A Phase 1/2, Open-label, Multi-center Study of the Safety and Efficacy of KY1044 as Single Agent and in Combination With Anti-PD-L1 (Atezolizumab) in Adult Patients With Selected Advanced Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 222
- 试验地点
- 22
- 主要终点
- Phase 1: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
研究概览
简要总结
A Phase 1/2, open label, multi-center study to evaluate the safety, efficacy and tolerability of alomfilimab as single agent and in combination with anti-PD-L1 (atezolizumab) in adult patients with selected advanced malignancies, who are ineligible for or there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options in each indication and therefore will be patients for whom a clinical trial is appropriate.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥18 years (≥20 years in Taiwan)
- •Histologically documented advanced/metastatic malignancies
- •Phase 1 and Phase 2 participants with advanced/metastatic malignancies who have measurable disease (non-measurable disease is allowed only in Phase 1) as determined by RECIST 1.1 will be eligible if, according to the National Comprehensive Cancer Network (NCCN) guidelines, there are no available therapies known to confer a clinical benefit for their disease, or they have exhausted all such available options. Additionally, the following specific tumor indications will be enrolled:
- •Phase 1: Participants with advanced/metastatic malignancies, and preferred indications (non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), melanoma, cervical, esophageal, gastric, renal, pancreatic, and triple negative breast cancer)
- •Phase 2 Alomfilimab single agent: Participants with advanced/metastatic malignancies in indications in which signs of anti-tumor activity (Complete Response (CR), Partial Response (PR) or durable stable disease (SD) with tumor shrinkage that does not qualify for PR) were seen during the dose escalation of Alomfilimab as single agent
- •Phase 2 Alomfilimab in combination with atezolizumab: Participants with advanced/metastatic malignancies in the selected indications below, and/or indications which have shown promising activity in Phase 1:
- •NSCLC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease)
- •Gastric (anti-PD-(L)1 therapy naïve and pre-treated)
- •Recurrent and/or metastatic HNSCC (anti-PD-(L)1 therapy naïve and pre-treated between 1 and 2 prior lines of systemic therapy for advanced disease)
- •Esophageal (anti-PD-(L)1 therapy naïve and pre-treated)
- •Cervical (anti-PD-(L)1 therapy naïve and pre-treated)
- •Indications, in which signs of anti-tumor activity has been observed in Phase 1 with Alomfilimab in combination with atezolizumab
- •Prior therapy with anti-PD-(L)1 inhibitors is allowed provided any toxicity attributed to prior anti-PD-(L)1-directed therapy did not lead to discontinuation of therapy
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
- •Life expectancy longer than 12 weeks
- •Must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating institution's guidelines. Participants must be willing to undergo a new tumor biopsy at screening, and during therapy on the study
排除标准
- •Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases that require local CNS-directed therapy, or increasing doses of corticosteroids within the prior 2 weeks of first dose of study treatment
- •History of severe hypersensitivity reactions to other monoclonal antibodies and/or their excipients
- •Known presence of neutralizing anti-atezolizumab antibodies (for patients previously treated with atezolizumab)
- •Having out of range laboratory values: creatinine, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), absolute neutrophil count (ANC), platelet count, hemoglobin
- •Impaired cardiac function or clinically significant cardiac disease, including any of the following:
- •Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association [NYHA] Grade ≥2), uncontrolled hypertension or clinically significant arrhythmia
- •QTcF >470 msec on screening (electrocardiogram) ECG using Fridericia's formula (QTcF) or congenital long QT syndrome
- •Acute myocardial infarction or unstable angina pectoris
- •Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection
- •Malignant disease, other than that being treated in this study
- •Any medical condition that would, in the Investigator's judgment, prevent participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
- •Active autoimmune disease or a documented history of autoimmune disease
- •Participants previously exposed to anti-PD-(L)1 treatment who are not adequately treated for skin rash or had no replacement therapy for endocrinopathies should be excluded
- •Participants with a history of drug-induced pneumonitis or current pneumonitis
- •Systemic steroid therapy or any immunosuppressive therapy. Topical, inhaled, nasal, and ophthalmic steroids are not prohibited
- •Use of live attenuated vaccines against infectious diseases within 4 weeks of the first dose of study treatment. SARS-CoV-2 vaccines authorized for use by the competent local regulatory health authorities for active immunization to prevent COVID 19 are allowed (unless the vaccine is live or live attenuated) and must be given in accordance with the prevailing immunization guidelines.
- •Anti-CTLA4, anti-PD-(L)1 treatment within 4 weeks of the first dose of study treatment
- •Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathway
- •Presence of Common Terminology Criteria for Adverse Events version 5 (CTCAE v5) ≥Grade 2 toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if CTCAE v5 ≥Grade 3) due to prior cancer therapy
- •Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass. To allow evaluation for response to treatment, participants enrolled in the Phase 2 part must have remaining measurable disease that has not been irradiated
- •Pregnant or lactating women
研究组 & 干预措施
Phase 1: Alomfilimab Monotherapy
Participants will receive alomfilimab 0.8 to 240 mg as a single agent via intravenous (IV) infusion every 3 weeks (Q3W).
