Invited Speaker, null: MSD; Financial Interests, Institutional, Invited Speaker, null: Bayer; Financial Interests, Institutional, Invited Speaker, null: RedX; Financial Interests, Institutional, Invited Speaker, null: GSK; Financial Interests, Institutional, Invited Speaker, null: Starpharma; Financial Interests, Institutional, Invited Speaker, null: Adaptimmune; Financial Interests, Institutional, Invited Speaker, null: Blueprint; Financial Interests, Institutional, Invited Speaker, null: H3; Financial Interests, Institutional, Invited Speaker, null: Regeneron; Financial Interests, Institutional, Invited Speaker, null: Taiho; Financial Interests, Institutional, Invited Speaker, null: AstraZeneca; Financial Interests, Institutional, Invited Speaker, null: Ipsen; Financial Interests, Institutional, Funding, null: Roche; Financial Interests, Institutional, Funding, null: Inspirata; Non-Financial Interests, Advisory Role, null: Medivir; Non-Financial Interests, Advisory Role, null: UCB; Non-Financial Interests, Advisory Role, null: MiNA Therapeutics. T.R..J. Evans: Financial Interests, Institutional, Advisory Role: Karus; Financial Interests, Institutional, Advisory Board: Eisai; Financial Interests, Institutional, Advisory Board: MSD; Financial Interests, Institutional, Advisory Board: Ascelia; Financial Interests, Institutional, Advisory Board: Nucana; Financial Interests, Institutional, Advisory Board: Roche/Genenetech; Financial Interests, Institutional, Speaker’s Bureau: BMS; Financial Interests, Institutional, Speaker’s Bureau: Eisai; Financial Interests, Institutional, Speaker’s Bureau: MSD; Financial Interests, Institutional, Speaker’s Bureau: Nucana; Other, Institutional, Other: Genmab; Financial Interests, Institutional, Expert Testimony: Medivir; Financial Interests, Institutional, Funding: Adaptimmune; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Athenex; Financial Interests, Institutional, Funding: Basilea; Financial Interests, Institutional, Funding: Beigene; Financial Interests, Institutional, Funding: Berg Pharma; Financial Interests, Institutional, Funding: Bicycle; Financial Interests, Institutional, Funding: BiolineRx; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Celgene; Financial Interests, Institutional, Funding: Clovis; Financial Interests, Institutional, Funding: CytomX; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: Halozyme; Financial Interests, Institutional, Funding: Immunocore; Financial Interests, Institutional, Funding: iOncologi; Financial Interests, Institutional, Funding: Iovance; Financial Interests, Institutional, Funding: Janssen; Financial Interests, Institutional, Funding: J&J; Financial Interests, Institutional, Funding: Lilly; Financial Interests, Institutional, Funding: Medivir; Financial Interests, Institutional, Funding: Merck; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: MiNA Therapeutics; Financial Interests, Institutional, Funding: Modulate; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Nucana; Financial Interests, Institutional, Funding: Plexxikon; Financial Interests, Institutional, Funding: Roche/Genentech; Financial Interests, Institutional, Funding: Sanofi/Aventis; Financial Interests, Institutional, Funding: Sierra; Financial Interests, Institutional, Funding: UCB; Financial Interests, Institutional, Funding: Verastem; Financial Interests, Institutional, Funding: Vertex. E. Van Cutsem: Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Advisory Role: BMS; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Halozyme; Financial Interests, Personal, Advisory Role: Array; Financial Interests, Personal, Advisory Role: Biocartis; Financial Interests, Personal, Advisory Role: GSK; Financial Interests, Personal, Advisory Role: Daiichi; Financial Interests, Personal, Advisory Role: PierreFabre; Financial Interests, Personal, Advisory Role: Sirtex; Financial Interests, Personal, Advisory Role: Taiho; Financial Interests, Personal, Advisory Role: Incyte; Financial Interests, Personal and Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Funding: Bayer; Financial Interests, Personal and Institutional, Funding: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Funding: Lilly; Financial Interests, Personal and Institutional, Funding: Novartis; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Funding: Celgene; Financial Interests, Personal and Institutional, Funding: Ipsen; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: Servier; Financial Interests, Personal and Institutional, Funding: BMS. H. Prenen: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Vfor; Financial Interests, Personal, Other: Amgen; Financial Interests, Personal, Other: Bayer; Financial Interests, Personal, Other: Roche. M.R. Middleton: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Immunocore; Financial Interests, Personal, Advisory Board: BiolineRx; Financial Interests, Personal, Advisory Board: J&J; Financial Interests, Personal, Advisory Board: Vista; Financial Interests, Personal, Advisory Board: Vaccitech; Financial Interests, Personal and Institutional, Funding: Immunocore; Financial Interests, Personal and Institutional, Funding: Novartis; Financial Interests, Personal and Institutional, Funding: AstraZeneca; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Funding: Millenium; Financial Interests, Personal and Institutional, Funding: BMS; Financial Interests, Personal and Institutional, Funding: Vertex; Financial Interests, Personal and Institutional, Funding: Merck; Financial Interests, Personal and Institutional, Funding: Array BioPharma; Financial Interests, Personal and Institutional, Funding: Regeneron; Financial Interests, Personal and Institutional, Funding: Pfizer; Financial Interests, Personal and Institutional, Funding: Replimmunen; Non-Financial Interests, Personal, Other: Genesis Care. S. Bhoi: Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB. K. Tunblad: Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB. F. Oberg: Financial Interests, Personal and Institutional, Leadership Role: Medivir AB; Financial Interests, Personal and Institutional, Member of the Board of Directors: Medivir AB; Financial Interests, Personal and Institutional, Full or part-time Employment: Medivir AB; Financial Interests, Personal and Institutional, Stocks/Shares: Medivir AB; Financial Interests, Personal and Institutional, Royalties: Medivir AB. T. Morris: Financial Interests, Personal, Leadership Role: Medivir AB; Financial Interests, Personal, Advisory Board: Medivir AB. R. Plummer: Financial Interests, Personal, Advisory Board: Astex; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Biosceptre; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: CV6 Therapeutics; Financial Interests, Personal, Advisory Board: Ellipses; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Sanofi Aventis; Financial Interests, Institutional, Royalties: Clovis Oncology; Financial Interests, Personal, Other: Beigene; Financial Interests, Personal, Other: SOTIO.
554P - Phase I clinical trial of OBP-301, a novel telomerase-specific oncolytic virus, in combination with radiotherapy in esophageal cancer patients
- Shunsuke Tanabe (Okayama, Japan)
Abstract
Background
OBP-301 is a novel condition-restricted, replication-competent adenovirus derived from human adenovirus type 5 that incorporates a human telomerase reverse transcriptase (hTERT) promoter. This construct causes tumor-specific viral replication and lytic death of a variety of cancer cells, and safety of OBP-301 monotherapy has been confirmed in patients with solid tumor in phase I clinical trial. We conducted phase I clinical trial to evaluate safety, tolerability and efficacy of OBP-301 in combination with radiotherapy.
