A PHASE 1, OPEN-LABEL, DOSE ESCALATION STUDY OF PF-04518600 AS A SINGLE AGENT AND IN COMBINATION WITH PF-05082566 IN PATIENTS WITH SELECTED LOCALLY ADVANCED OR METASTATIC CANCERS
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 174
- 试验地点
- 30
- 主要终点
- Number of Participants With Laboratory Test Abnormalities in Part B
研究概览
简要总结
To assess the safety and tolerability at increasing dose levels of PF-04518600 alone or in combination wtih PF-05082566 in patients with select advanced or metastatic carcinoma in order to determine the maximum tolerated dose and select the recommended Phase 2 dose.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open-label
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
- •Part A1 only: Patients with histological or cytological diagnosis of HNSCC, HCC, melanoma, or clear cell RCC who progressed on or are intolerant to standard therapy, for which no standard therapy is available or who decline standard therapy.
- •Part A2 only: Patients with histological or cytological diagnosis of advanced/metastatic HCC who are treatment naïve and have declined standard of care, or have had at least 1 prior line of systemic therapy. Prior anti PD L1/PD 1 therapy is allowed.
- •Part B1 only: Patients with histological or cytological diagnosis of NSCLC, HNSCC, melanoma, urothelial bladder carcinoma (including renal pelvis, ureters, urinary bladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or who decline standard therapy.
- •Arm 1 only:
- •Ocular melanoma patients with advanced/metastatic disease, or
- •Cutaneous/acral melanoma patients with advanced/metastatic disease who have received checkpoint inhibitor (anti PD L1, anti PD 1, or anti CTLA4) based treatment on which disease progressed. [Note: Checkpoint inhibitor may have been part of a combination therapy, as long as the combination did not contain OX40 or 4 1BB agonist.] Any questions on prior treatment may be discussed with the Sponsor.
- •Arm 2 only:
- •Histological or cytological diagnosis of NSCLC with advanced/metastatic disease. Patients must have previously received prior anti PD L1 or anti PD 1 mAb on which disease progressed. [Note: Previous anti PD L1 or anti PD 1 mAb may have been part of a combination therapy, eg, in combination with chemotherapy, as long as the combination did not contain OX40 or 4 1BB agonist.]
- •Performance Status of 0 or 1 - Adequate bone marrow, kidney and liver function
排除标准
- •Brain metastases requiring steroids
- •Major surgery, Radiation therapy within 4 weeks of starting study treatment (except: palliative radiotherapy to a limited field is allowed after consultation with sponsor's medical monitor at any time during study participation, including during screening), or systemic anti-cancer therapy within 4 weeks of study treatment start (6 weeks for mitomycin C or nitrosoureas)
- •Active and clinically significant bacterial, fungal, or viral infection
- •History of active autoimmune disorders
- •History of immune-mediated adverse events requiring immunosuppressive therapy or were grade 3 or higher related to prior immune-modulatory therapy
- •Prior treatment with an OX40 agonist and 4-1BB agonist (for Part B1/B2)
- •Prior anthracycline treatment and at risk of cardiac failure (New York Heart Association Class 2)
研究组 & 干预措施
PF-04518600
OX40 agonist
干预措施: PF-04518600 (Drug)
PF-04518600 plus PF-05082566
OX40 (CD134) agonist plus 4-1BB (CD137) agonist
干预措施: PF-04518600 plus PF-05082566 (Drug)
结局指标
主要结局
Number of Participants With Laboratory Test Abnormalities in Part B
时间窗: The first dosing date to the earlier date between the last dosing date + 35 days and the first new anti-cancer therapy date (if applicable)
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, partial thromboplastin time (PTT), Prothrombin (PT), PT international ratio); liver function (aspartate aminotransferase(AST), alanine aminotransferase(ALT), total bilirubin, gamma-glutamyl transpeptidase(GT), alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium , phosphate, magnesium); clinical chemistry (glucose, creatine kinase, thyroxine (T4), thyroid stimulating hormone(TSH)), Amylase, Lipase), urinalysis (dipstick \[protein, blood\], microscopy \[urine red blood cell (RBC), white blood cell (WBC), Epithelial Cells\], miscellaneous \[urine casts and bacteria\]).
