A Phase 1a/1b Study of FPA150, an Anti-B7-H4 Antibody, in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 早期 1 期
- 状态
- 终止
- 入组人数
- 95
- 试验地点
- 18
- 主要终点
- Phase 1a Monotherapy: Number of Participants Experiencing Grade 3 and Grade 4 Adverse Events (AEs)
研究概览
简要总结
This is a multi-center study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of FPA150, an anti-B7H4 antibody alone or in combination with pembrolizumab an anti-PD1 antibody in patients with advanced solid tumors. The Phase 1a, open-label, cohort will identify a recommended dose of FPA150 to use for Phase 1a Combination (FPA150 and Pembrolizumab) Safety Lead-in and for Phase 1b monotherapy cohorts.
详细描述
This is a Phase 1a/1b open-label, multicenter study to evaluate the dosing, safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of FPA150 as monotherapy and in combination with pembrolizumab, an anti-PD1 antibody, in patients with advanced solid tumors.
This study includes a Phase 1a FPA150 Monotherapy Dose Escalation, Phase 1a Monotherapy Dose Exploration, Phase 1a combination Safety Lead-in (FPA150 + pembrolizumab), a Phase 1b FPA150 Monotherapy Dose Expansion, and a Phase 1b combination Dose Expansion (FPA150 + pembrolizumab).
The Phase 1a Monotherapy Dose Escalation will include an initial accelerated titration design followed by a standard 3+3 dose escalation design until the MTD and/or RD for Phase 1b is determined. The Phase 1a combination Safety Lead-In will start enrolling once the FPA150 monotherapy RD is identified in Phase 1a monotherapy dose escalation and will continue until the FPA150 MTD/RD in combination is identified. Phase 1a FPA150 monotherapy Dose Exploration may include cohorts that may enroll beyond 3 patients whose tumors express high levels of B7-H4 protein and/or have varying levels of B7H4 expression including low (<10% IHC 2+ or 3+ scores) or no expression on their tumor cells (up to 20 additional patients across all dose levels) to further evaluate safety, PK, pharmacodynamics, and clinical activity at that dose (to be conditional upon the dose level clearing DLT criteria).
Phase 1b will be the Dose Expansion (monotherapy and combination) portion of the study.
Enrollment into Phase 1b Dose Expansion will begin after identification of the MTD and/or RD in Phase 1a (monotherapy and Safety Lead-in). Preliminary efficacy will be evaluated in Phase 1b in planned expansion cohorts that include patients with specific tumor types that are B7-H4+ advanced solid tumors.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- •Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids (doses > 10 mg/day prednisone or equivalent daily) must be discontinued at least 2 weeks before the first dose of study drug. Short courses of high dose steroids or continuous low dose (prednisone < 10 mg/day ) are allowed.
- •Decreased cardiac function with New York Heart Association (NYHA) > Class 2 at screening.
- •Uncontrolled or significant heart disorder such as unstable angina.
- •QT interval corrected for heart rate (QTc) per institutional guidelines > 450 msec for males or > 470 msec for females at screening.
- •Current unresolved infection or history of chronic, active, clinically significant infection (viral, bacterial, fungal, or other) which, in the opinion of the Investigator, would preclude the patient from exposure to a biologic agent or may pose a risk to patient safety.
- •Any uncontrolled medical condition or psychiatric disorder which, in the opinion of the Investigator, would pose a risk to patient safety or interfere with study participation or interpretation of individual patient results.
- •Active, known, or suspected autoimmune disease. Patients with Type I diabetes mellitus, hypothyroidism requiring only hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger, are permitted to enroll.
- •Known history of testing positive for human immunodeficiency virus (HIV) 1 or 2 or known acquired immunodeficiency syndrome (AIDS).
- •Positive test for hepatitis B virus surface antigen (HBsAg) or detectable hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.
- •Ongoing adverse effects from prior treatment > Grade 1 (with the exception of Grade 2 alopecia or peripheral neuropathy) based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).
- •Symptomatic interstitial lung disease or inflammatory pneumonitis.
- •Untreated or active CNS or leptomeningeal metastases. Patients are eligible if metastases have been treated and patients are neurologically returned to baseline or neurologically stable (except for residual signs or symptoms related to the CNS treatment) for at least 2 weeks before the first dose of study drug.
- •Evidence of coagulopathy or bleeding diathesis. Patients receiving stable therapeutic doses of anti-coagulants will be permitted.
- •Transfusion of blood or platelets completed within 72 hours before the first dose of study drug.