Methods
This is a phase I clinical trial (NCT03213054) to evaluate safety, tolerability and efficacy of OBP-301 in combination with radiotherapy in patient with esophageal cancer who are not applicable for standard therapy. This is an open-label trial designated as standard 3 + 3 dose escalation. The dose of OBP-301 will be started from 3 x 1011 virus particles (VP) in Cohort 1, and if no dose limiting toxicity (DLT) is observed, dose will be escalated to 3 x 1012 VP. OBP-301 will be injected to primary tumor by endoscopy at Day 1, Day 18 and Day 32. From Day 4, patients receive 6 weeks radiotherapy (60 Gy total).
Results
6 patients were enrolled to the phase I clinical trial, 3 patients were treated with 3 x 1011 VP and 3 x 1012 VP of OBP-301 in the Cohort 1 and Cohort 2, respectively. All patients were male, with median age of 81.5 years. No DLT was observed, thus maximum tolerable dose (MTD) of OBP-301 was not determined, and MTD was over 1012 VP. The adverse events related to OBP-301 were lymphocyte count decreased (83.3%, Grade2-4), pyrexia (83.3%, Grade1-2), upper respiratory tract infection (16.7%, Grade1), malaise (16.7%, Grade1), decreased appetite (16.7%, Grade2), esophagitis (16.7%, Grade2), radiation esophagitis (16.7%, Grade1), weight decreased (16.7%, Grade1). 4 of 6 patients experienced complete response (CR) in primary tumor and CR rate for primary tumor was 66.7%, and other 2 patients also experienced tumor shrinkage.
Conclusions
The combination of OBP-301 and radiotherapy was well tolerated, and able to provide definite clinical benefits in patients with esophageal cancer who are not applicable for surgery or standard chemotherapy.
Legal entity responsible for the study
Oncolys Biopharma Inc.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
523P - AFP-maytansine conjugate: A novel targeted cancer immunotherapy
- Igor A. Sherman (Toronto, Canada)
Abstract
Background
The alpha fetoprotein (AFP) receptor is an oncofetal antigen and a novel target for cancer therapeutics, This receptor is highly expressed on the surface of common cancers including many breast, lung, colorectal, prostate, ovarian and hematological malignancies, but is not expressed on normal adult cells. By covalently conjugating a novel maytansine toxin to a recombinant human form of AFP we can selectively deliver the toxin payload to cancer cells while sparing normal cells. Since AFP is a human protein, there is reduced risk of any harmful immune reaction to AFP conjugates.
Methods
Four novel AFP-maytansine conjugates of differing drug-protein ratios were administered intravenously (IV) to mice bearing human colon carcinoma (COLO-205) xenografts, at doses previously determined to be safe. Seven days after implantation, mice with tumors greater than 150 mm3 were randomized to receive control (vehicle) or one of the 4 conjugates (10 animals/ group). Animals were treated daily for 2 weeks with 2 days of rest after 5 doses; tumor volume was assessed twice weekly for 60 days following implantation. In a separate study, the biodistribution (BD) of AFP-maytansine conjugate in the COLO-205 model was investigated after a single IV dose.
Results
All animals in the control group were dead by day 38 due to uncontrolled tumor growth. Statistically significant reduction in tumor volume was observed in all treatment groups compared to control beginning at Day 17 and lasting until all control animals were euthanized. In one of the conjugate groups, tumor reduction continued following treatment discontinuation with tumor volumes falling below the limit of detection in 9 of 10 animals. All 10 mice in this group survived through Day 60 with only minimal tumor growth during the last week of the study. In this group, tumor volume was statistically different from two other conjugates on Day 24 (p<0.0001) and from the third group on Day 35 (p=0.001). No signs of toxicity were observed in treated mice. The BD study showed maytansine and metabolite accumulation in the tumor, while bone marrow levels were below detection.
Conclusions
Results support the development of an AFP-maytansine drug conjugate as a highly effective, safe and targeted cancer therapy. Studies are underway to support a phase I clinical trial.
Legal entity responsible for the study
Southern Research Institute.
Funding
Alpha Cancer Technologies Inc.
Disclosure
I.A. Sherman: Financial Interests, Institutional, Stocks/Shares: Alpha Cancer Technologies Inc.. All other authors have declared no conflicts of interest.
522P - Risk mitigation of ocular toxicities due to antibody drug conjugates (ADCs) in novel early-phase clinical trials
- Khobe Chandran (Sutton, SA, United Kingdom)
Abstract
Background
Ocular toxicities are emerging as important adverse events in patients treated with ADCs with significant impact on quality of life. There is a paucity of data on how best to detect and mitigate ocular toxicities in the clinical development of ADCs.
Methods
This is a retrospective audit of patients (pts) treated on early phase trials of ADCs within a dedicated drug development unit between January 2015 to December 2020. 95 pts were identified across seven clinical trials. Patient demographics, clinical variables, and ocular assessments were collected for analysis.
Results
31/95 (33%) pts developed ocular toxicities, 26/31 (84%) were grade 1 and 5/31 (16%) were grade 2. The majority of toxicities affected the eyelid 23/31 (74%), causing red eyes and tearing; and cornea 5/31(16%) presenting as ocular pain. No grade 3/4 toxicities or dose limiting toxicities were observed. Median time to onset of eye toxicities was 2 cycles (range 1-10 cycles). All patients who experienced ocular toxicities had ophthalmology review. 5/31 (16%) pts had transient deterioration in visual acuity and 18/31 (58%) pts had anterior eye findings detected on slit lamp examination. Lubricating eye drops were most commonly prescribed 21/31 (68%), followed by steroid eye drops 5/31 (16%) by an experienced ophthalmologist versed in the management of ocular toxicities seen on experimental early phase trials. Of the 95 pts included in this study, 33/95 (35%) received primary prophylaxis with either the use of cool eye masks or steroid eye drops prior to dosing. Of the 11/33 (33%) pts in this group who developed ocular symptoms, 10/11 (91%) were able to continue dosing. With the use of primary prophylaxis measures, the relative risk of treatment discontinuation due to significant eye toxicity was reduced by 53% (6.5% permanent discontinuation of ADC with no prophylaxis compared to 3% with the use of primary eye prophylaxis).
