A PHASE 1, OPEN-LABEL, DOSE ESCALATION AND EXPANSION STUDY EVALUATING THE SAFETY AND PHARMACODYNAMICS OF PF-07263689, EITHER ALONE OR IN COMBINATION WITH AN ANTI-PD-1 ANTIBODY, IN PREVIOUSLY TREATED PARTICIPANTS WITH SELECTED LOCALLY ADVANCED OR METASTATIC SOLID TUMORS
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- Pfizer
- 入组人数
- 13
- 试验地点
- 6
- 主要终点
- Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
研究概览
简要总结
This is a first-in-human, Phase 1, open label, multicenter, multiple dose, dose escalation and expansion study intended to evaluate the safety, viral load kinetics and shedding, pharmacodynamic, and anti-tumor activity of PF-07263689, either alone or in combination with sasanlimab (an investigational anti-programmed cell death protein 1 [PD-1] antibody), in patients with selected locally advanced or metastatic solid tumors who have exhausted all available standard of care therapies available to them.
The study consists of 2 parts: Part 1 dose escalation for PF-07263689 monotherapy (Part 1A) and in combination with sasanlimab (Part 1B), followed by Part 2 dose expansion for the combination therapy.
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
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
- •Histological or cytological diagnosis of locally advanced or metastatic solid tumors known to have approved therapies using immune checkpoint inhibitors or anti-vascular endothelial growth factor agents
- •Have exhausted (or refuse) all available standard of care therapy (e.g., including anti-PD1/programmed death ligand 1 [PDL1] if applicable) or for whom no standard therapy is available for their tumor type
- •Patients with prior anti-PD1/PDL1 must have documentation of primary or secondary resistance to last prior anti-PD1/PDL1 therapy according to Immunotherapy Resistance Committee (SITC) (Kluger et al, 2020)
- •Have at least 1 measurable lesion by RECIST 1.1 that has not been previously irradiated (for Part 2 only)
- •Have recently obtained archival tumor tissue sample available, or undergo de novo tumor biopsy
- •Eastern Cooperative Oncology Group (ECOG) PS 0-1
- •Adequate hematologic, renal, and liver functions
- •Dose Escalation (Part 1A and 1B): Any advanced or metastatic solid tumor fulfilling other relevant eligibility criteria.
- •Dose Expansion (Part 2): Tumor specific cohorts (NSCLC, RCC, melanoma, MSS CRC) must have received prior approved therapies (Part 2)
排除标准
- •Other active malignancy
- •Recent major surgery
- •Systemic anticancer therapy and chemotherapy within protocol-defined washout period
- •Known or suspected hypersensitivity to prior treatment with any vaccinia oncolytic, pox virus, or antiviral agents within the past 10 years
- •Current or history of myocarditis or congestive heart failure (New York Heart Association [NYHA] III-IV); unstable angina; or serious uncontrolled arrhythmia or recent myocardial infarction
- •Active or history of interstitial lung disease (ILD)/pneumonitis
- •Patients requiring chronic systemic immunosuppressants
- •History of severe immune mediated side effect that was considered related to prior immune modulatory therapy and requiring immunosuppressive therapy
- •Known symptomatic brain metastases requiring steroids
- •History of or ongoing severe inflammatory skin conditions or severe eczema having required medical treatment
- •Any prior or planned organ transplant
- •Presence of any open, active wound requiring treatment
结局指标
主要结局
Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
时间窗: Up to 28 days
DLTs=occurrence of any of following adverse events (AEs) attributable to PF-07263689 in first cycle (cycle=28 days): Hematologic: grade(G)4 neutropenia lasting \>5 days; febrile neutropenia; G3 neutropenia with infection, thrombocytopenia with bleeding; G4 thrombocytopenia. Non-hematologic: any treatment-related G\>=3 toxicity; clinical events consistent with Hy's law; any G3 cytokine release syndrome (CRS) not improving to G\<=2 within 72 hours despite medical management; any G4 CRC; G\>=3 toxicity of any duration affecting vital organs; G4 vaccinia infection lasting \>=6 days; G\>=3 toxicities persisting for \>3 days despite medical therapy (e.g. nausea, vomiting, diarrhea, fatigue); G \>=3 rash not resolving to G\<2 within 21 days with supportive measures; G\>=3 lab abnormalities not controlled to G \<=2 with or without appropriate medical management within 3 days; treatment-related AE inducing a delay by 2 weeks in receiving next scheduled dose; clinically important or persistent toxicities.
Part 2: Number of Participants With Treatment Emergent Adverse Events, Serious Adverse Events, Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events
时间窗: From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that at any dose met 1 or more of the following criteria: resulted in death, was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; an important medical event; required inpatient hospitalization or prolongation of existing hospitalization. TEAE was defined as any adverse event that occurred during the on-treatment period, on or after the first dose of study treatment. Relatedness was planned to be assessed by investigator.
Part 1: Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Treatment Related Treatment Emergent Adverse Events and Treatment Related Serious Adverse Events
时间窗: From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to maximum of 10.45 months)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was defined as any untoward medical occurrence that at any dose met 1 or more of the following criteria: resulted in death, was life-threatening; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic; an important medical event; required inpatient hospitalization or prolongation of existing hospitalization. TEAE was defined as any adverse event that occurred during the on-treatment period, on or after the first dose of study treatment. Relatedness was based on investigator's assessment.
