A Phase 1/2, First in Human, Dose Escalation and Dose Expansion Study of BHV-1510 (Previously PBI-410) as Monotherapy and in Combination With Anti-Cancer Agents in Participants With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 500
- 试验地点
- 30
- 主要终点
- Phase 1: Number of patients with adverse events (AEs)
研究概览
简要总结
This is a Phase 1/2, first in human (FIH), open-label, multicenter study of BHV-1510 monotherapy and in Combination with Cemiplimab in participants with previously treated, advanced solid tumors.
详细描述
This is a Phase 1/2, first in human (FIH), open-label, multicenter study of BHV-1510, a Trop-2 directed antibody-drug conjugate (ADC), in participants with previously treated, advanced solid tumors. The study comprises 2 parts: a Phase 1 Dose Escalation and a Phase 2 Dose Expansion. The Phase 1 will investigate the safety and tolerability of BHV-1510 given in monotherapy and given in combination with cemiplimab and identify one or more recommended doses for expansion (RDEs) and the maximum-tolerated dose (MTD) (if one exists). Once the RDE has been established, Phase 2 will open to investigate the preliminary efficacy of BHV-1510 in signal-finding expansion cohorts.
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
- •Male or female participants aged ≥18 years.
- •Unresectable, incurable, locally advanced or metastatic epithelial-origin solid tumor that is refractory to standard therapies, or has no approved standard therapies, or no approved standard therapies at its current treatment stage. If applicable to the tumor type, participants must have received platinum-based chemotherapy, standard of care immunotherapy, and standard of care targeted therapies.
- •Measurable disease (per RECIST 1.1).
- •Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or
- •Participants have adequate hematologic, renal, liver, and coagulation function as defined by the following (blood transfusion or growth factor support is not allowed within 7 days prior to blood samples that will be used to establish eligibility):
- •Hemoglobin ≥9 g/dL
- •Absolute neutrophil count >1,500/mm3; participants with known Duffy null phenotype who have absolute neutrophil count ≥1,200/mm3 may be enrolled
- •Platelets >100,000/mm3
- •Creatinine clearance ≥50 mL/min measured or estimated using the Cockcroft-Gault formula; 24-hour urine collection is allowed, but not required.
- •Total bilirubin ≤1.5 × upper limit of normal (ULN); participants with known Gilbert's syndrome who have total bilirubin level ≤3×ULN may be enrolled.
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5×ULN (or ≤5×ULN for participants with hepatic metastases)
- •Alkaline phosphatase <2.5×ULN (or ≤5×ULN for participants with hepatic and/or bone metastases)
- •International normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN
- •Activated partial thromboplastin time (aPTT) ≤1.5×ULN. Study participants on therapeutic doses of anticoagulation medication must have INR and/or aPTT ≤ the upper limit of the therapeutic range for intended use
- •Have recovered (ie, improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
- •BHV-1510 in Combination with specific inclusion criteria:
- •histologically or cytologically documented advanced (locally, recurrent, inoperable, cannot betreated with curative intent) or metastatic cancer including Endometrial Carcinoma that is confirmed as proficient mismatch repair (pMMR)
- •received ≤ 2 prior lines of systemic anti-cancer therapy and at most one prior anti-programmed cell death protein 1 (PD-1) (programmed death-ligand 1 [PD-L1]) therapy for advanced/ metastatic disease.
排除标准
- •Women who are pregnant or lactating.
- •Clinically significant intercurrent disease.
- •Has symptomatic brain metastases or has had any radiation or surgery for brain metastases within 4 weeks of C1D
- •Has clinically significant corneal disease.
- •Requires supplemental oxygen for daily activities.
- •Previous treatment with a Trop-2-targeted therapy, including Trop-2 ADCs.
- •Has a medical history of interstitial lung disease (eg, noninfectious interstitial pneumonia requiring steroid treatment, pneumonitis, pulmonary fibrosis, or severe radiation pneumonitis) or current interstitial lung disease or are suspected to have any of these diseases based on imaging at Screening.
- •Any standard cancer therapy (eg, chemotherapy, hormonal therapy, radiotherapy, immunotherapy, biologic therapy treatment) or experimental therapy within 3 weeks or 5 half-lives, whichever is shorter, prior to C1D
- •The interval may be reduced to 2 weeks for bone and visceral metastasis therapy. Any major surgical procedure within 6 weeks prior to C1D
- •History of severe hypersensitivity reactions to other monoclonal antibodies or either the drug substances or inactive ingredients of BHV-
- •Has current or previously treated leptomeningeal carcinomatosis.
