Phase 2, Open-Label, Randomized Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Evixapodlin Administered as 2nd Line Monotherapy in Subjects with Advanced Non-Small Cell Lung Cancer Expressing PD-L1
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 50
- 试验地点
- 22
- 主要终点
- To determine the
研究概览
简要总结
Checkpoint inhibitors targeting the programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) pathway are effective therapies across a range of immunogenic cancers. PD-1 is a receptor expressed on the surface of T cells, B cells and NK cells. One of its ligands, programmed cell death protein ligand 1 (PD-L1), is a cell surface protein found on different cell types including tumor cells. Blocking the PD-1 to PD-L1 interaction with monoclonal antibodies (mAb) results in anti-tumor response. Approved immune checkpoint inhibitors (ICIs) for cancer treatment include numerous antibodies to PD-1 and to PD-L1.
Evixapodlin is an orally bioavailable, small-molecule administered once daily that induces the homodimerization of PD-L1 and prevents binding to its receptor, PD-1. As a novel small molecule inhibitor of PD-L1, evixapodlin exhibits an on-target selectivity profile comparable with PD-L1 antibodies. The mechanism of action of evixapodlin results in potent and rapid PD-L1 occupancy on tumor cells that are expressing high levels of PD-L1 (PD-L1 high), versus on peripheral immune cells that are expressing basal levels of PD-L1 (PD-L1 low). This unique feature may translate to an improved therapeutic index in patients with PD-L1 high tumors.
Oral, small molecule PD-L1 inhibitors such as evixapodlin hold advantages over monoclonal antibodies providing an opportunity to expand access to ICI therapy for cancer patients both as monotherapy and combination therapy. Advantages include faster and more complete tumor penetration that could translate to better efficacy. The higher potency of evixapodlin on PD-L1 high tumors compared to PD-L1 low peripheral immune cells may translate to an improved therapeutic index compared to existing antibodies that saturate PD-L1 (or PD-1) irrespective of cellular expression level. The relatively short effective half-life of evixapodlin (17 hours) versus antibodies (~20 days) may translate to shorter lasting and easier-to-treat immune-related AE (irAE). Oral administration offers the potential for adjustable dosing regimens, convenience, elimination of the requirement for infusion facilities and staffing, and reduced complexity in manufacturing, transportation, storage and administration. These advantages also translate into opportunities for simplified combination therapies with other oral oncology agents.
Evixapodlin, also known as OX-4224, was previously under development by Gilead Sciences as GS-4224 and is currently being developed by OmRx Oncology, Inc.; it is supplied in the bisfumarate salt form. To provide efficacy and safety information in a tumor type highly responsive to ICI, this multicenter, open-label, randomized, Phase 2 study of evixapodlin will be conducted in subjects with advanced NSCLC expressing high tumor levels PD-L1 who progressed after first-line platinum-based chemotherapy. The planned study will enroll participants in India.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 75.00 Year(s)（—）
- 性别
- All
入选标准
- •18 to 75 years of age, inclusive at the time of signing informed consent form (ICF).
- •Voluntarily agreed to participate in this study by providing a signed, dated and ethics committee (EC) approved ICF before any protocol directed screening procedures are performed.
- •Capable of understanding and complying with protocol requirements, including daily compliance with administration of investigational medication, ability to travel to study visits and radiology appointments (in the opinion of the Investigator)
- •Regionally advanced, unresectable, histologically or cytologically documented, Stage IIIB or Stage IV NSCLC, who have recurrence or progression during or after one prior platinum containing chemotherapy regimen for advanced or metastatic disease.
- •At least one measurable non central nervous system NSCLC lesion qualifying as measurable disease per RECIST based on assessment by central radiologist
- •Tumor PD L1 high expression with one of the prespecified commercial IHC assays above the defined threshold.
- •Subjects must agree to provide a fresh biopsy sample or sufficient archival tumor tissue for Screening Period testing if (1) PD L1 expression or (2) AGA results for ALK or ROS rearrangement, EGFR mutations, are not available in the participants medical record.
- •At least 28 days must have elapsed since the last thoracic surgery and subjects should have recovered from all associated toxicities by the time of the first planned dose of study medication (Baseline C1D1).
- •The last dose of prior, systemic, anti cancer therapy must have been administered grater than or equal to 21 days prior to Baseline (C1D1), with the exception being TKIs approved for treatment of NSCLC have to be discontinued greater than or equal to 7 days prior to Baseline (C1D1).
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 at Screening and pre dose at Baseline, prior to the first dose of study medication.
- •Life expectancy greater or equal to 3 months, as assessed by Investigator (at Screening and at Baseline prior to first dose of study medication).
- •Negative serum pregnancy test for female subjects who are of childbearing potential within 14 days prior to the first dose of study drug at Baseline or be of non childbearing potential defined as postmenopausal or be surgically sterile (as documented in the medical record).
- •Female subjects of childbearing potential must agree to use protocol specified method(s) of contraception.
- •Females who are nursing must agree to permanently discontinue nursing (breastfeeding) before the first dose of evixapodlin.
- •Male subjects must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study, for 90 days following the last dose of study, and must agree to use protocol specified method(s) of contraception.