- •Any uncontrolled inflammatory GI disease including Crohn's Disease and ulcerative colitis
- •For Cohort 1b1 only: Patients with HER2 positive disease
研究组 & 干预措施
Phase 1a dose escalation/1b dose expansion
The study consists of Phase 1a dose escalation, Phase 1a dose exploration, Phase 1a combination safety-lead-in and Phase 1b dose expansion
干预措施: FPA150 (Biological)
Phase 1a dose escalation/1b dose expansion
The study consists of Phase 1a dose escalation, Phase 1a dose exploration, Phase 1a combination safety-lead-in and Phase 1b dose expansion
干预措施: Pembrolizumab (Biological)
结局指标
主要结局
Phase 1a Monotherapy: Number of Participants Experiencing Grade 3 and Grade 4 Adverse Events (AEs)
时间窗: From day 1 up to 28 days after last dose (median [min, max] treatment duration= 9.143 [3.00, 52.00] weeks)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject that was administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. Grade 3 and 4 severity ratings were defined as follows: Grade 3: Severe or medically significant but non-immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living; severe AE Grade 4: Life-threatening consequences; urgent intervention indicated
Phase 1a Monotherapy: Number of Participants Experiencing Dose Limiting Toxicities (DLTs)
时间窗: Up to 21 days
DLTs were defined as any of the following events regardless of attribution (except for those events clearly due to the underlying disease or extraneous causes): Any Grade 3 or higher non-hematologic toxicity (except Grade 3 nausea, vomiting, and diarrhea) that occurred within the first 21 days of treatment. Grade 3 nausea, vomiting, diarrhea lasting \>72 hours, that occurred within the first 21 days of treatment. Febrile neutropenia and/or documented infection, Grade 4 neutropenia that lasted more than 7 days, Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia accompanied by bleeding within first 21 days of treatment. Aspartate aminotransferase (AST) / alanine transaminase (ALT) \>3 × upper limit of normal (ULN) and concurrent total bilirubin \> 2 × ULN that was not related to liver involvement with cancer. Other Grade 3 laboratory values that did not resolve within 72 hours. Any Grade 4 laboratory value regardless of clinical sequelae
Phase 1a Monotherapy: Number of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
时间窗: From day 1 up to 28 days after last dose (median [min, max] treatment duration= 9.143 [3.00, 52.00] weeks)
TEAEs were defined as an AE that began or worsened in severity after at least one dose of study treatment (FPA150) had been administered. Clinically significant laboratory abnormalities and ECG abnormalities are included as TEAEs.
Phase 1b Monotherapy: Number of Participants Experiencing AEs
时间窗: From day 1 up to 28 days after last dose (median [min, max] treatment duration= 6.35 [3.00, 108.14] weeks)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject that was administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. A serious AE is defined as any AE that resulted in death, was life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital abnormality/birth defect or important medical events. Clinically significant laboratory abnormalities and ECG abnormalities were included as TEAEs.
Phase 1a Combination Safety Lead-In & Phase 1b Combination: Number of Participants Experiencing AEs
时间窗: From day 1 up to 28 days after last dose (median [min, max] treatment duration= 12.00 [6.00, 36.43] weeks)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject that was administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. A serious AE is defined as any AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect or important medical events that do not meet the preceding criteria but based on appropriate medical judgment may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above.
Phase 1a Combination Safety Lead-In & Phase 1b Combination: Number of Participants Experiencing Grade 3 and Grade 4 AEs
时间窗: From day 1 up to 28 days after last dose (median [min, max] treatment duration= 12.00 [6.00, 36.43] weeks)
An AE is defined as any untoward medical occurrence in a participant or clinical investigation subject that was administered a pharmaceutical product, which does not necessarily have to have a causal relationship with this treatment. A serious AE is defined as any AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital abnormality/birth defect or important medical events that do not meet the preceding criteria but based on appropriate medical judgment may jeopardize the participant or may require medical or surgical intervention to prevent any of the outcomes listed above.
次要结局
- Phase 1a Monotherapy: Number of Participants With ADAs to FPA150(From day 1 up to 28 days after last dose (median [min, max] treatment duration= 9.143 [3.00, 52.00] weeks))
- Phase 1b Monotherapy: Number of Participants With ADAs to FPA150 at Baseline(Cycle 1 day 1 pre-dose (baseline))
- Phase 1b Monotherapy: Number of Participants With ADAs to FPA150 Postbaseline(From day 1 up to 28 days after last dose (median [min, max] treatment duration= 6.35 [3.00, 108.14] weeks))
- Phase 1b Monotherapy: Overall Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)(Up to approximately 24 months)
- Phase 1b Monotherapy: Duration of Response (DOR) Per RECIST v1.1(Up to approximately 24 months)
- Phase 1b Monotherapy: Progression-free Survival (PFS) Per RECIST v1.1(Up to approximately 24 months)
- Phase 1b Combination: PFS Per RECIST v1.1(Up to approximately 24 months)
- Phase 1b Combination: ORR Per RECIST v1.1(Up to approximately 24 months)
- Phase 1b Combination: DOR Per RECIST v1.1(Up to approximately 24 months)
- Phase 1a Monotherapy: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUClast) of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 52 weeks)
- Phase 1a Monotherapy: Time to Reach Maximum Serum Concentration (Tmax) of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 52 weeks)
- Phase 1a Monotherapy: Maximum Serum Concentration (Cmax) of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 52 weeks)
- Phase 1a Monotherapy: Trough Serum Concentration (Ctrough) of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 52 weeks)
- Phase 1a Monotherapy: Terminal Half-Life (T1/2) of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 52 weeks)
- Phase 1b Monotherapy: AUClast of FPA150(Cycle 1 (one cycle = 21 days) day 1 pre-dose, day 1 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks))
- Phase 1b Monotherapy: Time to Reach Cmax of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 108 weeks)
- Phase 1b Monotherapy: Cmax of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 108 weeks)
- Phase 1b Monotherapy: Cthrough of FPA150(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 108 weeks)
- Phase 1b Monotherapy: T1/2 of FPA150 in Days(Cycle 1 (cycle = 21 days) day 1 pre-dose, 15min and 4h post-dose, day 2 (24h), day 4 (72h), day 8 (168h) post-dose, and day 15. Cycle 2, 3, 4 ,5 ,7, 9, day 1 pre-dose, day 1 (15min) post-dose. After cycle 9, day 1 every 4th dose (12 weeks) up to 108 weeks)