Conclusions
Ocular toxicities from novel ADCs can be successfully mitigated. Proactive early detection, collaboration with engaged ophthalmology specialists, and prompt institution of prophylactic measures can reduce morbidity.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
556TiP - A phase I study of SGN-STNV, a novel antibody–drug conjugate targeting sialyl-thomsen-nouveau antigen (STn), in adults with advanced solid tumors (SGNSTNV-001)
- Nehal J. Lakhani (Grand Rapids, United States of America)
Abstract
Background
STn is a tumor-associated carbohydrate antigen with high prevalence across various solid tumor types, including ovarian and non-small cell lung cancer (NSCLC). While its expression is restricted in normal tissues, it presents with several tumor-associated proteins, such as MUC1 and MUC16. STn is thought to influence cancer progression by affecting cell adhesion, migration and propagation of invasiveness, and has been linked to advanced disease, chemotherapy resistance, and decreased survival. SGN-STNV is an investigational antibody–drug conjugate which directs monomethyl auristatin E (MMAE) to STn-expressing cells. In preclinical studies, SGN-STNV showed promising inhibition of metastatic growth and improved animal survival in STn-expressing tumor models.
Trial design
SGNSTNV-001 (NCT04665921) is a phase 1, open-label, multicenter, first-in-human study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-STNV in adults with select advanced solid tumors. Part A (dose escalation) and Part B (dose expansion) will include up to 25 and 180 patients (in up to 6 expansion cohorts), respectively. The primary endpoint is to evaluate safety and tolerability, and identify the maximum tolerated dose, recommended dose, and dosing schedule for SGN-STNV. Secondary endpoints include antitumor activity, PK and immunogenicity of SGN-STNV. In addition, biomarkers relating to response, toxicity, PK/pharmacodynamics, and resistance to SGN-STNV will be assessed. Eligible patients must be 18 years or older with advanced/refractory solid tumors in any of the following cancers: NSCLC, HER2-negative breast cancer, ovarian, cervical, endometrial, esophageal, gastric, gastroesophageal junction or colorectal cancer, appendiceal or exocrine pancreatic adenocarcinoma, or pseudomyxoma peritonei of unknown origin. Patients must have an Eastern Cooperative Oncology Group performance status score of 0 or 1 and measurable disease per RECIST version 1.1. Study accrual is ongoing in the USA, Canada, and Europe.
Clinical trial identification
NCT04665921.
Editorial acknowledgement
Medical writing support was provided by Calum Suggett, MSc, and editorial support by Travis Taylor, BA, all of Scion, London, supported by Seagen Inc.
Legal entity responsible for the study
Seagen Inc.
Funding
Seagen Inc.
Disclosure
N.J. Lakhani: Financial Interests, Personal, Other, Consultancy: Innovent Biologics; Financial Interests, Institutional, Other, Research Funding/Grants: Alexion, Alexo, Alpine Bio, Alpine Immune Sciences, Apexian, Asana, Ascentage, Astellas, BeiGene, Biologics, Celgene, Cerulean, Constellation, Coordination Therapeutics, CytomX, Epizyme, Formation, Forty-Seven, Genmab, Helsinn, Ikena, Incyte, InhibTx, Inn. I. Braña: Financial Interests, Personal, Other, Consultancy: Achilles Therapeutics, Cancer Expert Now, eTheRNA Immunotherapies, Merck Sharp & Dohme, Rakuten Medical, Sanofi; Financial Interests, Other, Research Funding/Grants: AstraZeneca, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Gliknik, Janssen, Kuro Oncology, Merck Sharp & Dohme, Nanobiotix, Novartis, Orion Pharma, Pfizer, Roche, Seagen, Shattuck Labs; Financial Interests, Speaker’s Bureau: Bristol-Myers Squibb, Merck Serono, Roche; Financial Interests, Other, Travel Expenses: AstraZeneca Spain, Merck Serono. V.K. Chiu: Financial Interests, Personal, Other, Research Funding/Grants: Alkermes, Arcus Biosciences, Incyte, Intra-IMMUSG Pte, Leap Therapeutics, Seagen/Astellas. A. Dowlati: Financial Interests, Personal, Other, Consultancy: AbbVie/Stemcentrx, AstraZeneca, Bayer, Bristol-Myers Squibb, G1 Therapeutics, Ipsen, Seagen, Takeda, Merck; Financial Interests, Institutional, Other, Research Funding/Grants: AbbVie/Stemcentrx, Amgen, Bayer, Bristol-Myers Squibb, EMD Serono, Ipsen, Lilly/ImClone, Mirati Therapeutics, Regeneron, Seagen, Symphogen, Takeda, Tesaro, United Therapeutics, Harpoon Therapeutics. S.M. McGoldrick: Financial Interests, Personal and Institutional, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal, Other, Consultancy: AbbVie and Near Future Allergan; Financial Interests, Personal, Other, Travel, accommodation and expenses: Seagen Inc.; Financial Interests, Personal and Institutional, Other, Stock and other ownership interests: Seagen Inc.; Financial Interests, Institutional, Other, Research Funding/Grants: AbbVie, Janssen and Takeda. A. Minchom: Financial Interests, Personal, Other, Consultancy: Janssen; Financial Interests, Personal, Other, Honoraria: Bayer, Chugai Pharma, Faron Pharma, Merck, Novartis; Financial Interests, Institutional, Other, Research Funding/Grants: Seagen Inc.; Financial Interests, Personal, Other, Travel Expenses: Amgen. X. Tian: Financial Interests, Personal and Institutional, Full or part-time Employment: Seagen Inc.; Financial Interests, Personal and Institutional, Other, Stock and other ownership interests: Seagen Inc.. A. Patnaik: Financial Interests, Personal, Other, Consultancy: Bayer, Bristol-Myers Squibb, Genentech/Roche, Merck, Novartis, Seagen, Silverback Therapeutics; Financial Interests, Personal, Other, Honoraria: Texas Society of Clinical Oncology (TxSCO); Financial Interests, Institutional, Other, Research Funding/Grants: AbbVie, Arcus Ventures, Astellas Pharma, Bolt Biotherapeutics, Corvus, Daiichi Sankyo, Exelixis, Five Prime Therapeutics, Fochon Pharmaceuticals, Forty Seven, Infinity Pharmaceuticals, Ionova, Klus Pharma, Lilly, Livzon, Merck, Pfizer, Pieris Pharmaceutic. All other authors have declared no conflicts of interest.
525P - Efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) data from phase I dose escalation of a novel therapeutic peptide, ST101, targeting the oncogenic transcription factor C/EBPβ, in patients (pts) with advanced and metastatic solid tumors
- Meredith A. Mckean (Nashville, United States of America)
Abstract
Background
The oncogenic transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) promotes tumor survival and proliferation, while inhibiting differentiation. ST101 is a small peptide antagonist of C/EBPβ, with anti-tumor activity in glioblastoma (GBM), breast, prostate cancer (PC), melanoma and other models.