Part 2: Number of Participants With Treatment Emergent Adverse Events Based on Maximum CTCAE Version 5 Grade
时间窗: From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)
AEs were planned to be graded using CTCAE version 5 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
Part 1: Number of Participants With Treatment Emergent Adverse Events Based on Maximum Common Terminology Criteria for Adverse Events (CTCAE) Version 5 Grade
时间窗: From first dose of study treatment until 90 days after last dose of study treatment or before start of new anti-cancer therapy (up to maximum of 10.45 months)
An AE was any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAE was defined as any AE that occurred during the on-treatment period, on or after the first dose of study treatment. AEs were graded using CTCAE version 5 where, grade 1=mild AE; grade 2=moderate AE; grade 3=severe AE; grade 4= life-threatening; urgent intervention indicated; and grade 5= death related to AE.
Part 1: Number of Participants With Hematology Abnormalities by Maximum On-Treatment CTCAE Grade
时间窗: From first dose of study treatment until 1 month follow-up (28+/-7) days after last dose of study treatment (up to 24 days of treatment exposure)
Hematology abnormalities were graded using CTCAE version 5 where, grade 0=non-missing lab value outside the grading range for the corresponding lab parameter; grade 1=mild; grade 2=moderate; grade 3=severe; grade 4= life-threatening. Only those categories with non-zero values for any of the arms have been reported.
Part 1: Number of Participants With Clinical Chemistry Abnormalities by Maximum On-Treatment CTCAE Grade
时间窗: From first dose of study treatment until 1 month follow-up (28+/-7) days after last dose of study treatment (up to 24 days of treatment exposure)
Clinical chemistry abnormalities were graded using CTCAE version 5 where, grade 0=non-missing lab value outside the grading range for the corresponding lab parameter; grade 1=mild; grade 2=moderate; grade 3=severe; grade 4= life-threatening. Only those categories with non-zero values for any of the arms have been reported.
Part 2: Number of Participants With Laboratory Abnormalities by Maximum On-Treatment CTCAE Grade
时间窗: From first dose of study treatment until 35 days after last dose of study treatment or before start of new anti-cancer therapy (up to 2 years)
Hematology and clinical chemistry parameters were planned to be assessed.
Part 2: Objective Response Rate
时间窗: From first dose of study treatment until CR or PR (up to 2 years)
ORR was defined as the percentage of participants with a best overall response of complete response (CR) or partial response (PR) and was determined using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (\<10 millimeter \[mm\] short axis), PR: at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. Short diameter was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions.
次要结局
- Part 1: Objective Response Rate(From first dose of study treatment until CR or PR (up to maximum follow-up of 10.45 months))
- Part 1: Time to Progression(From start date of treatment to the date of first documentation of PD (up to maximum follow-up of 10.45 months))
- Part 1: Duration of Response(From first documentation of CR or PR to date of first documentation of PD or death due to any cause (up to maximum follow-up of 10.45 months))
- Part 1: Maximum Observed Concentration (Cmax) of PF-07263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 1: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration of PF-07263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 2: Trough Concentration of Sasanlimab(Pre-dose on Day 1, 8, 15 and 22)
- Part 1: Progression Free Survival(From start date of treatment to the date of first documentation of PD or death due to any cause (up to maximum follow-up of 10.45 months))
- Part 1b: Trough Concentration of Sasanlimab(pre-dose on Day 1, 8, 15 and 22)
- Part 1: Percentage of Participants With Positive Neutralizing Antibodies Against PF-07263689 and Sasanlimab(From Baseline (pre-dose) on Day 1 up to Day 22)
- Part 1: Time to Maximum Concentration (Tmax) of PF-07263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 1: Viral Titers in Saliva, Urine and Skin Swabs During 30, 45 and 60 Days After the Last PF-07263689 Dose(At 30, 45 and 60 days post last dose of study treatment (up to 24 days of treatment exposure))
- Part 2: Maximum Observed Concentration (Cmax) of PF-7263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 2: Time to Maximum Concentration (Tmax) of PF-07263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 2: Percentage of Participants With Positive Anti-interleukin 2 Antibodies(From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years))
- Part 1: Percentage of Participants With Positive Anti-interleukin 2 Antibodies(From Baseline (pre-dose) on Day 1 up to Day 22)
- Part 2: Area Under the Concentration-Time Curve From Time 0 to Time of Last Measurable Concentration of PF-07263689 in Blood(Day 1 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 2, Day 3, Day 4, Day 8 (pre-dose, 0.5, 1, 4, 8 hours post-dose), Day 9, Day 10, Day 15 and 22 (pre-dose and 4 hours post-dose))
- Part 2: Viral Titers in Saliva, Urine and Skin Swabs During 30, 45 and 60 Days After the Last PF-07263689 Dose(30, 45 and 60 days after the last PF-07263689 dose)
- Part 2: Percentage of Participants With Positive Anti-drug Antibodies Against PF-07263689 and Sasanlimab(From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years))
- Part 2: Disease Control Rate(From start of study treatment until CR, PR or SD (up to 2 years))
- Part 2: Titer for Anti-PF-07263689 Antibody(From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years))
- Part 2: Titer for Anti-IL2 Antibodies(From first dose of study treatment until 60 days after last dose of study treatment (up to 2 years))
- Part 2: Duration of Response(From first documentation of CR or PR to date of first documentation of PD or death due to any cause (up to 2 years))
- Part 2: Progression Free Survival(From start date of treatment to the date of first documentation of PD or death due to any cause (up to 2 years))
- Part 2: Time to Progression(From start date of treatment to the date of first documentation of PD (up to 2 years))
- Part 2: Overall Survival(From start of study treatment to the date of death from any cause (up to 2 years))