干预措施: Alomfilimab (Drug)
Phase 1: Alomfilimab + Atezolizumab Combination Therapy
Participants will receive alomfilimab 2.4 to 80 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Alomfilimab (Drug)
Phase 1: Alomfilimab + Atezolizumab Combination Therapy
Participants will receive alomfilimab 2.4 to 80 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Atezolizumab (Drug)
Phase 2: Alomfilimab + Atezolizumab in Anti-PD-(L)1 Naïve Participants
Anti-PD-(L)1 naïve participants with pancreatic cancer, triple negative breast cancer (BC) or head and neck squamous cell carcinoma (HNSCC) will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Alomfilimab (Drug)
Phase 2: Alomfilimab + Atezolizumab in Anti-PD-(L)1 Naïve Participants
Anti-PD-(L)1 naïve participants with pancreatic cancer, triple negative breast cancer (BC) or head and neck squamous cell carcinoma (HNSCC) will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Atezolizumab (Drug)
Phase 2: Alomfilimab + Atezolizumab in Pre-treated Participants
Pre-treated participants with pancreatic cancer, triple negative BC or HNSCC will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Alomfilimab (Drug)
Phase 2: Alomfilimab + Atezolizumab in Pre-treated Participants
Pre-treated participants with pancreatic cancer, triple negative BC or HNSCC will receive alomfilimab 2.4 to 24 mg in combination with atezolizumab 1200 mg via IV infusion Q3W.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Phase 1: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
时间窗: From first dose of study treatment (Day 1) up to 21 days
A DLT was defined as a clinically relevant AE or abnormal laboratory value of Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) ≥ Grade 3 assessed as unrelated to disease, PD, inter-current illness or concomitant medications, which occurs within the first cycle (21 days) of treatment with alomfilimab as single agent or in combination with atezolizumab during the dose escalation part of the study.
Phase 2: Overall Response Rate (ORR) Per RECIST 1.1
时间窗: From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 162 weeks
ORR was the percentage of participants with a measurable disease at baseline and with a confirmed response of complete response (CR) or partial response (PR) according to RECIST v1.1 as the best response. The response is confirmed by a later scan conducted at least 4 weeks after the initial response is observed. The 95% confidence interval (CI) was calculated using the exact binomial method (Clopper-Pearson). CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.
Phase 1: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
时间窗: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
An adverse event (AE) was any untoward medical occurrence in a participant administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. An serious AE (SAE) was any AE that: * resulted in death; * was life-threatening; * resulted in inpatient hospitalization or prolongation of existing hospitalization; * resulted in a persistent or significant disability/incapacity; * resulted in congenital anomaly/birth defect in the offspring of a participant who received IMPs; * constituted an important medical event. Clinically significant changes in laboratory parameters, vital signs and electrocardiogram results were reported as AEs. A TEAE was defined as an AE observed after starting administration of the specific treatment.
Phase 1: Number of Participants Experiencing Dose Changes
时间窗: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
Dose changes were defined as infusion interruption and dose reduction.
Phase 1: Absolute Dose Intensity
时间窗: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
Absolute dose intensity was calculated as cumulative dose received (mg) / study treatment duration (weeks).
Phase 1: Relative Dose Intensity
时间窗: From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 212 weeks
Relative dose intensity was calculated as the cumulative dose received (mg) / initial planned cumulative dose (mg). Initial planned cumulative dose was calculated as the starting dose multiplied by the scheduled number of administrations within the study treatment duration.
次要结局
- Best Overall Response (BOR) Per RECIST 1.1(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively)
- ORR Per iRECIST(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively)
- Progression-free Survival (PFS) Per RECIST 1.1(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively)
- Duration of Response Per RECIST 1.1(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively)
- PFS Per iRECIST(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 and 162 weeks for Phase 1 and 2, respectively)
- Phase 1: ORR Per RECIST 1.1(From first dose of study treatment (Day 1) up to the end of the long term follow-up, approximately 236 weeks)
- Overall Survival Rate at 12 and 24 Months(Months 12 and 24)
- Phase 2: Relative Dose Intensity(From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks)
- Phase 2: Number of Participants Experiencing TEAEs(From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks)
- Phase 1: Half-life (t1/2) of Alomfilimab(Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length))
- Phase 2: Number of Participants Experiencing Dose Changes(From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks)
- Change From Baseline in Tumor-infiltrating Lymphocytes Per mm^2 at Cycle 2 Day 8(Baseline and Cycle 2 Day 8 (21 day cycle length))
- Phase 2: Absolute Dose Intensity(From first dose of study treatment (Day 1) up to 30 days post last dose of study treatment; maximum duration of treatment exposure was up to approximately 86 weeks)
- Phase 1: Maximum Concentration (Cmax) of Alomfilimab(Cycles 1 and 3 Day 1 pre-infusion to 336 hours post-infusion start (21 day cycle length))
- Number of Participants Experiencing Anti-drug Antibodies (ADA) at Anytime(Phase 1: pre-infusion at all cycles (up to 69 cycles) + 90 days SFUP; Phase 2: pre-infusion at all cycles (up to 28 cycles) + 90 day SFUP (21 day cycle length))