Methods
We conducted the phase 1 portion of a phase 1-2 study in pts with refractory solid tumors. The primary objective was to evaluate safety/tolerability of ST101. Secondary and exploratory objectives included PK, preliminary efficacy and PD from serial biopsies. The study used a 3+3 design, dosing ST101 IV at 0.5, 1, 2, 4, and 6 mg/kg weekly (QW). Phase 2 will include 4 cohorts of pts with specific cancers: breast, melanoma, GBM and castrate-resistant PC.
Results
As of May 2021, 15 pts were enrolled and the last cohort underway. Pts received a median of 6 weeks’ treatment (range 2 – 39). There were no DLTs, dose modifications or SAEs related to ST101. The only AEs of note were G1-2 histaminergic infusion-related reactions (IRRs), largely pruritis and urticaria, managed with antihistamines and interruption/slowing of infusion. IRRs affected 100% pts on 1st dose at ≥4mg/kg. Intensity and frequency of IRRs decreased with repeat dosing. No other AEs were consistently reported. PK was dose-proportionate, with continued exposure pre-dose QW, no evidence of accumulation and no anti-drug antibodies. Tumor immunohistochemistry showed dose-proportionate staining for ST101 and an inverse relationship with Ki67, suggesting decreasing tumor proliferation with increasing dose. There was 1 partial response in a pt with multi-metastatic cutaneous melanoma refractory to all standard therapy (confirmation pending) and 3 pts with varied histologies had stable disease lasting 18-39 weeks (1 ongoing).
Conclusions
ST101 demonstrated safety at all doses explored and evidence of efficacy across dose levels, particularly higher doses. PK and PD support a dose relationship for efficacy and selection of a QW dose to open phase 2 expansion cohorts by September 2021.
Clinical trial identification
ST101-101 (NCT04478279).
Legal entity responsible for the study
Sapience Therapeutics.
Funding
Sapience Therapeutics.
Disclosure
M.A. Mckean: Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Medpage Today; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Epizyme; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: GSK; Financial Interests, Institutional, Research Grant: Infinity; Financial Interests, Institutional, Research Grant: Jacobio; Financial Interests, Institutional, Research Grant: Moderna; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Tizona; Financial Interests, Institutional, Research Grant: Topalliance Biosciences; Financial Interests, Institutional, Research Grant: Prelude; Financial Interests, Institutional, Research Grant: Ascentage; Financial Interests, Institutional, Research Grant: Ideaya; Financial Interests, Institutional, Research Grant: Oncorus; Financial Interests, Institutional, Research Grant: Ikena; Financial Interests, Institutional, Research Grant: Tmunity; Financial Interests, Personal, Principal Investigator: Sapience Therapeutics. N.J. Lakhani: Financial Interests, Institutional, Sponsor/Funding: Beigene; Financial Interests, Personal, Advisory Role: Innovent; Financial Interests, Institutional, Sponsor/Funding: Innovent; Financial Interests, Institutional, Sponsor/Funding: ALX; Financial Interests, Institutional, Sponsor/Funding: Ascentage; Financial Interests, Institutional, Sponsor/Funding: Asana; Financial Interests, Institutional, Sponsor/Funding: Cpnstellation; Financial Interests, Institutional, Sponsor/Funding: alexion; Financial Interests, Institutional, Sponsor/Funding: cerulean; Financial Interests, Institutional, Sponsor/Funding: Forty Seven; Financial Interests, Institutional, Sponsor/Funding: Alpine; Financial Interests, Institutional, Sponsor/Funding: Merck; Financial Interests, Institutional, Sponsor/Funding: Pfizer; Financial Interests, Institutional, Sponsor/Funding: Regeneron; Financial Interests, Institutional, Sponsor/Funding: TaiRx; Financial Interests, Institutional, Sponsor/Funding: Apexian; Financial Interests, Institutional, Sponsor/Funding: Formation biologics; Financial Interests, Institutional, Sponsor/Funding: Symphogen; Financial Interests, Institutional, Sponsor/Funding: CytomX; Financial Interests, Institutional, Sponsor/Funding: InhibRx; Financial Interests, Institutional, Sponsor/Funding: Incyte; Financial Interests, Institutional, Sponsor/Funding: Jounce; Financial Interests, Institutional, Sponsor/Funding: Lizvon; Financial Interests, Institutional, Sponsor/Funding: Northern Biologics; Financial Interests, Institutional, Sponsor/Funding: Ikena; Financial Interests, Institutional, Sponsor/Funding: Mersana; Financial Interests, Institutional, Sponsor/Funding: Odonate; Financial Interests, Institutional, Sponsor/Funding: Loxo; Financial Interests, Institutional, Sponsor/Funding: Alpine; Financial Interests, Institutional, Sponsor/Funding: Macrogenics; Financial Interests, Personal, Principal Investigator: Sapience Therapeutics. H. Arkenau: Financial Interests, Personal, Principal Investigator: Sapience Therapeutics. S. Symeonides: Financial Interests, Institutional, Training: Ipsen; Financial Interests, Institutional, Advisory Role: BMS; Financial Interests, Institutional, Advisory Role: Ellipses; Financial Interests, Institutional, Advisory Role: Vaccitech; Financial Interests, Institutional, Advisory Role: MedAnnex; Financial Interests, Institutional, Advisory Role: EUSA; Financial Interests, Institutional, Advisory Role: EISAI; Financial Interests, Institutional, Advisory Role: Merck; Financial Interests, Institutional, Advisory Role: EMD Serono; Financial Interests, Institutional, Advisory Role: Pfizer; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Verastem; Financial Interests, Personal, Principal Investigator: BioLineRx; Financial Interests, Personal, Principal Investigator: BioNTech; Financial Interests, Personal, Principal Investigator: Boston; Financial Interests, Personal, Principal Investigator: MSD; Financial Interests, Personal, Principal Investigator: Nouscom; Financial Interests, Personal, Principal Investigator: Sierra Oncology; Financial Interests, Personal, Principal Investigator: Verastem; Financial Interests, Personal, Principal Investigator: Sapience Therapeutics. T.R..J. Evans: Financial Interests, Institutional, Principal Investigator: Sapience Therapeutics. E.A. Lim: Financial Interests, Personal, Principal Investigator: Sapience Therapeutics; Financial Interests, Personal, Stocks/Shares: Pfizer; Financial Interests, Personal, Other, Travel, accomodations, expenses: BMS. S.R. Chandana: Financial Interests, Personal, Advisory Role: Heron; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: J&J; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Advisory Role: Array; Financial Interests, Personal, Advisory Role: Deciphera; Financial Interests, Personal, Research Grant: Abbvie; Financial Interests, Institutional, Research Grant: Alexion; Financial Interests, Institutional, Research Grant: Alexo; Financial Interests, Institutional, Research Grant: Arqule; Financial Interests, Institutional, Research Grant: Asana; Financial Interests, Institutional, Research Grant: Ascentage; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: Cerulean; Financial Interests, Institutional, Research Grant: Constellation; Financial Interests, Institutional, Research Grant: DSI; Financial Interests, Institutional, Research Grant: Dicerna; Financial Interests, Institutional, Research Grant: Formation Biologics; Financial Interests, Institutional, Research Grant: Forty Seven; Financial Interests, Institutional, Research Grant: Lizvon; Financial Interests, Institutional, Research Grant: Loxo; Financial Interests, Institutional, Research Grant: Macrogenics; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Regeneron; Financial Interests, Institutional, Research Grant: Symphony evolution; Financial Interests, Institutional, Research Grant: TaiRx. J. Rotolo: Financial Interests, Personal, Full or part-time Employment: Sapience Therapeutics. G. Capiaux: Financial Interests, Personal, Advisory Role: Sapience Therapeutics. R. Michel: Financial Interests, Personal, Advisory Role: Sapience Therapeutics. S. Kaesshaefer: Financial Interests, Personal, Advisory Role: Sapience Therapeutics. A. Bexon: Financial Interests, Personal, Officer: Sapience Therapeutics; Financial Interests, Personal, Officer: Vyriad; Financial Interests, Personal, Officer: Bexon Clinical Consulting. G.S. Falchook: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Advisory Role: Fujifilm; Financial Interests, Institutional, Advisory Role: Silicon; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Other, Travel: BMS; Financial Interests, Personal, Other, Travel: EMD Serono; Financial Interests, Personal, Other, Travel: Fujifilm; Financial Interests, Personal, Other, Travel: Millenium; Financial Interests, Personal, Other, Travel: SCRI; Financial Interests, Personal, Invited Speaker: Total Health Conferencing; Financial Interests, Personal, Invited Speaker: Rocky Mountain Oncology Society; Financial Interests, Institutional, Principal Investigator: 70 other biotechs and pharma companies. All other authors have declared no conflicts of interest.