- •Use of OAP1B1 and OATP1B3 inhibitors within 14 days prior to starting trial.
- •BHV-1510 in Combination Specific Exclusion Criteria:
- •Hypersensitivity to cemiplimab or any of its excipients or contraindicated to cemiplimab per approved local labeling.
- •Experienced Grade 3 or higher immune-related AEs with prior treatment of anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
- •Prior allogeneic stem cell or solid organ transplantation.
- •Patients with history of myocarditis.
- •Presence of cardiovascular disease
研究组 & 干预措施
BHV-1510 Monotherapy Dose Escalation
干预措施: BHV-1510 (Drug)
BHV-1510 in combination with Cemiplimab dose escalation
干预措施: BHV-1510 (Drug)
BHV-1510 in combination with Cemiplimab dose escalation
干预措施: Cemiplimab (Drug)
结局指标
主要结局
Phase 1: Number of patients with adverse events (AEs)
时间窗: Through study completion, estimated as an average of 47 months
Description: Incidence and severity of AEs, serious adverse events (SAEs) and dose limiting toxicities (DLTs). Severity of AEs will be assessed according to the NCI CTCAE v5.0. This applies to both the BHV-1510 monotherapy arm and BHV-1510 in combination with Cemiplimab arm.
Phase 1: Recommended doses or schedules for expansion (RDEs) and maximum tolerated dose (MTD)
时间窗: Approximately 15 months
Based on tolerability and preliminary antitumor activity. This applies to both the BHV-1510 monotherapy arm and BHV-1510 in combination with Cemiplimab arm.
Phase 2: Objective Response Rate (ORR) for BHV-1510 for monotherapy and in combination with cemiplimab
时间窗: Through study completion, estimated as an average of 47 months
Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.
Phase 2: Number of patients with AEs for BHV-1510 for monotherapy and in combination with cemiplimab
时间窗: Through study completion, estimated as an average of 47 months
Incidence and severity of AEs, SAEs and DLTs. Severity of AEs will be assessed according to the NCI CTCAE v5.0
Phase 2: Duration of Response (DoR) for BHV-1510 for monotherapy and in combination with cemiplimab
时间窗: Through study completion, estimated as an average of 47 months
Assessed by RECIST v 1.1
次要结局
- Phase 1 and 2: Maximum Plasma Concentration (Cmax) of BHV-1510, total antibody and payload (BHC-0080269)(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Area Under the Concentration versus time Curve from the end of infusion to the last measurable concentration (AUClast) of BHV-1510, total antibody and payload(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Area Under the Concentration versus time curve extrapolated to infinity (AUCinf) of BHV-1510, total antibody and payload(Up to 8 timepoints, but not exceeding, 22 days in Cycle 1)
- Phase 1 and 2: Area under the concentration versus time curve over the dosing interval (AUCtau) of BHV-1510, total antibody and payload(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Elimination half-life (t1/2) of BHV-1510, total antibody and payload(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Trough concentration (Ctrough) of BHV-1510, total antibody and payload(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Total body clearance (CL) after IV administration or apparent total body clearance (CL/F) after SC administration of BHV-1510 and total antibody(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Percent bioavailability (%F) after SC administration of BHV-1510 and total antibody(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1 and 2: Volume of distribution at steady state (Vss) after IV administration or apparent volume of distribution at steady state (Vss/F) after SC administration of BHV-1510 and total antibody(Up to 8 timepoints, but not exceeding, 22 days in Cycles 1 and 3)
- Phase 1: ORR(Through study completion, estimated as an average of 47 months)
- Phase 1: Duration of Response (DoR)(Through study completion, estimated as an average of 47 months)
- Phase 1 and 2: Immunogenicity of BHV-1510(Through study completion, estimated as an average of 47 months)
- Phase 2: Disease control rate (DCR) for BHV-1510 for monotherapy and in combination with cemiplimab(Through study completion, estimated as an average of 47 months)
- Phase 2: Progression free survival (PFS) for BHV-1510 for monotherapy and in combination with cemiplimab(Through study completion, estimated as an average of 47 months)
- Phase 2: Overall survival (OS) for BHV-1510 for monotherapy and in combination with cemiplimab(Through study completion, estimated as an average of 47 months)
- Phase 2: Effects of BHV-1510 monotherapy and payload on the QTc interval using the Fridericia's correction method (QTcF), and on other ECG parameters (heart rate [HR], PR, and QRS interval)(Approximately 15 months)