Number of Participants With All-Causality Treatment Emergent Adverse Events(TEAEs) and Serious Adverse Event(SAEs), Treatment-Related TEAEs and SAEs in Part A
时间窗: AEs: The informed consent date up to the last dosing date + 28 days or all drug-related toxicities resolved date. SAEs: The informed consent date through first dosing date + 98 days or up to the last dosing date + 60 days, and any post-reporting period.
Adverse event (AE) was graded by the investigator according to CTCAE version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA): Grade 3 (Severe) events=unacceptable or intolerable events. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent events=between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. TEAEs were defined as those with initial onset or increasing in severity after the first dose of study medication. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Laboratory Test Abnormalities in Part A
时间窗: The first dosing date to the earlier date between the last dosing date + 35 days and the first new anti-cancer therapy date (if applicable)
Following parameters were analyzed for laboratory examination: hematology (hemoglobin, hematocrit, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes, partial thromboplastin time (PTT), Prothrombin (PT), PT international ratio); liver function (aspartate aminotransferase(AST), alanine aminotransferase(ALT), total bilirubin, gamma-glutamyl transpeptidase(GT), alkaline phosphatase, albumin, total protein); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium , phosphate, magnesium); clinical chemistry (glucose, creatine kinase, thyroxine (T4), thyroid stimulating hormone(TSH)), Amylase, Lipase), urinalysis (dipstick \[protein, blood\], microscopy \[urine red blood cell (RBC), white blood cell (WBC), Epithelial Cells\], miscellaneous \[urine casts and bacteria\]).
Number of Participants With All-causality TEAEs and SAEs, and Treatment-Related TEAEs and SAEs in Part B
时间窗: AEs: The informed consent date up to the last dosing date + 60 days or all drug-related toxicities resolved date. SAEs: The informed consent date through first dosing date + 98 days or up to the last dosing date + 60 days, and any post-reporting period.
Adverse event (AE) was graded by the investigator according to CTCAE version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA): Grade 3 (Severe) events=unacceptable or intolerable events. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 (Death) events=death related to an AE. Treatment-emergent events=between first dose of study drug and up to 35 days after last dose that were absent before treatment or that worsened relative to pretreatment state. TEAEs were defined as those with initial onset or increasing in severity after the first dose of study medication. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
Number of Participants With Dose Limiting Toxicities (DLTs) in Part A1
时间窗: The first 2 cycles of treatment (Day 1 up to Day 28)
DLT was defined as any of the following adverse events occurring in the first two cycle of treatment (28 days), unless there was a clear alternative explanation: hematologic: grade 4 neutropenia lasting \>7 days, febrile neutropenia; grade ≥3 neutropenic infection; grade ≥3 thrombocytopenia with clinically significant bleeding or requiring medical intervention; grade 4 thrombocytopenia; grade 4 anemia; grade ≥3 anemia related to hemolysis or autoimmune disease. non hematologic: grade ≥3 toxicities that were considered clinically significant, including cytokine release syndrome, infusion reactions and allergic reactions, except those that had not been maximally treated or could be easily treated. The severity of adverse events was graded as per common terminology criteria for adverse events(CTCAE) version 4.03, and there were no DLTs reported.
Number of Participants With DLTs in Part B1
时间窗: The First 2 Cycles of Treatment (Day 1 up to Day 28)
DLT was defined as any of the following adverse events occurring in the first two cycle of treatment (28 days), unless there was a clear alternative explanation: hematologic: grade 4 neutropenia lasting \>7 days, febrile neutropenia; grade ≥3 neutropenic infection; grade ≥3 thrombocytopenia with clinically significant bleeding or requiring medical intervention; grade 4 thrombocytopenia; grade 4 anemia; grade ≥3 anemia related to hemolysis or autoimmune disease. non hematologic: grade ≥3 toxicities that were considered clinically significant, including cytokine release syndrome, infusion reactions and allergic reactions, except those that had not been maximally treated or could be easily treated. The severity of adverse events was graded as per common terminology criteria for adverse events(CTCAE) version 4.03, and there were no DLTs reported.