544P - A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) exerts significant anti-tumor effects through tumor-directed T cell activation
- Eunjung Lee (Yongin, Korea, Republic of)
Abstract
Background
HER2-directed therapies have improved clinical outcomes for solid cancer patients with HER2 overexpression. Despite this success, it still remains a challenge to cure the HER2 positive cancer patients with resistance to current HER2-directed therapy. Therefore, effective HER2-directed therapy needs to be developed for them, and one approach would be to combine with immunotherapy. 4-1BB (TNFSF9, CD137) is a member of the tumor necrosis factor receptor superfamily that functions as a potent co-stimulator to immune cells, especially on primed T and NK cells in tumors.
Methods
We have developed a bispecific antibody (BsAb) which induce tumor-directed T cell activation to overcome the challenges with HER2 resistance. Its activity was determined using cell-based 4-1BB bioassay and co-culture assay with human peripheral blood mononuclear cells (hPBMC). Also,
Results
A novel HER2/4-1BB BsAb, YH32367 simultaneously targets human epidermal growth factor receptor 2 (HER2) and h4-1BB and binds to both targets. YH32367 exhibited a strong 4-1BB signal activation in HER2-expressing tumor cells such as NCI-N87, JIMT-1 and HCC1954 cells. YH32367 stimulated IFN-γ secretion and thereby inducing tumor cells lysis in co-culture assay with hPBMC and HER2-expressing tumor cells. YH32367 also showed superior efficacies on immune cells activation as well as tumor growth inhibition in both HER2-expressing tumor-bearing hPBMC humanized mice and h4-1BB knock-in mice models compared to the equimolar dosing of trastuzumab and benchmark 4-1BB agonistic antibodies. In particular, even a single dosing of YH32367 at doses of 1, 3 and 10 mg/kg elicited complete tumor regression in most tumors of MC38/hHER2-bearing h4-1BB knock-in mice
Conclusions
In conclusion, YH32367 exhibited potent
Legal entity responsible for the study
Yuhan Corporation.
Funding
Has not received any funding.
Disclosure
E. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. H. Chung: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. Y. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. E. Lee: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. Y.B. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. Y. Kim: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. J.Y. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. S. Ahn: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. J. Kim: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. K.K. Ahn: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm. K. Park: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. W. Son: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. D. Yeom: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. J. Jung: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. J. Won: Financial Interests, Personal and Institutional, Full or part-time Employment: ABL bio Inc. S. Oh: Financial Interests, Personal and Institutional, Full or part-time Employment: Yuhan coporatopm.
565TiP - A phase I/II dose-escalation and expansion study of ZN-c5, an oral selective estrogen receptor degrader (SERD), as monotherapy and in combination with palbociclib in patients with advanced estrogen receptor (ER)+/HER2- breast cancer
- Vandana Abramson (Nashville, TN, United States of America)
Abstract
Background
Most patients with ER+/HER2- breast cancer are diagnosed at an early stage, receive adjuvant endocrine therapy (ET), and have a good prognosis. However, a subset relapses while on or after adjuvant ET and are placed on first-line ET. After initially responding, they however will progress. These patients account for the majority of breast cancer-related deaths. Fulvestrant, currently the only approved drug that binds and selectively degrades the ER, shows significant anti-tumor activity following ET failure. While effective, it is limited by its poor pharmacological properties, with administration via intramuscular injection leading to sub-optimal exposure and injection-related adverse events such as pain and ecchymosis; in addition, caution is advised when treating patients with bleeding disorders, thrombocytopenia or receiving anticoagulants. ZN-c5 is a novel and potentially potent SERD with oral bioavailability, which demonstrated activity in estrogen-dependent tumor models. Combination therapy of fulvestrant or letrozole with palbociclib, a CDK4/6 inhibitor, significantly improved progression-free survival compared to ET alone in phase 3 trials.
Trial design
This phase 1/2, open-label, multicenter study is evaluating the safety, pharmacokinetics, and anti-tumor activity of ZN-c5 alone and in combination with palbociclib. The primary objectives are to determine maximum tolerated doses and recommended phase 2 doses by standard 3+3 dose escalation in phase 1 and preliminary anti-tumor efficacy in phase 2. Subjects are adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) with advanced and incurable adenocarcinoma of the breast, ER+/HER2- disease, and appropriate protocol-specified prior therapy. ZN-c5 is taken orally once or twice daily until disease progression or unacceptable toxicity. Palbociclib is administered per the approved dosing schedule. Biomarkers and pharmacodynamic effects of therapy will be explored. Subject recruitment is ongoing.
Clinical trial identification
NCT03560531.