- •Subjects must have body weight 30 kg and may not present with severe weight loss (greater than 10 percent) within 6 weeks prior to randomization at Baseline Visit (based on subject self report and Investigator judgment).
排除标准
- •NSCLC diagnosis with positive AGA for ALK or ROS rearrangement, or EGFR mutations.
- •Known history of an additional malignancy likely to interfere with NSCLC treatment.
- •Toxicity from prior therapy without demonstrating sufficient recovery.
- •Prior treatment with immune modulators, including prior treatment with evixapodlin or another investigational oral checkpoint inhibitor.
- •Central nervous system (CNS) metastases that are symptomatic or require treatment and/or carcinomatous meningitis (i.e., leptomeningeal metastasis).
- •Received thoracic radiation within 3 months of Baseline (the first planned dose of study medication (C1D1)) and any concurrent or planned palliative radiotherapy.
- •Major medical conditions that might affect study participation (e.g., uncontrolled pulmonary, renal, or hepatic dysfunction, uncontrolled serious infection).
- •Impaired cardiac function, or clinically significant cardiac disease, or clinically important abnormalities in conduction or morphology of resting ECG at Screening, including: a.
- •Unstable angina b.
- •Myocardial infarction within 6 months prior to screening c.
- •New York Heart Association Class II or greater congestive heart failure d.
- •Uncontrolled hypertension e.
- •Poorly controlled arrhythmias within the last 6 months of first dose of study drug f.
- •Clinically important abnormalities in conduction defined as corrected QT interval by Fridericia method (QTcF) ≥450 msec in men, ≥470 msec in women.
- •History or evidence of interstitial lung disease including noninfectious pneumonitis, hypersensitivity pneumonitis OR a history of pneumonitis that required oral or IV steroids OR pulmonary conditions such as clinically significant sarcoidosis, silicosis, or idiopathic pulmonary fibrosis.
- •Symptomatic pleural effusion.
- •Stroke or transient ischemic attack or seizure disorder within 6 months prior to Screening.
- •Gastrointestinal (GI) or bowel conditions, surgery or symptoms that may affect drug absorption, a.
- •GI surgery within 6 weeks of Screening b.
- •GI symptoms of nausea, diarrhoea, or vomiting greater than CTCAE Grade 1 at time of Screening or at first dose of study drug or that in the opinion of the Investigator will interfere with study participation.
- •Risk factors for bowel obstruction or bowel perforation (e.g., acute diverticulitis) d.
- •Abdominal carcinomatosis
- •Active autoimmune disease such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjogren syndrome, Bells palsy, Guillain Barre syndrome, multiple sclerosis, vasculitis or glomerulonephritis.
- •Subjects with Type 1 diabetes mellitus, or Type 2 diabetes mellitus with HbA1c ≥9% at Screening
- •Inability to discontinue sulfonylureas (e.g., glipizide, glyburide), be safely switched to another hypoglycemic agent (e.g. sitagliptin or another DPP4 inhibitor) and be on stable dose for at least 14 days before Baseline (C1D1)
- •Receipt of chronic systemic steroid therapy at daily dose exceeding 10 mg/day of prednisone or equivalent within 14 days of first planned dose of study medication (C1D1).
- •Active infection requiring use of systemic antibiotic therapy for more than 7 days within 28 days of first planned dose of study medication (C1D1).
- •History of any substance use disorder or alcohol use disorder in the past 2 years, as based on the diagnostic criteria in the Diagnostic and Statistical Manual Fifth Edition
- •History of organ transplantation, including allogeneic stem cell transplantation.
- •Received a live attenuated vaccine within 28 days of first planned dose of study medication at Baseline (C1D1).
- •Acute or chronic HBV infection based on serology at Screening.
- •Hepatitis C Virus (HCV) infection based on positive anti-HCV antibody and presence of HCV RNA at Screening.
- •Concomitant use of strong cytochrome P450 (CYP)3A4 inhibitors, including but not limited to ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin or voriconazole.
- •Inability to discontinue warfarin, be safely switched to another anticoagulant (e.g., dabigatran or low molecular weight heparin), be on stable dose for at least 14 days before Baseline (C1D1) and have PT or aPTT values within therapeutic range of intended use of anticoagulants.
- •Concomitant use of herbal medication and ayurvedic preparations is prohibited due to cytochrome P450 inhibitory and liver toxicity potential.
- •Use of an investigational agent ≥28 days or 5-half-lives, whichever is greater, prior to Baseline (C1D1)
- •Any condition that, in the opinion of the Investigator, may interfere with the conduct or interpretation of the current study.
- •Absence of adequate organ function based on having central laboratory values outside the parameters defined in the protocol at Screening.
结局指标
主要结局
To determine the
时间窗: Week 96
overall response rate
时间窗: Week 96
(ORR) to evixapodlin
时间窗: Week 96
in NSCLC
时间窗: Week 96
次要结局
- To determine the(disease control rate)
- To determine overall(survival (OS) and)
- To determine the safety(of evixapodlin in)
- To characterize the(pharmacokinetic (PK))
- To evaluate the change(in circulating tumor)
研究者
Dr Kishor Khotkar
KlinEra Global Services