次要结局
- Kaplan-Meier Estimate of Median Progression-Free Survival (PFS) in Part A(Baseline up to 24 months post first dose)
- Kaplan-Meier Estimate of Median Time to Progression (TTP) in Part A(Baseline up to 24 months post first dose)
- Maximum Serum Concentration (Cmax) of PF-04518600 Following Single Dose on Cycle 1 Day 1 (C1D1) and Steady-State Maximum Serum Concentration(Css,Max) Following Multiple Doses on Cycle 3 Day 1 (C3D1) in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Clearance (CL) of PF-04518600 Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Lowest Serum Concentration Observed During the Dosing Interval (Cmin) of PF-04518600 Following Multiple Doses on C3D1 in Part A.(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- ORR Assessed by RECIST Version 1.1 and irRECIST in Part B(Baseline up to 24 months post first dose.)
- Objective Response Rate (ORR) Assessed by Response Evaluation Criteria in Solid Tumor (RECIST) Version 1.1 and Immune Related Response Evaluation Criteria in Solid Tumors (irRECIST) in Part A(Baseline up to 24 months post first dose.)
- Overall Survival Rates at Months 6, 12, and 24 in Part A(Baseline up to 24 months post first dose.)
- Terminal Half-Life (t1/2) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Average Serum Concentration Over the Dosing Interval (Cav) of PF-04518600 Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Kaplan-Meier Estimate of Median Overall Survival (OS) in Part A(Baseline up to 24 months post first dose.)
- Area Under the Concentration-Time Profile From Time 0 to Time Tau (AUCtau) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Number of Participants With Anti Drug Antibody (ADA) and Neutralizing Antibody (NAb) Against PF-04518600 in Part A(Baseline up to end of treatment (maximum of 14 weeks).)
- Number of Participants Having Stable Disease (SD) in Part A(Baseline up to 24 months post first dose.)
- Kaplan-Meier Estimate of Median Duration of Response (DoR) in Part A(Baseline up to 24 months post first dose.)
- Area Under the Concentration-Time Profile From Time 0 Extrapolated to Infinite Time (AUCinf) of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Apparent Volume of Distribution at Steady State (Vss) of PF-04518600 Following Multiple Doses on C3D1 in Part A.(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Mean Unbound Cell Surface OX40 in Part A1(Pre-dose, 4 and 24 hours post dose on Cycle 1 Day 1, and Day 8 on Cycles 1 to 3, then pre-dose on Cycles 4 and 7 and end of treatment in Part A1)
- AUCtau of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- CL of Utomilumab Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Accumulation Ratio (Rac) of PF-04518600 at C3D1 Following Multiple Doses on C3D1 in Part A(For Part A1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1, and 4 hours post dose on Day 1 of Cycles 3; For Par A2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Kaplan-Meier Estimate of Median PFS in Part B(Baseline up to 24 months post first dose.)
- Kaplan-Meier Estimate of Median OS in Part B(Baseline up to 24 months post first dose.)
- Cmax of PF-04518600 Following Single Dose on C1D1 and Css,Max Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Cav of PF-04518600 Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Rac of Utomilumab Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Kaplan-Meier Estimate of Median TTP in Part B(Baseline up to 24 months post first dose.)
- t1/2 of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Cmax of Utomilumab Following Single Dose on C1D1 and Css,Max Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- AUCinf of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Number of Participants Having SD in Part B(Baseline up to 24 months post first dose.)
- Kaplan-Meier Estimate of Median DoR in Part B(Baseline up to 24 months post first dose.)
- Overall Survival Rates at Months 6, 12, and 24 in Part B(Baseline up to 24 months post first dose.)
- Cmin of PF-04518600 Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- CL of PF-04518600 Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Vss of Utomilumab Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- AUCinf of PF-04518600 Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Vss of PF-04518600 Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Rac of PF-04518600 Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- AUCtau of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- t1/2 of Utomilumab Following Single Dose on C1D1 and Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Cmin of Utomilumab Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Cav of Utomilumab Following Multiple Doses on C3D1 in Part B(For Part B1, pre-dose, 1, 4, and 24 hours post dose on C1D1, pre-dose, 1 hour post dose on Day 1 of Cycles 3; For Part B2, pre-dose, 1, and 4 hours post dose on C1D1, pre-dose and 1 hour post dose on Day 1 of Cycles 3.)
- Number of Participants With ADA and NAb Against PF-04518600 in Part B(Baseline up to end of treatment (maximum of 14 weeks).)
- Number of Participants With ADA and NAb Against Utomilumab in Part B(Baseline up to end of treatment (maximum of 14 weeks).)