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
V. Abramson: Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Genentech; Financial Interests, Institutional, Research Grant: Eli Lilly; Non-Financial Interests, Personal, Member: ASCO. H.M. Linden: Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: Sanofi; Financial Interests, Institutional, Research Grant: Eisai. J. Mortimer: Financial Interests, Personal, Invited Speaker: Puma; Financial Interests, Personal, Invited Speaker: Mesoblast; Financial Interests, Personal, Invited Speaker: GlaxoSmithKline; Financial Interests, Personal, Invited Speaker: Incyte; Financial Interests, Personal, Invited Speaker: Novartis. J. Nangia: Financial Interests, Institutional, Research Grant: Paxman Coolers Ltd. R. Layman: Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Institutional, Research Grant: Zentalis; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Celcuity. J. Suarez: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Suster: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Ptaszynski: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. P. Chalasani: Financial Interests, Personal, Advisory Board: Zentalis Parmaceuticals; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer. All other authors have declared no conflicts of interest.
526P - Pharmacodynamic evidence for WEE1 target engagement in surrogate and tumor tissues from a phase I study of the WEE1 inhibitor ZN-c3
- Pavani Chalasani (Tucson, United States of America)
Abstract
Background
WEE1 tyrosine kinase is a critical component of the G2/M cell cycle checkpoint that phosphorylates CDK1 (p-CDK1), inducing cell cycle arrest in the presence of DNA damage to allow for DNA repair. Inhibition of WEE1 can induce mitotic catastrophe and apoptosis. ZN-c3 is a novel, selective inhibitor of WEE1 being evaluated in a phase 1 trial in patients with advanced solid tumors. Nonclinical and clinical pharmacodynamic (PD) and pharmacokinetic (PK) data are presented.
Methods
Biomarker assays using immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) tissues were developed for p-CDK1, the DNA damage marker γH2AX, and the proliferation marker Ki67. A xenograft model of non-small cell lung cancer (A427) was used for preclinical PD studies. In humans, skin punch biopsies were obtained at baseline and after 15 days of treatment and tumor tissue biopsies were obtained at baseline and after 22 days of treatment.
Results
Anti-p-CDK1 antibodies were tested across a variety of FFPE normal and cancer tissues to evaluate their selectivity, specificity, and accuracy and a monoclonal antibody (10A11, CST) was selected for this biomarker assay. Tumor-bearing mice treated with ZN-c3 (80 mg/kg QD x 3) showed significant inhibition of p-CDK1 in tumors. In the phase 1 trial, skin punch biopsies (baseline and on-treatment) were obtained from 23 patients treated at the recommended phase 2 dose (RP2D) of 300 mg QD or higher; 18/23 patients (78.3%) showed target engagement (≥50% decrease in p-CDK1 levels), including 4/4 patients (100%) with confirmed radiographic partial responses following ZN-c3 treatment. The plasma levels of ZN-c3 and p-CDK1 inhibition in skin punch biopsies showed a clear correlation between drug exposure and WEE1 inhibition. Paired tumor tissue biopsies were obtained from 4 patients; evidence for WEE1 pathway modulation (decreased p-CDK1, increased γH2AX, or Ki67) was observed for 2/3 patients (66.7%) dosed at the RP2D or higher.
Conclusions
Target engagement by the WEE1 inhibitor ZN-c3 was demonstrated in skin and tumor tissue biopsies from patients treated at the RP2D or higher in a phase 1 trial. PK/PD analysis confirmed a correlation between ZN-c3 plasma levels and WEE1 pathway modulation.
Clinical trial identification
NCT04158336.
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
P. Chalasani: Financial Interests, Personal, Advisory Board: Zentalis Parmaceuticals; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Oncosec; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer. A. Tolcher: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Agenus; Financial Interests, Personal, Advisory Role: Asana Biosciences; Financial Interests, Personal, Advisory Role: Ascentage; Financial Interests, Personal, Advisory Role: AxImmune; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Gilde Healthcare Partners; Financial Interests, Personal, Advisory Role: HBM Partners; Financial Interests, Personal, Advisory Role: Immunomet Therapeutics; Financial Interests, Personal, Advisory Role: Karma Oncology; Financial Interests, Personal, Advisory Role: Mekanistic Therapeutics; Financial Interests, Personal, Advisory Role: Menarini Ricerche; Financial Interests, Personal, Advisory Role: Nanobiotix; Financial Interests, Personal, Advisory Role: Partner Therapeutics; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Ryvu Therapeutics; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Sotio Biotechnoogy; Financial Interests, Personal, Advisory Role: Spirea Limited; Financial Interests, Personal, Advisory Role: Transcenta Therapeutics; Financial Interests, Personal, Advisory Role: Trillium Therapeutics; Financial Interests, Personal, Advisory Board: Adagene; Financial Interests, Personal, Advisory Board: Aro Biotherapeutics; Financial Interests, Personal, Advisory Board: Bioinvent; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Deka Biosciences; Financial Interests, Personal, Advisory Board: Eleven Bio; Financial Interests, Personal, Advisory Board: Elucida; Financial Interests, Personal, Advisory Board: EMD Serono; Financial Interests, Personal, Advisory Board: Immunome; Financial Interests, Personal, Advisory Board: NME Therapeutics; Financial Interests, Personal, Advisory Board: Pelican; Financial Interests, Personal, Advisory Board: Pieris Pharma; Financial Interests, Personal, Advisory Board: Pyxis Oncology; Financial Interests, Personal, Advisory Board: Vincerx; Financial Interests, Personal, Advisory Board: Zymeworks Biopharmaceuticals; Financial Interests, Personal, Other, IDMC: Mirati; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Personal, Stocks/Shares: Pyxis Oncology; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: ABL Bio; Financial Interests, Institutional, Principal Investigator: ADC Therapeutics; Financial Interests, Institutional, Principal Investigator: Agenus; Financial Interests, Institutional, Principal Investigator: Aminex Therapeutics; Financial Interests, Institutional, Principal Investigator: Amphivena Therapeutics; Financial Interests, Institutional, Principal Investigator: Apros Therapeutics; Financial Interests, Institutional, Principal Investigator: Arcellx; Financial Interests, Institutional, Principal Investigator: ARMO Biosciences; Financial Interests, Institutional, Principal Investigator: Arrys Therapeutics; Financial Interests, Institutional, Principal Investigator: Artios Pharma Limited; Financial Interests, Institutional, Principal Investigator: Asana BioSciences; Financial Interests, Institutional, Principal Investigator: Ascentage; Financial Interests, Institutional, Principal Investigator: Astex Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Basilea Pharmaceutica; Financial Interests, Institutional, Principal Investigator: BioInvent; Financial Interests, Institutional, Principal Investigator: BioNTech RNA Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Birdie Biopharmaceuticals; Financial Interests, Institutional, Principal Investigator: BJ Bioscience; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Boston Biomedical; Financial Interests, Institutional, Principal Investigator: Calgent Biotechnology; Financial Interests, Institutional, Principal Investigator: Codiak BioSciences; Financial Interests, Institutional, Principal Investigator: CStone Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Cybrexa Therapeutics; Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: Deciphera Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: eFFECTOR Therapeutics; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: EMD Serono; Financial Interests, Institutional, Principal Investigator: Gilead Sciences; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Principal Investigator: Haihe Biopharma; Financial Interests, Institutional, Principal Investigator: Heat Biologics; Financial Interests, Institutional, Principal Investigator: IDEAYA Biosciences; Financial Interests, Institutional, Principal Investigator: ImmuneOncia Therapeutics; Financial Interests, Institutional, Principal Investigator: IMPACT Therapeutics; Financial Interests, Institutional, Principal Investigator: Inhibrx; Financial Interests, Institutional, Principal Investigator: Innate Pharma; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: K-Group Beta; Financial Interests, Institutional, Principal Investigator: KeChow Pharma; Financial Interests, Institutional, Principal Investigator: Kiromic Biopharma; Financial Interests, Institutional, Principal Investigator: Mabspace Biosciences; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: Mersana Therapeutics; Financial Interests, Institutional, Principal Investigator: Mirati Therapeutics; Financial Interests, Institutional, Principal Investigator: NatureWise Biotech & Medicals; Financial Interests, Institutional, Principal Investigator: Navire Pharma; Financial Interests, Institutional, Principal Investigator: NBE-Therapeutics; Financial Interests, Institutional, Principal Investigator: NextCure; Financial Interests, Institutional, Principal Investigator: Nitto BioPharma; Financial Interests, Institutional, Principal Investigator: Odonate Therapeutics; Financial Interests, Institutional, Principal Investigator: ORIC Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Pelican Therapeutics; Financial Interests, Institutional, Principal Investigator: Petra Pharma; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Pieris Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: PMV Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Qilu Puget Sound Biotherapeutics; Financial Interests, Institutional, Principal Investigator: Samumed; Financial Interests, Institutional, Principal Investigator: Seattle Genetics; Financial Interests, Institutional, Principal Investigator: Spring Bank Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Sunshine Guojian Pharmaceutical; Financial Interests, Institutional, Principal Investigator: Symphogen; Financial Interests, Institutional, Principal Investigator: Syndax Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: Synthorx; Financial Interests, Institutional, Principal Investigator: Takeda; Financial Interests, Institutional, Principal Investigator: Tizona Therapeutics; Financial Interests, Institutional, Principal Investigator: Zymeworks.F. Meric-Bernstam: Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Aduro BioTech Inc.; Financial Interests, Personal, Advisory Role: Alkermes; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: DebioPharm; Financial Interests, Personal, Advisory Role: eFFECTOR Therapeutics; Financial Interests, Personal, Advisory Role: F. Hoffman-La Roche Ltd.; Financial Interests, Personal, Advisory Role: Genentech Inc.; Financial Interests, Personal, Advisory Role: IBM Watson; Financial Interests, Personal, Advisory Role: Infinity Pharmaceuticals; Financial Interests, Personal, Advisory Role: Jackson Laboratory; Financial Interests, Personal, Advisory Role: Kolon Life Science; Financial Interests, Personal, Advisory Role: OrigiMed; Financial Interests, Personal, Advisory Role: PACT Pharma; Financial Interests, Personal, Advisory Role: Parexel International; Financial Interests, Personal, Advisory Role: Pfizer Inc.; Financial Interests, Personal, Advisory Role: Samsung Bioepis; Financial Interests, Personal, Advisory Role: Seattle Genetics Inc.; Financial Interests, Personal, Advisory Role: Tyra Biosciences; Financial Interests, Personal, Advisory Role: Xencor; Financial Interests, Personal, Advisory Role: Zymeworks; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Advisory Board: Inflection Biosciences; Financial Interests, Personal, Advisory Board: Mersana Therapeutics; Financial Interests, Personal, Advisory Board: Puma Biotechnology Inc.; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Silverback Therapeutics; Financial Interests, Personal, Advisory Board: Spectrum Pharmaceuticals; Financial Interests, Personal, Advisory Board: Zentalis Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Chugai Biopharmaceuticals; Financial Interests, Personal, Full or part-time Employment: MD Anderson Cancer Center; Non-Financial Interests, Institutional, Principal Investigator: Aileron Therapeutics, Inc; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca; Non-Financial Interests, Institutional, Principal Investigator: Bayer Healthcare Pharmaceutical; Non-Financial Interests, Institutional, Principal Investigator: Calithera Biosciences Inc.; Non-Financial Interests, Institutional, Principal Investigator: Curis Inc.; Non-Financial Interests, Institutional, Principal Investigator: CytomX Therapeutics Inc.; Non-Financial Interests, Institutional, Principal Investigator: Daiichi Sankyo Co. Ltd.; Non-Financial Interests, Institutional, Principal Investigator: Debiopharm International; Non-Financial Interests, Institutional, Principal Investigator: eFFECTOR Therapeutics; Non-Financial Interests, Institutional, Principal Investigator: Genentech Inc.; Non-Financial Interests, Institutional, Principal Investigator: Guardant Health Inc.; Non-Financial Interests, Institutional, Principal Investigator: Klus Pharma; Non-Financial Interests, Institutional, Research Grant: Takeda Pharmaceutical; Non-Financial Interests, Institutional, Principal Investigator: Novartis; Non-Financial Interests, Institutional, Research Grant: Puma Biotechnology Inc.; Non-Financial Interests, Institutional, Principal Investigator: Taiho Pharmaceutical Co..H. Mamdani: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. P.R. de Jong: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. K. Anderes: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. A.A. Samatar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Sergeeva: Financial Interests, Personal, Advisory Role: Zentalis Parmaceuticals. M. Gazdoiu: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M.R. Viana: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. P. Pultar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. D. Voliotis: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. F. Donate: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals.
548P - Phase I study of oral GZ17-6.02 in patients with advanced solid tumors or lymphoma
- Alain Mita (Los Angeles, CA, United States of America)
Abstract
Background
Botanical molecules, such as curcumin, have been extensively studied as a potential anti-cancer therapeutics. Research has recently identified a combination of three synthetically manufactured natural molecules for clinical study in oncology. An optimized ratio of isovanillin, harmine, and curcumin has shown preclinical evidence of in-vitro and in-vivo activity with evidence of super enhancer modulation providing rationale for clinical study.
Methods
Phase I, multicenter, open-label, dose-escalation, safety, pharmacodynamic and pharmacokinetic study of GZ17-6.02 given orally on a daily x 28 day of schedule in patients with advanced solid tumors or lymphoma. The dose escalation followed a standard 3+3 design. Thirty-six patients have accrued to the study, 24 in the dose escalation phase and 12 in the dose expansion phase at the recommended phase two dose (RP2D) of 375mg bid.
Results
GZ17-6.02 has demonstrated to be generally well tolerated with an acceptable safety profile. Grade 3/4 transaminitis was observed in 6 out of 32 evaluable patients and was the dose limiting toxicity. Transaminitis was readily reversible upon discontinuation, no elevations of bilirubin were observed and 3 of the 6 cases of elevated transaminitis occurred above the RP2D. Grade 3/4 dizziness was observed in one patient. Two patients contracted COVID-19 while on study, though no dose interruptions or modifications were necessary. An investigator assessed partial response was reported in a patient with EGFR mutated Non-Small Cell Lung Cancer. Stable disease was observed in six additional patients at various dose levels within the study. Additional evidence of radiological tumor regression was also observed. Clinical benefit was observed in seven patients as assessed by investigators.
Conclusions
GZ17-6.02 was biologically active and demonstrated an acceptable and manageable safety profile in a heavily pretreated patient population with various malignancies. This phase 1 data provides rational for further investigation in a phase 2 setting to determine GZ17-6.02’s safety and potential efficacy in defined patient populations, both as monotherapy and in combination with other therapeutics.
Clinical trial identification
NCT03775525
Legal entity responsible for the study
Genzada Pharmaceuticals USA, Inc.
Funding
Genzada Pharmaceuticals USA, Inc.
Disclosure
R.P. Moore: Financial Interests, Personal and Institutional, Member: Genzada Pharmaceuticals. J. Bailes: Financial Interests, Personal and Institutional, Member: Genzada Pharmaceuticals. All other authors have declared no conflicts of interest.
564TiP - A phase Ib dose-escalation study of ZN-c5, an oral selective estrogen receptor degrader (SERD), in combination with abemaciclib in patients with advanced estrogen receptor (ER)+/HER2- breast cancer
- George P. Keogh (Charleston SC, AL, United States of America)
Abstract
Background
Hormone receptor+/HER2- breast cancer is the most common subset of breast cancer. Despite the availability of first-line endocrine therapy, one-third of patients diagnosed with early-stage disease experience disease recurrence. Resistance to endocrine therapy is a major clinical challenge. Although fulvestrant binds and degrades the ER and shows anti-tumor activity in this population, intramuscular injection is inconvenient, associated with injection-site reactions, and precludes achievement of higher and potentially more efficacious exposures. Combinations of a SERD with CDK4/6 inhibitors like abemaciclib have demonstrated efficacy in large, randomized trials in women with advanced ER+/HER2- breast cancer after endocrine therapy failure. ZN-c5 is a novel, potentially potent, orally bioavailable SERD with demonstrated activity in estrogen-dependent tumor models and a well-tolerated clinical safety profile.
Trial design
This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, and preliminary anti-tumor activity of ZN-c5 in combination with abemaciclib. The primary objective is to determine the maximum tolerated dose and recommended phase 2 dose. Subjects are adult, post-menopausal (or receiving a gonadotropin-releasing hormone agonist) women with advanced adenocarcinoma of the breast and ER+/HER2- disease; they may have received 1 prior hormonal-based therapy but no prior chemotherapy or CDK4/6 inhibitors. Study drug treatment is administered orally and continuously in repeated 28-day cycles until disease progression or unacceptable toxicity. In Cycle 1, subjects receive abemaciclib as of Day 1 and ZN-c5 as of Day 8. In subsequent cycles, both study drugs are taken as of Day 1. Cohorts of subjects are being sequentially enrolled at several dose levels of ZN-c5, based on a modified 3+3 design; the initial dose level of 50 mg was well tolerated in the first-in-human study of ZN-c5. For all cohorts, the dose of abemaciclib is 150 mg BID. Correlations between biomarkers and clinical outcomes will be explored. Subject recruitment is ongoing.
Clinical trial identification
NCT04514159.
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
G.P. Keogh: Non-Financial Interests, Personal, Member: ASCO. B. Jackson: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Suster: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. M. Ptaszynski: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. All other authors have declared no conflicts of interest.
562TiP - A phase Ib dose-escalation study of ZN-c3, a WEE1 inhibitor, in combination with chemotherapy in patients with platinum-resistant or -refractory ovarian, peritoneal, or fallopian tube cancer
- Siqing Fu (Houston, TX, United States of America)
Abstract
Background
Ovarian, peritoneal, and fallopian tube cancer are deadly diseases with similar pathological and clinical features. Despite initial therapy with cytoreductive surgery and platinum-based therapy, many patients experience disease relapse either during (refractory) or within 6 months after (resistant) first-line platinum-based therapy. In these patients, various chemotherapies offer clinical activity but none is universally preferred. WEE1 tyrosine kinase is a critical component of G2/M cell cycle checkpoint control and mediates cell cycle arrest by regulating the phosphorylation of cyclin-dependent kinase 1 (CDK1). Inhibition of WEE1 leads to premature mitotic entry, DNA damage and apoptosis induction, and cell death. ZN-c3 is a novel, selective, and orally bioavailable WEE1 inhibitor that has demonstrated significant antitumor activity in nonclinical in vitro and in vivo models. A first-in-human study identified the maximum tolerated dose (MTD) of ZN-c3 when given as monotherapy. Combining ZN-c3 with chemotherapy may inhibit repair of chemotherapy-induced DNA damage and provide therapeutic benefit in this population.
Trial design
This phase 1b, open-label, multicenter study is evaluating the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activity of ZN-c3 in combination with pegylated liposomal doxorubicin, carboplatin, paclitaxel, or gemcitabine. The primary objectives are to determine MTDs and recommended phase 2 doses for each combination by a modified Bayesian continual reassessment method. Subjects are adult women with high-grade serous epithelial ovarian, peritoneal, or fallopian tube carcinoma who have received 1 or 2 prior chemotherapy regimens including platinum-based therapy and are refractory or resistant to platinum-based therapy. Study drug therapy is given in repeated 21- or 28-day cycles until disease progression or unacceptable toxicity. ZN-c3 is taken orally once daily. Chemotherapy is administered per protocol. Pharmacodynamic effects of therapy in tumor tissue and hair follicle samples will be explored. Subject recruitment is ongoing.
Clinical trial identification
NCT04516447
Legal entity responsible for the study
Zentalis Pharmaceuticals.
Funding
Zentalis Pharmaceuticals.
Disclosure
A. Pasic: Financial Interests, Personal, Principal Investigator: Zentalis Parmaceuticals. T. Meniawy: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Therapim Therapeutics; Financial Interests, Institutional, Research Grant: Beigene; Financial Interests, Institutional, Research Grant: Roche. P.R. de Jong: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. F. Donate: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. A.A. Samatar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. J. Rodriguez: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. P. Pultar: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. D. Voliotis: Financial Interests, Personal, Full or part-time Employment: Zentalis Parmaceuticals; Financial Interests, Personal, Stocks/Shares: Zentalis Parmaceuticals. All other authors have declared no conflicts of interest.